by Elisa F. Cascade and Amir H. Kalali, MD
Featuring expert commentary from Sheldon H. Preskorn, MD
Ms. Cascade is Vice President, Strategic Research and Safety, Quintiles Inc., Falls Church, Virginia; Dr. Kalali is Vice President, Global Therapeutic Group Leader CNS, Quintiles Inc., San Diego, California, and Professor of Psychiatry, University of California, San Diego; and Dr. Preskorn is Professor, Department of Psychiatry and Behavioral Sciences, University of Kansas School of Medicine and Chief Executive Officer, Clinical Research Institute, Wichita, Kansas.
Financial Disclosures: Relative to the transdermal delivery system for selegiline, Dr. Preskorn was a principal investigator for registration trials of the product for the treatment of major depression, a consultant to Somerset and Bristol-Myers Squibb during the approval process, and a presenter at the FDA Psychopharmacology Advisory Committee meeting on the product. Dr. Preskorn has been in drug development research for 30 years and has served or is serving in one or more of the following capacities: as a principal investigator, on the speakers bureau, and/or as a consultant for the following companies—Abbott Laboratories, AstraZeneca, Aventis, Biovail, Boehringer-Ingleheim, Bristol-Meyers Squibb, Comentis, E. Merck, Eisai, Eli Lilly, Glaxo-SmithKline, Hoffman LaRoche, Johnson & Johnson, Lundbeck, Memory, Merck, Neurosearch, Novartis, Organon, Otusak, Pfizer, Solvay, Sommerset, Sumitomo, Wyeth, and Yamanouchi.
Key words: EMSAM, selegiline, transdermal delivery system, MAOI, depression
Abstract
We investigated the use of EMSAM in the first year post-launch in the US—April of 2006 through March of 2007. According to our data, EMSAM represents <0.1 percent of total prescriptions for antidepressants in the US and is prescribed most often by psychiatrists (83%of prescriptions). The impact of the product on the MAO inhibitor class, however, has been significant. We found that EMSAM now represents 30 percent of all MAO inhibitor use and has been a catalyst for growth in the overall MAO inhibitor class. An expert commentary is provided on the data.
Introduction
In April of 2006, Bristol-Myers Squibb and Somerset Pharmaceuticals launched EMSAM® (selegiline transdermal system), the first new MAO inhibitor in over 20 years, into the US market. Recognizing that the transdermal delivery system of EMSAM offers safety benefits over older, oral MAO inhibitors, in this article we examine the use of EMSAM in its first year on the US market.
Methods
We examined retail pharmacy prescription data from Verispan, which captures more than 1.4 billion patient-centric prescriptions per year, nearly half of all prescription activity in the US. This data set includes prescriptions from a variety of retail channels (e.g., national retail chains, mass merchandisers) from a near-census of US pharmacies. The Verispan retail pharmacy database also captures information from all payer types, including cash.
Results
According to data from Verispan, a total of 33,000 prescriptions for EMSAM were written in the first year of launch (April of 2006 through March of 2007). To put this in perspective with other new antidepressant launches, there were 13,600 total prescriptions for Pexeva® in the first year and approximately 3,000,000 for Cymbalta® (Table 1). Unlike Pexeva and Cymbalta, where psychiatrists represent approximately 30 percent of prescriptions, psychiatrists are the predominant users of EMSAM, accounting for close to 83 percent of the prescriptions in the first year post-launch.
Figure 1 displays quarterly prescriptions for the total depression market and several antidepressant classes from first quarter 2005 (Q1/2005) to first quarter 2007 (Q1/2007). To account for vast differences in total prescription volume across classes, data in Figure 1 are presented as indices based on total prescriptions for Q1/2005. As seen in Figure 1, in the year prior to EMSAM’s launch, the MAO inhibitor class had been in decline. Since April of 2006, the MAO inhibitor class has grown about 31 percent, second to only the SNRI class, which grew about 37 percent, primarily driven by the growth of Cymbalta.
Expert Commentary
Prescribers must be given a reason to prescribe a product. That is particularly true when they have many alternatives. The prescriber weighs the risk versus the benefit of his or her choices for the patient and for him- or herself (the latter because of our litigious society).
When balancing risk, one must consider the risk of ineffectively treating the illness as well as the risk of the treatment. Relative to the first point, major depression can be a fatal illness.
Thanks to advances in drug development over the last 20 years, the prescriber has many antidepressant alternatives that are generally safe, well tolerated, and effective, such as the serotonin selective reuptake inhibitors (SSRIs) and the serotonin-norepinephrine reuptake inhibitors (SNRIs).[1]
Based on the Trend Watch data, transdermal selegiline (EMSAM) accounts for only 0.1 percent of total US prescriptions for antidepressants, a crowded therapeutic class. A compelling reason to prescribe this product apparently has not been either articulated or received by prescribers.
All of the current antidepressants owe their existence in part to the chance discovery of the monoamine oxidase inhibitors (MAOIs) in the 1950s.[1] While MAOIs were among the first effective antidepressants marketed, they fell out of favor due to concerns about hypertensive crises caused by a drug-food interaction. Oral, irreversible MAOIs inhibit the enzyme, MAO-A, in the gut wall during their absorption into the systemic circulation. That enzyme is the natural barrier to tyramine entering the systemic circulation. Without that enzyme, tyramine can enter the body and produce a hypertensive crisis.[2]
Transdermal selegiline at 6mg/day has been proven to avoid that problem and hence was approved without the need for dietary restriction.[2] Sufficient safety data was not provided with the higher dose strengths to convince the Food and Drug Administration (FDA) that they were safe to use without dietary restrictions. Hence, a tyramine-restricted diet is recommended when using those dose strengths, but because of an absence of data about safety rather than because of evidence of a clinically relevant risk.
In this case, the burden of proof of safety lies with the manufacturer because of the known risk and the known mechanism underlying that risk with oral MAOIs. The latter point is relevant to the concept of class labeling, which this commentary will not further pursue.
Why has sufficient data not been presented to prove whether higher doses of transdermal selegiline are or are not safe without dietary restriction? One would have to ask the manufacturer to know for certain, but usually such decisions are based on a cost-benefit analysis. Such an analysis would consider the following variables: (a) How much would it cost in time as well as money to develop such data? (b) What is the likelihood that the results would be favorable? and (c) How much of a difference would the data make in the acceptability of the product? Time is an issue because the time on the exclusivity of the sale of the product begins at a minimum when the product is marketed. Usually, a return on investment in such research can only be realized during that exclusivity period.
In the case of transdermal selegiline, the prescription figures indicate that the absence of a diet restriction at the lowest dose is not a compelling reason in and of itself to encourage most prescribers to recommend this product.
The concern may instead be the issue of drug-drug interactions (DDIs). The goal of transdermal delivery of selegiline is two-fold: (a) reduce the amount of selegiline (an irreversible and relatively selective MAO-B inhibitor) reaching the gut and (b) deliver more to the brain. At a high enough concentration in the brain, selegiline can inhibit both MAO-B and MAO-A, and thus can increase the cystolic concentrations of dopamine, norepinephrine, and serotonin.
A decrease in the functional activity of one or more of these neurotransmitters has been a cornerstone of the biochemical theories of major depression for over 40 years.[3] The increase of those neurotransmitters should be good for depression and consistent with the positive efficacy trials that led to the approval of transdermal selegiline as an effective antidepressant by the FDA.
However, that inhibition also raises the potential for drug-drug interactions with other agents that can potentiate the effect of one or more of these three neurotransmitters just as can happen with the oral irreversible MAOIs. The two major adverse outcomes are hypertensive crisis and serotonin syndrome.[1] The former is due to potentiation of central norepinephrine and the latter is due to potentiation of central serotonin.[1] Both are potentially fatal DDIs.
For these reasons, the first-time prescriber might be more comfortable using transdermal selegiline in a patient who is not taking any other medication or at least not taking those that promote central biogenic amine neurotransmission. Such patients more likely would be found in primary care than in psychiatry, but the Trend Watch data reveals that the overwhelming majority (83%) of the prescribers of transdermal selegiline have been psychiatrists.
Patients tend to go to psychiatrists because they have not responded to trials of SSRIs or SNRIs in primary care and thus are likely to be on more complicated regimens, particularly with drugs that affect the central nervous system,1 and this may dissuade some psychiatric prescribers from considering transdermal selegiline.
The questions with any new product are as follows: (a) What is the gain that can be reasonably expected by using this product? (b) What is the relative risk of adverse reactions occurring due to the product? (c) What steps can be taken to minimize the risk? and (d) What steps can be taken to deal with these problems should they occur? The trend data suggest that those questions have not been adequately addressed for the majority of prescribers to be motivated to try the product for their patients.
If a drug is not used, there are several consequences. First, prescribers do not think about the drug because they are not prescribing it and are not seeing it being prescribed by other physicians. Second, they do not become comfortable with the drug because they do not know what it will or will not do for good or ill. The market share for transdermal selegiline is so small that both are true.
That may be a loss opportunity for a several reasons. First, MAOIs have a long history of being effective antidepressants and there is some reason to believe that they may be uniquely effective in some types of depression.[1] Second, transdermal selegiline had sufficient evidence of efficacy to gain FDA approval. Third, a recent study by a group of investigators at the University of Toronto reported a 35-percent increase in the monoamine oxidase activity in the brains of depressed patients using a novel imaging method. That provides a biochemical rationale for antidepressant efficacy of MAOIs.[3]
Nevertheless, this commentary is not intended to suggest that transdermal selegiline is underutilized nor to advocate its greater use. Instead, this commentary is intended to highlight general principles of clinical psychopharmacology that came to mind when I reviewed the Trend Watch data at the request of the journal.
REFERENCES
1. Preskorn SH, Feighner JP, Stanga CY, Ross R (eds). Antidepressants: Past, Present, and Future. Heidelberg: Springer-Verlag, 2004.
2. Preskorn S. Why the transdermal delivery of selegiline (6mg/24hr) obviates the need for a dietary restriction on tyramine. J Psychiatr Prac 2006;12(3):168–72.
3. Meyer JH, Ginovart N, Boovariwala A. Elevated monoamine oxidase a levels in the brain: An explanation for the monoamine imbalance of major depression. Arch Gen Psychiatry 2006;63:1209–16.
