Friday, January 07, 2005

Attenace: Upcoming Treatment Option For ADHD

For decades, the options for pharmacological treatment of ADHD have been limited to methylphenidate (Ritalin), various forms of amphetamine, atomoxetine (Strattera), and pemoline (Cylert).  Methylphenidate and amphetamine are Schedule-II drugs, meaning that they are designated as having a high potential for abuse.  Pemoline has been associated with liver damage, so it is not a first-line option.  There have been recent reports of liver damage with Strattera as well.  Although it remains to be seen how widespread the atomoxetine problem is, it is difficult to be enthusiastic about atomoxetine until that question is resolved.  Other options, such as bupropion and tricyclic antidepressants, have limited efficacy.  Therefore, there is a need for a better option.  See CNS Spectrums Apr 2003, 8(4) p253-8 for a review of nonstimulant treatment options for ADHD. 

Recently, there has been some interest in using modafinil to treat ADHD.  Modafinil (Provigil) is a wakefulness-promoting agent that is used for treatment of narcolepsy, sleepiness associated with sleep apnea, and fatigue associated with multiple sclerosis.  It is a controlled substance, but is classified as Schedule-IV.  This means that the FDA thinks it has a low potential for abuse.   Years of experience with modafinil have led to no particular safety concerns.

These factors indicate that there is a need for another option, and that modafinil might be a good one.  Now we see a report that this may come to pass:
Cephalon (CEPH) Files Application For Marketing Approval Of New Modafinil Formulation For The Treatment Of Children And Adolescents With Attention-Deficit/Hyperactivity Disorder

WEST CHESTER, Pa., Dec. 21  /PRNewswire-FirstCall/ -- Cephalon, Inc.  today announced that it has filed a supplemental new drug application (sNDA) with the U.S. Food and Drug Administration (FDA) requesting marketing approval of ATTENACE(TM) (modafinil) Tablets [C-IV], a new proprietary dosage form of modafinil for the treatment of attention- deficit/hyperactivity disorder (ADHD) in children and adolescents between the ages of six and 17.

In August 2004, Cephalon announced results from three multi-center clinical trials that showed that ATTENACE 340 mg and 425 mg tablets significantly improve symptoms of ADHD in children and adolescents. Based upon the strength of the study results, the company accelerated the filing of its application with the FDA from the first quarter of 2005 to the fourth quarter of 2004. The company is targeting a launch of ATTENACE by early 2006.

"Physicians and parents continue to seek treatment for children and adolescents with ADHD that provides a balanced efficacy and tolerability profile. In our phase 3 trials, we were encouraged that ATTENACE improved the symptoms of many children and adolescents with ADHD to levels within the range considered normal for those without ADHD, as measured by the ADHD rating scales used in our studies. There was a low discontinuation rate due to adverse events in these studies as well," said Paul Blake, MB, FRCP, Senior Vice President of Clinical Research and Regulatory Affairs. [...]
It is not clear why Cephalon is marketing modafinil with a different name  Modafinil currently is sold in 100mg and 200mg strengths as Provigil.  It makes sense to make a larger tablets, if those are the doses required to see sufficient effect, but why the different name?.  I suspect the FDA required them to use a name other than Provigil, for reasons that make sense to bureaucrats and nobody else.

I can't comment much on the effectiveness of modafinil for treatment of ADHD.  A cursory Medline (Medscape Medline, free registration required) search turned up a  few reports, but there were small studies.  All I can really say is that the pilot studies look encouraging. 

What about the down side?  The main concerns are the abuse potential, and the risk of adverse effects.  The FDA has indicated that modafinil has a low abuse potential.  As I've mentioned before, here at Corpus Callosum, abuse potential is difficult to assess a priori.  Still, as far as I know, there is no particular black market for the product, despite a fair amount of publicity.  This could change when it is marketed for use in children.  Personally, I think people will try to abuse it, but most serious drug abusers are not going to be impressed.  It does not cause euphoria, and dose escalation does not lead to a proportional increase in effect, beyond a certain point.  That is, there is a limit to what the drug can do for a person; increasing the dose beyond that is pointless.  On the other hand, there are people out there who will abuse anything.  Some people abuse Haldol, for example.  Cripes, some people abuse organic solvents.

Are there dangerous adverse effects?  So far, none is apparent.  The usual cautions apply to this;  it should not be used casually.  In fact, sleep disorders carry a definite risk to health, so even a moderate risk with the drug could be acceptable.  ADHD, on the other hand, is not directly hazardous to health.  Therefore, a higher standard should be set for the safety of modafinil when used for this new indication.

I am not prepared to recommend that modafinil be used for ADHD, because I have not seen the larger studies that the FDA requires for approval for a new indication.  Once they get the approval (and they almost certainly will), I'm sure I'll see the studies, and comment further. 

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