The Bitter Pill

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The Rise and Fall of Provigil – Part II

Evelyn Pringle

A little over a year after the Volkow study reported that Provigil (modafinil), affects the same brain chemicals as stimulants and may be addictive, on July 20, 2010, in the Atlanta Science News Examiner, Kevin Murnane reported that research showed modafinil “produces some effects that are similar to abused stimulants, such as cocaine.”

In what may turn out to be the final nail in the modafinil coffin, rhesus monkeys were given modafinil prior to undergoing behavioral, neurochemical, and brain imaging studies for a study led by Monica Andersen, conducted at the Yerkes National Primate Research Center at Emory University, in the June 2010, “Psychopharmacology” journal.

“Similar to other stimulants, these researchers found that modafinil increased movement or locomotion in their subjects,” Murnane wrote. “Furthermore, an acute bolus of modafinil elicited a return or reinstatement of cocaine self-administration that had been previously diminished through extinction training.”

“These behavioral effects are very consistent with those of other stimulant-type drugs,” he reported.

Mechanistically, the researchers found “using Positron Emission Tomography (PET) imaging that modafinil bound to and occupied a protein in the brain called the dopamine transporter,” he explained. “This protein is the same one that cocaine binds to.”

“Furthermore, they found that modafinil increased dopamine neurotransmission,” Murnane said. “This is the same mechanism thought to mediate the euphoric and addictive properties of cocaine.”

He pointed out that the findings “closely paralleled those of a study by Volkow and colleagues in human subjects that was published in the March 2009 issue of the Journal of the American Medical Association.”

“Collectively, these studies show that modafinil has similar behavioral and pharmacological effects to stimulant-type drugs of abuse, such as cocaine,” he wrote.

“These data indicate that modafinil has the potential to be abused or produce dependence,” Murnane said. “Accordingly, closer monitoring of the modafinil supply and abuse patterns may be warranted.”

Read the rest of this entry »

Filed under: 'ADHD', 2010, addiction, off-label, Provigil

The Rise and Fall of Provigil – Part I

Evelyn Pringle

On July 22, 2010, 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% 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 eleven 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 fourteen 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)

(Evelyn Pringle is an investigative journalist focused on exposing corruption in government and corporate America)

Filed under: 'ADHD', 2010, addiction, Biederman, Provigil

Reviewing ADHD Drugs – FDA Goes Through the Motions

Evelyn Pringle March 12, 2006

Some of the top-selling drugs of all time are those prescribed to treat attention deficit disorders. Drug companies have physicians in every field of medicine pushing these medications and dole out millions of dollars worth of free samples each year to make sure they are passed out like candy.

A new ADHD drug is set to come on the market that supposedly can keep people awake for days at a time with no problems. Just what we needed, especially for hyper little kids.

I wonder if this means they will remain calm as they sit wide-awake watching TV and playing video games for days while the rest of the family sleeps.

The drug Sparlon is manufactured by Cephalon and is a clone of Provigil, another drug already on the market. Sparlon contains modafinil, the same exact active ingredient contained in Provigil which is approved for the treatment of patients with narcolepsy, sleep apnea and shift work sleep disorder, according to the FDA.

The drug’s approval will be considered by the FDA’s Psychopharmacologic Drugs Advisory Committee at a public hearing scheduled for March 23, 2006.

The day before the Sparlon hearing, the FDA’s Pediatric Advisory Committee is scheduled to meet to discuss neuropsychiatric adverse events and cardiovascular adverse events reported on patients who were treated with ADHD stimulant drugs already on the market.

The drugs under review include Ritalin from Novartis, Adderall and Adderall XR from Shire Pharmaceuticals, Concerta from Johnson & Johnson, and generic versions of Ritalin.

On February 9 and 10, 2006, the FDA’s Drug Safety & Risk Management Advisory Committee held hearings on the same topic, and after reviewing the information provided at the hearing, the panel recommended that black box labels be added to the labels of all stimulants.

However, the FDA is not bound by the recommendations of its advisory panels, and critics of the drugs say the close 8-7 vote by the panel, means there will be spirited debate within the agency over whether black box labels will be added.

Several members of the panel said they voted for the warning in part, because they were alarmed over the sharp rise in prescriptions written for both children and adults. During the hearing, the committee was informed that between 1999 and 2003, roughly 78 million prescriptions were written for children under the age of 18, and 14 million more were written for adults.

In a stark contrast, only 190 million prescriptions were issued for children and adults during the 12 year period between 1992 and 2004.

According to the FDA numbers on adverse events, between 1999 and 2003, there were 25 deaths reported for persons using ADHD drugs, and 19 were children. The agency also acknowledged that more than 50 cases of cardiovascular-related events were reported in the same time period including stoke, heart attack, hypertension, palpitations and arrhythmia.

Critics say the numbers revealed at the hearings represent a gross understatement because only 1% to 10% of adverse reactions are ever reported to the FDA, and it would therefore be better to add a black box now and remove it later if studies prove there is no link between the stimulants and sudden death and heart disease.

Supporters of the drugs, say the warning is based on inconclusive evidence and would deter physicians from prescribing the medications and scare patients away from taking the drugs.

Because Cephalon claims Sparlon should not be classified as a stimulant, analysts predict the company could get a boost if the FDA agrees and requires the other drugs to carry a black box warning. One of the issues discussed at the March 23, hearing will likely be how to distinguish Sparlon’s labeling from other ADHD drugs.

If approved, Sparlon will be co-marketed under an agreement with Johnson & Johnson, which will focus on the pediatric market through its McNeil Consumer & Specialty Pharmaceuticals unit.

McNeil’s sales team will promote Sparlon to psychiatrists, pediatric neurologists and pediatricians, while Cephalon’s 400-person sales force will focus on non-pediatric specialists and primary care physicians.

When Cephalon requested FDA approval for Sparlon, it submitted the results from three clinical trials on children aged 6 to 17 that the company said indicated better results in children taking Sparlon compared to children who received a placebo. Each trial lasted 9 weeks and the most common side effects noted were loss of appetite, mild insomnia and headaches.

But Cephalon has not been sitting idle while waiting for approval of its Provigil clone. Last year it had to figure out a way to deal with the fact that Provigil’s patent was set to expire in 2006. Through some last minute legal footwork, the company was able to negotiate agreements with 4 generic firms that will allow Cephalon to continue to sell the drug unchallenged until at least 2011

Provigil’s approval for a silly diagnosis like “shift-work sleep disorder” is a good example of disease-mongering, described in the book, “Selling Sickness: How The World’s Biggest Pharmaceutical Companies Are Turning Us All Into Patients,” by Ray Moynihan and Alan Cassels, which explains how drug companies foster the creation of bogus disorders to create markets for their pills, through “medicalization” of normal states of health.

In the same vein, many experts say the sale of ADHD drugs in general is nothing but a racket. Dr Fred Baughman, a board certified child neurologist and Fellow of the American Academy of Neurology, calls ADHD the “greatest health care fraud of modern times.”

Clinical social worker Peter Dwyer, has seven years’ experience working with troubled children, and has served as director of a large therapeutic foster care program. He also attributes the ever-rising sales numbers for ADHD drugs to a grand marketing scheme.

“It is easy to see why stimulants dominate the treatment of ADHD,” he says, “drug companies spend over $20 billion a year on promotion – more than they spend on research.”

“The bottom line,” Mr Dwyer explains, “professionals and the public are bombarded with a stream of “research” and “information” financed and spun by the people who make and sell these drugs.”

“The conflict of interest is palpable,” he adds.

And anyone who believes Provigil is free of the side effects associated with other ADHD medications needs to speak to Susan Florence who experienced a terrifying adverse reaction to the drug.

“I took one pill and I thought I was coming out of my skin,” she recalls, “I felt as if someone had climbed inside me.”

“It was one of the worst experiences of my life,” she says.

Nonetheless, Cephalon has done an excellent job of promoting Provigil. The US Air Force has even adopted the drug as one of its official “go pills” for pilots whose missions stretch out more than 12 hours, according to Business Week on November 1, 2004.

Ever since Provigil hit the market, Cephalon stayed busy figuring out ways to promote its off-label use for a multitude of ailments including ADHD, and with obvious success. SG Cowen & Co analyst, Eric Schmidt, told Business Week he figures more than 50% of Provigil sales are for unapproved uses.

And 50% in off-label sales adds up to enormous profits. In 2004, US doctors wrote 1.9 million prescriptions for Provigil, generating $414 million in sales. In 2005, Cephalon saw Provigil sales reach $512 million, according to Forbes.com on March 13, 2006.

While waiting for Sparlon to be approved, the company has been using every trick in the book to boost sales of Provigil for the treatment of ADHD.

For instance, Dr Fletcher Taylor, from Tacoma, Washington, was paid to meet with small groups of doctors to talk about Provigil.

He conducted a study on the use of Provigil for ADHD, which he claims showed positive results. However, according to Business Week, Dr Taylor says “he does not bring up the use of Provigil for ADHD in his talks, but he answers questions – as he is permitted to do – if one of the doctors in the group brings it up.”

“Usually people do ask,” he told Business Week.

I’m quite sure they do ask, probably much like the people on TV who used to just happen to step out of the audience to be cured by faith-healer 50 years ago.

Cephalon also employs the well-known off-label marking technique of funding continuing medical education seminars (CMEs), under the guise of providing doctors with information related to how certain ailments can be treated by drugs that the company just happens to sell.

For example, Cephalon paid for a CME that focused on the treatment of daytime sleepiness experienced by Parkinson patients and explained how Provigil might be a useful therapy.

The sponsor of the program, a firm called Projects in Knowledge, told Business Week that Cephalon paid for the program but had no input on the material discussed.

And of course I believe that.

Another tried and true method of promoting off-label use involves publishing the results of favorable studies funded by drug companies in medical journals. “Journals have devolved into information laundering operations for the pharmaceutical industry,” according to Richard Horton, editor of the Lancet, in March 2004

In a prime example of this practice, the August 4, 2005 New England Journal of Medicine, published a report on a study funded by Cephalon in which the lead author, Dr Charles Czeisler, from Harvard Medical School and Brigham and Women’s Hospital, had a professorship endowed by $2 million from Cephalon.

In the report, Dr Czeisler claimed night-shift workers remained more alert with Provigil and wrote a glowing summary of the study. “I would characterize [Provigil] as the treatment of choice with patients with shift-work disorder,” he said.

However, Dr Robert Basner, director of Columbia University’s Cardiopulmonary Sleep and Ventilatory Disorders Center, published an editorial on the study in the same issue of the NEJM and said the researchers’ data showed only slight improvements in workers wakefulness and productivity with Provigil, and pointed out that the drug seemed to exacerbate insomnia for some patients.

“That’s not a very robust endorsement of the drug coming from the investigators themselves,” Dr Basner wrote. “This drug is little better than nothing in terms of making them less sleepy during shift work at night,” he added.

Experts pretty much agree that Sparlon will be approved for treating children with ADHD so before too long the “little better than nothing” clone will not doubt be ringing up the cash registers all over the US.

Filed under: 'ADHD', 2006, Adderall, Cephalon, Concerta, FDA, FDA hearing, Johnson and Johnson, Novartis, Provigil, Ritalin, Shire, Sparlon

Legal ADHD Speed – Becoming Drug Of Choice For Americans

Evelyn Pringle March 20, 2006

A study published online in the February 2006, Journal of Drug and Alcohol Dependence, that examined data from a 2002 survey of about 67,000 households, estimates that more than 7 million Americans have misused stimulant drugs meant to treat ADHD, and “substantial numbers of teenagers and young adults appear to show signs of addiction, according to a comprehensive national analysis tracking such abuse.”

The statistics are alarming because people are using the drugs recreationally or to boost academic and professional performance. The scientists who published the study concluded that about 1.6 million teenagers and young adults had misused these stimulants during a 12-month period and that 75,000 showed signs of addiction.

Last month, the FDA’s Drug Safety and Risk Management Advisory Committee held 2 days of hearings, and after listening to all the testimony and reviewing the data presented, recommended that all ADHD drugs carry a black box warning on increased cardiovascular risks.

This month, the Pediatric Advisory Committee is meeting on March 22, 2006, and will focus on neuropsychiatric adverse event reports and trial data on ADHD medications. The committee will also receive an update on efforts to better understand cardiovascular adverse events possibly related to ADHD medications, according to the FDA web site.

During the hearings last month, the Alliance for Human Research Protection, asked the FDA to issue (1) a public advisory; (2) a “dear doctor” letter to every doctor in America to apprise them of the essentially lethal side effects that are being tracked; and (3) to solicit the reporting of any and all adverse events of which they are aware.

Allen Jones, speaking as a representative of the Alliance, told the panel the FDA should instruct the pharmaceutical industry to advise the FDA of all adverse events that have been reported concerning ADHD drugs immediately, and also it should demand that all clinical trials in possession of the drug companies be turned over to the FDA so that independent researchers can review them for adverse events.

“We don’t have the luxury of time to wait for the future trials,” he pointed out. “Children are dying,” he said.

Ellen Liversridge, having lost her son to side effects of the drug Zyprexa before they were made known in a black box warnings, appeared to speak on behalf of all parents who have lost their children due to adverse reactions to prescription drugs.

“I grieve particularly today for the 51 dead of ADHD drugs that were announced yesterday by the FDA,” she told the panel.

“I guess my up-front message, front and center,” she continued, “is that you know that ADHD drugs can cause serious side effects and death, including sudden death, hypertension, myocardial infarction, stroke, and possibly bipolar disorder.

“This being the case,” she said, “I urge you to recommend that these drugs have an appropriate black box warning placed on the label starting immediately.”

Sandra Lucas, appeared at the hearing to speak on behalf of the Citizens Commission on Human Rights, a psychiatric watchdog group, and told the panel, “we do know that the side effects of the stimulants are not only present, they are extremely serious and sometimes lethal.”

“So,“ she asked the committee, “while the FDA ponders the problem of studying the issue and conducting the studies that may have inherent flaws, what real, immediate protections are to be put in place for parents and children?”

During the hearing, Drug Safety panel member, Dr Art Levin, told the committee, “I think we have to recognize that when a drug is approved and marketed the public assumes a level of comfort in the safety of that drug unless they are told otherwise.”

“And, for us to sit around and talk about this,” he continued, “to have three advisory committee meetings discussing the signals and not to make, at the very least, a very strong warning to people that there is uncertainty here about the safety of these drugs and that they need to be aware of that pending clarification I just think is inappropriate, unethical behavior.”

Committee member, Dr Steve Nissan advised, “we have to elevate the level of concern and if it slows the growth of this, that is probably appropriate because I think most observers would argue that ten percent of ten year-olds do not have this disease and what has happened is that this is out-of-control use of drugs that have profound cardiovascular effects and, as a cardiologist, I can tell you that,” he said.

Panel member, Dr Curt Furberg, recommended that ADHD drugs also come with a patient guide “so that when parents are filling prescriptions for their kids they get a written document laying out the state of knowledge, or lack of the state of knowledge and the potential risks so they are reminded each time that there is a potential risk and we are trying to find solutions to it,” he advised.

Since last month’s recommendation for a black box warning on cardiovascular events, FDA reviewers announced a recommendation for stronger warnings on all ADHD drugs due to reports of numerous adverse events like mania and psychosis in clinical trials, including modafinil.

On March 14, 2006, an FDA review was posted to the agency’s web site in advance of next week’s meeting. The FDA said stronger warnings are needed on the risk of psychosis, a mental disorder characterized by the inability to distinguish real and imaginary events.

“The most important finding of this review is that signs of psychosis or mania, particularly hallucinations, can occur in patients with no identifiable risk factors, at usual doses of any of the drugs used to treat ADHD,” according to a memo dated March 3 from two members of the agency’s ADHD psychiatric review team.

The review said current labeling neither addresses those concerns nor does it “clearly state the importance of stopping drug therapy in any patient who develops hallucinations or other signs or symptoms of psychosis or mania during drug treatment of ADHD.”

From January 2000, through June 30, 2005, the review found nearly 1,000 reports of psychosis or mania possibly linked to the drugs, including Adderall, Concerta, Ritalin and Strattera. The reports were pulled from the FDA’s database and from the drug makers themselves after the FDA had requested additional information from the drug companies.

The FDA found a “substantial portion of the psychosis-related cases were reported to occur in children 10 years or less,” an age group which according to the FDA, does not typically suffer from psychosis.

“The predominance in young children of hallucinations, both visual and tactile, involving insects, snakes and worms is striking and deserves further evaluation,” the FDA noted.

Last fall, on September 29, 2005, the FDA issued a public health advisory to alert physicians of reports of suicidal thinking in children and adolescents associated with Strattera, and directed Eli Lilly, manufacturer of Strattera, to develop a Medication Guide for patients and caregivers.

Although Strattera is marketed as a “nonstimulant” medication, according to pediatrician, Dr DuBose Ravenel, MD, FAAP, of Cornerstone Pediatrics, “it is in fact a stimulant every bit as much as the traditional stimulants, as evidenced by even a cursory consideration of its pharmacological action, and evidenced by the fact that it is classified as such by the World Health Organization.”

Dr Fred Baughman, ADHD expert and well-known author, will testify before the committee next week on behalf of the International Center for the Study of Psychiatry and Psychology.

“We know these drugs are poisons,” Dr Bughman warns, “and we know they are highly addictive, dangerous and sometimes deadly.” He points to the senseless death of children on ADHD drugs. “Matthew Smith is dead today not because of ADHD,” he says, “but, as carefully delineated by the medical examiner, his chronic Ritalin/methylphenidate exposure.”

“Nor is there any other plausible explanation for the death of Stephanie Hall, 11 years old of Canton, OH,” he advises. “No physical predisposing factor other than Ritalin was present,” he notes, “leading up to her death, in bed, by cardiac arrhythmia.”

“The main question the FDA needs to answer concerns ADHD,” Dr Baughman says, “the “disorder” these addictive, dangerous, sometimes deadly drugs are used to treat.”

“The shocking fact of the matter is that it is not a disorder/disease at all,” he explains, “children said to have it are entirely normal meaning they bear no objective, demonstrable, diagnosable, abnormality, meaning there is no justification for prescribing these or any other drugs for so-called ADHD–a wholly fictitious, wholly subjective entity.”

According to Dr David Stein, Ph D, Professor of Psychology at Longwood University, “the risks of psychiatric drugs in the bodies of children and teenagers is well documented and needs no further elaboration.”

He wants the advisory committee to address two issues: (1) the validity of ADD/ADHD as diseases; and (2) effective alternative behavioral treatments that reduce reliance on drugs.

Dr Stein’s behavioral/cognitive treatment methods have won awards from the American Psychological Association (One of top ten research projects at the 1998), the International Center for Psychiatry and Psychology (2005), and the Ritalin Litigation Conference (2001).

“It is my hope,” he says, “that the committee will consider that within the decision tree, the physician’s choice to use drugs can be lowered in favor of, at the very least, recommending properly designed behavioral parent training.”

“The risks of legal liability and the risks of medical damage to children,” Dr Stein advises, “can be reduced with the augmentation and further development of proper behavioral treatments.”

According to court certified expert and author of many books on ADHD, Dr Peter Breggin, all stimulants commonly cause “a continuum of stimulation, including agitation and irritability, anger, hostility, disinhibition, hypomania and mania.”

The stimulant or activation syndrome, he advises, was originally observed decades ago with stimulant drugs such as amphetamines, Adderall, and Dexedrine, and methylphenidates such as Ritalin and Concerta.

It also occurs, he notes, with dexmethylphenidate such as Focalin, and selegilines like Sparlon and Provigil, as well as the atomoxetine, Strattera.

In a review of the summary data for the FDA Spontaneous Reporting System through March 1997, Dr Breggin counted the following: Psychosis, 43; hallucinations, 44; and psychotic depression, 11. His review also counted more than 50 reports in the combined category of overdose, overdose intentional, and suicide attempt.

“In regard to both amphetamines and methylphenidate,” he explains, “there are a surprising number of animal and human studies showing persistent biochemical changes and atrophy after several weeks or more exposure.”

“While the changes in children are sometimes mistakenly attributed to ADHD or OCD, they are a known effect of stimulants on the animal brain,” he advises. “A known toxic drug effect is a far more likely culprit than a highly speculative “biochemical imbalance” in these children,” he adds.

Dr Breggin will also testify at the advisory committee hearing on behalf of the International Center for Psychiatry and Psychology, and will recommend that labels for stimulant drugs include the following neuropsychiatric warnings:

(1) A warning concerning depressive/OCD ADRs that includes depression, apathy, lethargy, listlessness, tiredness, sadness, crying, withdrawal, and social isolation as well as worrying, ruminating, over-focusing, and other obsessive-compulsive behaviors.

(2) A warning concerning stimulation or activation ADRs that includes insomnia, anxiety, agitation, panic attacks, irritability, hostility, aggressiveness, violence, impulsivity, disinhibition, hypomania, and mania.

(3) Strengthened warning concerning psychosis, paranoid ideation and hallucinations.

(4) Strengthened warning about rebound, dependence and abuse, especially for methylphenidate products (all current methylphenidate labels especially inadequate).

(5) A specific warning that the combination of depressive, obsessive-compulsive and stimulant ADRs poses a serious risk of dyscontrol or disinhibition with suicidal and/or violent behavior.

(6) A warning in the labels for amphetamine and methylphenidate products about persistent brain dysfunction and atrophy.

Information released by the FDA last month showed that between 1999 and 2003, seventy-eight million prescriptions were written for ADHD drugs in children ages 1 to 18, and more than 14 million prescriptions were written for adults.

During last month’s hearings, Safety Drug committee member, Dr Steve Nissen, said he is certain the public is not aware of the risks. “If the current warnings were adequate we wouldn’t have 2.5 million children and 1.5 million adults taking these drugs.”

Filed under: 'ADHD', 2006, Adderall, Concerta, FDA, Focalin, front groups, Provigil, Ritalin, Sparlon, Strattera

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