Friday, December 17, 2004

Lunesta Receives Final FDA Approval
Initial Comments on New Insomnia Drug

As reported in CCN Money, among other sources, a pharmaceutical company called Sepracor had obtained FDA approval for its new drug, Lunesta (eszopiclone).  Their stock went up by 15% immediately.  Looking through the news reports, most of them focus upon the financial implications of the impending release of this new product.  Patients, however, probably don't care much about that.  They want to know about the drug itself.

It turns out that technical information is hard to come by.  For a short, general discussion of insomnia, see this Medscape CME article (free registration required.)  For the package insert, see this PDF file.  A list of references can be found at the Sepracor site, here.  A Medline search reveals only one article with relevant information. 
Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia.

Krystal AD, Walsh JK, Laska E, Caron J, Amato DA, Wessel TC, Roth T.

Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. krystal@phy.duke.edu

STUDY OBJECTIVES: To determine the long-term efficacy of eszopiclone in patients with chronic insomnia. DESIGN: Randomized, double-blind, multicenter, placebo-controlled. SETTING: Out-patient, with monthly visits. PATIENTS: Aged 21 to 69 years meeting DSM IV criteria for primary insomnia and reporting less than 6.5 hours of sleep per night, and/or a sleep latency of more than 30 minutes each night for at least 1 month before screening. INTERVENTIONS: Eszopiclone 3 mg (n = 593) or placebo (n = 195), nightly for 6 months MEASUREMENTS AND RESULTS: Efficacy was evaluated weekly using an interactive voice-response system. Endpoints included sleep latency; total sleep time; number of awakenings; wake time after sleep onset; quality of sleep; and next-day ratings of ability to function, daytime alertness, and sense of physical well-being. At the first week and each month for the study duration, eszopiclone produced significant and sustained improvements in sleep latency, wake time after sleep onset, number of awakenings, number of nights awakened per week, total sleep time, and quality of sleep compared with placebo (P < or = 0.003). Monthly ratings of next-day function, alertness, and sense of physical well-being were also significantly better with the use of eszopiclone than with placebo (P < or = 0.002). There was no evidence of tolerance, and the most common adverse events were unpleasant taste and headache. CONCLUSIONS: Throughout 6 months, eszopiclone improved all of the components of insomnia as defined by DSM-IV, including patient ratings of daytime function. This placebo-controlled study of eszopiclone provides compelling evidence that long-term pharmacologic treatment of insomnia is efficacious.
The paucity of hard information is a byproduct of the competitiveness of the pharmaceutical industry, as well as the extent to which the Industry now controls medical research.  Fifteen years ago, I usually knew what drugs were under development, and I knew quite a bit about the pharmacology of the drug before it was put on the market.  Now, everything is a tightly held secret. 

At this point, most of the technical information available is in the package insert.  The PI is a monograph that is written by the drug company, according to FDA specifications.   Every word, literally, has to conform to the specifications; every word has to be approved before the PI can be published. 

The main points are these: eszopiclone is chemically unrelated to most other sleeping pills.  It is similar to zopiclone, which is available in countries other than the USA.  It is absorbed best if taken on an empty stomach.  It reaches a peak blood level in about one hour, and has a half-life of about six hours, on average.  It is not water soluble, but it dissolves easily in ethanol.  As a relatively lipophilic drug, one would expect that it would cross the blood-brain barrier rapidly.  This is desirable for a sleeping pill, since it means it will take effect quickly.  It is broken down in the liver and the metabolites are excreted by the kidneys.  There are two enzymes responsible for breaking it down (catabolism).  This reduces the risk of drug interactions.  It is not highly protein-bound, which also reduces the risk of interactions.  It does not inhibit the action of many of the major drug-metabolizing enzymes in the liver, which further reduces the risk of interactions with other drugs. 

It appears that the primary risk of interaction occurs with drugs that inhibit the cytochrome P450 3A4 enzyme.  That would include itraconazole, nefazodone, clarithromycin, ritonavir, troleandomycin, and nelfinavir.  It would be expected to have additive sedating effects if given with other sedatives. 

According to the PI, eszopiclone binds to GABA receptors, although they do not specif what subtype of receptor, and they do not say what it does once it binds.  Presumably, it either is an agonist, or it acts to potentiate the natural effect of GABA.  GABA is the primary inhibitory neurotransmitter in the human brain, so it basically helps put the brain to sleep. 

Prior to marketing, the drug was studied in 2,100 patients, which is about average.  What is a bit unusual is that it was studied in many patients for up to six months.  That is a positive step by the company, and the FDA, that helps reassure us (somewhat) about the safety of the product.  The company claims that there was no evidnce for tolerance or dependence, which also is positive.  There was slight rebound insomnia the first night after stopping the drug, but this effect disappeared by the second night.  These findings indicate a low potential for abuse.  However, there have been other drugs that were marketed with claims of low potential for abuse, which turned out to be erroneous.  Stadol and Ultram probably are the best examples of this.  The fact is, some people will abuse anything, or at least will try to abuse it.  Therefore, we need to be cautious about any claims of low abuse potential.  To their credit, Sepracor did not make any claims about an absence of abuse potential in any of the literature I found. 

There were a few overdoses reported in clinical trials, but no fatalities.  The PI states "Individuals have fully recovered from racemic zopiclone overdosages of up to 340mg."  Lunesta is provided as the pure s-enatiomer, so 340mg racemic zopiclone is equivalent to 170mg of eszopiclone,  which is 57 times the maximum recommended dose.  That means that taking an entire one-month supply would not be expected to be fatal, if ingested alone.  Since people commonly overdose on more that one drug simultaneously, though, the real-world safety in overdose is not yet known. 

I'm sure it won't be long before we have more information on this.  As an aside, I would like to state that insurance companies that give patients a discount for getting a 3-month supply of medication should consider revising this policy, for drugs that people are especially likely to be used in suicide attempts. 

In premarketing trials, the adverse effects of eszopiclone were mild, and most occurred at a rate comparable to that with placebo. 

Overall, it appears that Lunesta will be a useful product, although there are so many sleeping pills on the market that there probably is little reason to use it, in the average patient, within the first six months of it coming on the market.  After that, if clinical experience is positive, it probably will be used widely.  Competitors likely will undertake six-month trials of their own products, to try to compete.  Insurance companies will urge doctors to use the less-expensive alternatives, even though some of the alternatives probably will have a higher potential for abuse. 

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