Download Emerging Drug List SELEGILINE TRANSDERMAL PATCH

Emerging Drug List
SELEGILINE TRANSDERMAL PATCH
CANADIAN COORDINATING
OFFICE FOR HEALTH
TECHNOLOGY ASSESSMENT
NO. 72
Generic (Trade Name):
Manufacturer:
Indication:
Current Regulatory
Status:
Description:
FEBRUARY 2006
Selegiline transdermal patch (EMSAM®)
Somerset Pharmaceuticals, Inc. (a joint venture of Mylan Laboratories Inc. and Watson
Pharmaceuticals, Inc.) and Bristol-Myers Squibb Company (commercialization and
distribution)1
Acute and maintenance treatment of patients with major depressive disorder (MDD)2
On January 31, 2004, the US Food and Drug Administration (FDA) issued an
“Approvable” letter to Somerset for EMSAM® (20 mg, 30 mg, and 40 mg).3
Selegiline is a monoamine oxidase inhibitor (MAOI). It is available in tablet form to treat
Parkinson’s disease.4 EMSAM® delivers a constant dose of selegiline through the skin.
There are two types of MAO isoenzymes: MAO-A and MAO-B. MAO-A is the predominant form in the digestive tract, and MAO-B is predominant in the central nervous
system (CNS).
In the CNS, MAO helps control the concentration of dopamine, serotonin, and norepinephrine. MAOIs, including selegiline, inhibit the breakdown of these neurotransmitters.
This inhibition increases the concentrations of neurotransmitters in the brain, and may
ease depressive symptoms.5
In the digestive tract, MAO protects against the hypertensive effects of dietary tyramine,
a compound that is commonly found in aged cheese, red wine, and chocolate.5 At doses
required to achieve antidepressant efficacy (i.e., 30 mg to 60 mg), selegiline interferes
with the breakdown of tyramine, which may result in dangerous and sudden increases in
blood pressure. EMSAM® bypasses the gastrointestinal system, permitting adequate brain
MAO inhibition, while maintaining the integrity of the gastrointestinal barrier to ingested
tyramine.4
Current Treatment:
MDD is characterized by at least two weeks of depressed mood, or loss of interest or
pleasure in nearly all activities. These and other symptoms cause substantial distress or
functional impairment.6 Treatment approaches include pharmacotherapy and psychotherapy.7,8 Antidepressant medications include tricyclic agents (e.g., amitriptyline), selective
serotonin reuptake inhibitors (e.g., citalopram, fluoxetine, paroxetine, and sertraline), and
atypical antidepressants (e.g., bupropion, nefazodone, and venlafaxine). Oral MAO
inhibitors such as phenelzine are also used but with dietary restrictions. Psychotherapy
interventions include cognitive-behavioural therapy, interpersonal therapy, and problemsolving therapy. Electroconvulsive therapy is generally reserved for patients with severe,
unmanageable MDD.7,8
The Canadian Coordinating Office for Health Technology Assessment (CCOHTA)
is funded by Canadian federal, provincial and territorial governments. (www.ccohta.ca)
Emerging Drug List
SELEGILINE TRANSDERMAL PATCH
Cost:
Evidence:
CANADIAN COORDINATING
OFFICE FOR HEALTH
TECHNOLOGY ASSESSMENT
There is no costing information for EMSAM®, as it is not currently marketed in any
country.
The efficacy and safety of EMSAM® has been demonstrated in two randomized, doubleblind, placebo-controlled studies of six and eight weeks’ duration in adult outpatients (18
years to 70 years of age) meeting DSM-IV criteria for MDD.9,10 In both studies, patients
were randomized to receive treatment with EMSAM® (20 mg/20 cm2) or placebo.
Treatment was preceded by a one-week, single-blind, placebo run-in period to identify
and eliminate placebo responders. In the six-week study, 177 patients followed a tyramine-restricted diet during treatment, and for two weeks after the study. At six weeks,
EMSAM®-treated patients demonstrated significant improvements on the 17-item
(p=0.01) and 28-item (p=0.004) Hamilton Depression Scale (HAM-D), but not on the
item assessing suicide. A significant improvement over placebo was also observed on the
Clinical Global Impression scale (CGI, p=0.007) and the Montgomery-Asberg
Depression Rating Scale (MADRS, p=0.005). In the eight-week study, 289 patients were
not subjected to dietary tryamine restrictions.10 At eight weeks, EMSAM®-treated patients
showed a significant improvement compared to placebo on MADRS (p=0.001) and
HAM-D-28 (p=0.039).10 No hypertensive effects were observed in either study.
In a longer, unpublished trial, 322 patients with MDD who had responded to 20 mg
EMSAM® during an initial 10-week open-label treatment phase were randomized to continue EMSAM® or to take placebo for up to 52 weeks.2 Patients who continued treatment
with EMSAM® experienced a significantly longer time to relapse compared with those
receiving placebo (p=0.006). No specific data on the time to relapse were provided.
Based on these trials, the US FDA’s Psychopharmacologic Drugs Advisory Committee
concluded (October 2005) that the 20 mg formulation of EMSAM® could be safely
administered without tyramine dietary modifications, and that there was insufficient
evidence to waive the dietary warning for higher doses.11
Adverse Effects:
Commentary:
The most common adverse effects are application site reactions, including rash, itching,
or irritation, all of which are mild or moderate in severity, and generally do not require
further treatment.12 Weight changes and levels of sexual dysfunction are similar between
EMSAM® and placebo-treated patients.2,9,10
EMSAM® offers a better drug interaction and adverse event profile than oral selegiline.13
If approved, it would be the first transdermal treatment for MDD. The advantages associated with transdermal drug delivery include avoidance of first-pass metabolism and
improved patients’ compliance.14 Limitations include the inability to precisely control the
dosage to each patient, and cost, as many oral antidepressants are available in generic
The Canadian Coordinating Office for Health Technology Assessment (CCOHTA)
is funded by Canadian federal, provincial and territorial governments. (www.ccohta.ca)
Emerging Drug List
SELEGILINE TRANSDERMAL PATCH
CANADIAN COORDINATING
OFFICE FOR HEALTH
TECHNOLOGY ASSESSMENT
form. Dietary tyramine restrictions for higher EMSAM® doses could lead to confusion for
patients who are titrating 20 mg to 30 mg and 40 mg doses, and could discourage some
from using EMSAM®. More safety data on higher EMSAM® doses should be gathered,
so that the dietary warning can be appropriately interpreted. Studies that compare
EMSAM® with conventional antidepressant medications would also be beneficial.
References:
1.
Bristol-Myers Squibb and Somerset Pharmaceuticals enter into agreement to distribute and commercialize Emsam, investigational transdermal treatment for major depressive disorder [news release].
New York: Bristol-Myers Squibb; 2004 Dec 22. Available:
http://www.selegiline.com/article/emsam.html (accessed 2005 Dec 15).
2.
Psychopharmacologic Drugs Advisory Committee, U.S. Food and Drug Administration. EMSAM®
selegiline transdermal system: NDA 21,336/21,708 [FDA briefing information]. Rockville (MD): The
Committee; 2005 Oct 26. Available: http://www.fda.gov/ohrms/dockets/ac/05/briefing/20054186B2_01_01_Somerset-EMSAM.pdf (accessed 2005 Dec 30).
3.
Mylan Laboratories and Watson Pharmaceuticals announce receipt of "Approvable" letter for Emsam
[news release]. Canonsburg (PA): Mylan Laboratories Inc.; 2004 Feb 2. Available: http://mylan.mediaroom.com/index.php?s=press_releases&item=124 (accessed 2005 Dec 15).
4.
Mahmood I. Selegiline transdermal system: Somerset. Curr Opin Investig Drugs 2002;3(8):1230-3.
5.
Amsterdam JD, Chopra M. Monoamine oxidase inhibitors revisited. Psychiatr Ann 2001;31(6):361-70.
6.
Diagnostic and statistical manual of mental disorders: DSM-IV-TR. 4th ed., text revision.
Washington: American Psychiatric Association; 2000.
7.
Remick RA. Diagnosis and management of depression in primary care: a clinical update and review.
CMAJ 2002;167(11):1253-60. Available: http://www.cmaj.ca/cgi/content/full/167/11/1253 (accessed
2006 Jan).
8.
Guidelines and Protocols Advisory Committee. Diagnosis and management of major depressive disorder. Victoria: B.C. Ministry of Health; 2004. Available: http://www.healthservices.gov.bc.ca/msp/protoguides/gps/depression.pdf (accessed 2005 Dec 15).
9.
Bodkin JA, Amsterdam JD. Transdermal selegiline in major depression: a double-blind, placebo-controlled, parallel-group study in outpatients. Am J Psychiatry 2002;159(11):1869-75. Available:
http://ajp.psychiatryonline.org/cgi/reprint/159/11/1869 (accessed 2005 Dec 5).
10. Amsterdam JD. A double-blind, placebo-controlled trial of the safety and efficacy of selegiline transdermal system without dietary restrictions in patients with major depressive disorder. J Clin Psychiatry
2003;64(2):208-14.
11. Mechcatie E. FDA panel backs selegiline patch for depression: majority view 20-mg formulation as
safe. Clin Psychiatry News 2005;33(12):1,10. Available: http://www.clinicalpsychiatrynews.com/article/PIIS0270664405710158/fulltext (accessed 2005 Dec 17).
12. Pauporte M, Azzaro AJ, Moonsammy G, Maibach H. Selegiline transdermal system (STS):
Assessments of dermal safety in human. J Toxicol Cutaneous Ocul Toxicol 2004;23(3):179-87.
The Canadian Coordinating Office for Health Technology Assessment (CCOHTA)
is funded by Canadian federal, provincial and territorial governments. (www.ccohta.ca)
Emerging Drug List
SELEGILINE TRANSDERMAL PATCH
CANADIAN COORDINATING
OFFICE FOR HEALTH
TECHNOLOGY ASSESSMENT
13. Barrett JS, Hochadel TJ, Morales RJ, Rohatagi S, DeWitt KE, Watson SK, et al. Pharmacokinetics and
safety of a selegiline transdermal system relative to single-dose oral administration in the elderly. Am J
Ther 1996;3(10):688-98.
14. Murphy M, Carmichael AJ. Transdermal drug delivery systems and skin sensitivity reactions.
Incidence and management. Am J Clin Dermatol 2000;1(6):361-8.
This series highlights medical technologies that are not yet in widespread use in Canada and that may have a
significant impact on health care. The contents are based on information from early experience with the
technology; however, further evidence may become available in the future. These summaries are not intended
to replace professional medical advice. They are compiled as an information service for those involved in
planning and providing health care in Canada.
These summaries have not been externally peer reviewed.
Production of this report is made possible by financial contributions from Health Canada and the governments
of Alberta, British Columbia, Manitoba, New Brunswick, Newfoundland and Labrador, Northwest Territories,
Nova Scotia, Nunavut, Ontario, Prince Edward Island, Québec, Saskatchewan, and Yukon. The Canadian
Coordinating Office for Health Technology Assessment takes sole responsibility for the final form and content
of this report. The views expressed herein do not necessarily represent the views of Health Canada or any
provincial or territorial government.
ISSN 1496-8398 (online only)
The Canadian Coordinating Office for Health Technology Assessment (CCOHTA)
is funded by Canadian federal, provincial and territorial governments. (www.ccohta.ca)