Posted by jrbecker on February 28, 2006, at 8:11:40
http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/02-28-2006/0004308046&EDATE=
U.S. Food and Drug Administration Approves EMSAM(R) (selegiline transdermal system), the First Transdermal Patch for the Treatment of Major Depressive Disorder
Clinical Trials Showed Significant Improvement in Depressive Symptoms;
No Tyramine Dietary Modifications Required at the Starting & Target Dose of
6 Milligram (mg)/24 hour (hr); Tyramine Dietary Modifications Required at
9 mg/24 hr and 12 mg/24 hr DosesPRINCETON, N.J. and TAMPA, Fla., Feb. 28 /PRNewswire-FirstCall/ --
Bristol-Myers Squibb Company (NYSE: BMY) and Somerset Pharmaceuticals, Inc., a
joint venture between Mylan Laboratories Inc. (NYSE: MYL) and Watson
Pharmaceuticals, Inc., (NYSE: WPI), announced today that the U.S. Food and
Drug Administration (FDA) approved EMSAM(R) (selegiline transdermal system),
the first transdermal patch for the treatment of major depressive disorder
(MDD) in adults. EMSAM, a transdermal delivery system manufactured by Mylan
Technologies, Inc. for Somerset, is a monoamine oxidase inhibitor (MAOI) that
has been shown to relieve depressive symptoms in patients with MDD.
"We are pleased to be able to provide this important treatment to people
with major depressive disorder," said Peter R. Dolan, chief executive officer,
Bristol-Myers Squibb Company. "We believe EMSAM will help physicians treat
their patients living with this illness through a new and unique delivery
system."
"Together with Bristol-Myers Squibb, we are excited to be able to utilize
transdermal technology to administer EMSAM, belonging to the MAOI class of
agents that have proven antidepressant efficacy," said Mel Sharoky, M.D.,
president and chief executive officer, Somerset Pharmaceuticals.About Monoamine Oxidase Inhibitors (MAOIs)
Although their mechanisms of action are not fully understood, MAOIs,
including EMSAM, are presumed to work through potentiation of monoamine
neurotransmitter activity in the brain by inhibiting the MAO enzyme. In an in
vivo animal model, EMSAM exhibited antidepressant properties only at doses
that inhibited both MAO-A and MAO-B in the brain. In the brain, MAO-A and MAO-
B play important roles in the breakdown of neurotransmitter amines such as
norepinephrine, dopamine and serotonin.
Oral MAOI antidepressants pass through the digestive tract, thus
inhibiting intestinal MAO-A, which is needed to break down tyramine,(1) a
substance found in certain foods and beverages such as aged cheese and tap
beer.(2) If a large amount of tyramine is absorbed systemically it can lead
to a sudden and large increase in blood pressure called a hypertensive crisis,
which is potentially life-threatening and requires immediate medical
treatment. While most foods contain negligible amounts or no tyramine, a few
food products may contain large amounts of tyramine that represent a potential
risk for patients with significant inhibition of intestinal MAO-A resulting
from administration of MAO inhibitors. As a result, patients taking oral
MAOIs for MDD are required to avoid foods high in tyramine.(3)About Transdermal Delivery of EMSAM
Through transdermal delivery, EMSAM is directly and continuously absorbed
into the bloodstream over a 24-hour period. As a result, initial exposure of
the drug to the digestive tract is minimized. As indicated in animal studies,
the EMSAM 6 mg/24 hr patch allows for levels of medicine to inhibit MAO in the
brain thought to be necessary for antidepressant effect while sufficiently
preserving MAO-A in the digestive tract to break down tyramine. In its
entirety, the data for EMSAM 6 mg/24 hr support the recommendation that
tyramine dietary modifications are not needed. To reduce the risk of
hypertensive crisis, dietary modifications are required with the EMSAM
9 mg/24 hr patch and the 12 mg/24 hr patch.Clinical Studies
The efficacy of EMSAM in relieving depressive symptoms was established in
two double-blind, placebo-controlled studies of six- (N=176) and eight-
(N=265) week durations that included adult outpatients ages 18- to 70-years-
old with single and recurrent episodes of MDD. The antidepressant action of
EMSAM in hospitalized depressed patients has not been studied.
The six-week trial showed that a 6 mg/24 hr dose of EMSAM was
significantly more effective than placebo in improving depressive symptoms as
determined using the 17-item Hamilton Depression Rating Scale (HAM-D).
In the eight-week dose titration trial, patients with major depressive
disorder who received EMSAM or placebo at a starting dose of 6 mg/24 hr, with
possible increases to 9 mg/24 hr or 12 mg/24 hr based on clinical response,
showed significant improvement compared with placebo on the primary outcome
measure, the 28-item HAM-D total score.
The benefit of maintaining patients with MDD on therapy with EMSAM after
achieving a responder status for an average of 25 days was demonstrated in a
controlled clinical trial. Three hundred twenty-two patients with major
depressive disorder who had responded to EMSAM 6 mg/24 hr during an initial
10-week open-label treatment phase were randomized either to continuation of
EMSAM 6 mg/24 hr (n=159), or to placebo (n=163) under double-blind conditions
for observation of relapse. Approximately 52 percent of the EMSAM-treated
patients as well as about 52 percent of the placebo-treated patients had
discontinued treatment by week 12 of the double-blind phase. Patients
continually receiving EMSAM experienced a significantly longer time to
relapse.
"Using an innovative antidepressant delivery system, EMSAM provides
significant relief of depressive symptoms with demonstrated safety and
tolerability," said Alexander Bodkin, M.D., Chief of the Clinical
Psychopharmacology Research Program at Harvard University-affiliated McLean
Hospital. "Major depressive disorder is a serious illness and not all
treatments work equally well in all patients. The FDA approval of EMSAM is
important because it adds another valuable treatment option to our
armamentarium."
In clinical trials with EMSAM, application site reaction was the most
commonly reported adverse event (EMSAM, 24 percent; placebo, 12 percent).
Most were mild to moderate in severity with only two percent resulting in
discontinuation. Overall, the rate of discontinuation due to adverse events
was low (EMSAM 7.1 percent; placebo 3.6 percent). Additionally, EMSAM
patients reported sexual dysfunction at a rate similar to placebo and
experienced minimal weight change (mean weight change from baseline: EMSAM
-1.2 lbs.; placebo +0.3 lbs.)Dosing and Dietary Modifications
The recommended starting and target dose of EMSAM is one 6 mg/24 hr patch
administered once daily without tyramine dietary modifications. EMSAM will
also be available in 9 mg/24 hr and 12 mg/24 hr once-daily doses (one patch
per day). The trials were not designed to assess if higher doses are more
effective than the starting and target dose of 6 mg/24 hr. To reduce the risk
of hypertensive crisis, which is potentially life-threatening, foods and
beverages high in tyramine must be avoided while on EMSAM 9 mg/24 hr or
12 mg/24 hr, and for two weeks following discontinuation of EMSAM at these
doses or reducing the dose to EMSAM 6 mg/24 hr. Patients should be instructed
to inform all of their healthcare professionals that they are using EMSAM, and
not to stop or change treatment with EMSAM without consulting their healthcare
professional.Important Safety Information
Antidepressants increased the risk of suicidal thinking and behavior
(suicidality) in short-term studies in children and adolescents with major
depressive disorder (MDD) and other psychiatric disorders. All pediatric
patients being treated with antidepressants for any indication should be
observed closely for clinical worsening, suicidality, or unusual changes in
behavior, especially during the initial few months of a course of drug
therapy, or at time of dose changes, either increases or decreases. Families
and caregivers should be advised for the need for close observation and
communication with the prescriber. EMSAM is not approved for use in pediatric
patients (see Boxed WARNING).
Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of
nine antidepressant drugs (SSRIs and others) in children and adolescents with
major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other
psychiatric disorders (a total of 24 trials involving over 4,400 patients)
have revealed a greater risk of adverse events representing suicidal thinking
and behavior (suicidality) during the first few months of treatment in those
receiving antidepressants. The average risk of such events in patients
receiving antidepressants was 4 percent, twice the placebo risk of 2 percent.
No suicides occurred in these trials.
To reduce the risk of hypertensive crisis, which is potentially life-
threatening, foods and beverages high in tyramine must be avoided while on
EMSAM 9 mg/24 hr or 12 mg/24 hr, and for two weeks following discontinuation
of EMSAM at these doses or reducing the dose to EMSAM 6 mg/24 hr.
Due to the potential for serotonin syndrome, which is potentially life-
threatening, EMSAM should not be used with the following antidepressants:
selective serotonin reuptake inhibitors (SSRIs), dual serotonin and
norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs),
monoamine oxidase inhibitors (MAOIs), mirtazapine, and bupropion; meperidine
and analgesics such as tramadol, methadone, propoxyphene, and pentazocine; the
antitussive dextromethorphan; cyclobenzaprine; oral selegiline; and
St. John's wort.
After stopping treatment with SSRIs, SNRIs, TCAs, MAOIs, mirtazapine,
bupropion; meperidine and analgesics such as: tramadol, methadone, and
propoxyphene; dextromethophan; St. John's wort; and buspirone, approximately 1
week (5 weeks for fluoxetine) should elapse before starting therapy with
EMSAM. At least 2 weeks should elapse after stopping EMSAM before starting
therapy with buspirone or a drug that is contraindicated with EMSAM.
Carbamazepine and oxcarbazepine are contraindicated in patients taking MAO
inhibitors, including EMSAM.
The use of EMSAM is contraindicated for use with sympathomimetic amines,
including amphetamines as well as cold products and weight-reducing
preparations that contain vasoconstrictors (eg, pseudoephedrine,
phenylephrine, phenylpropanolamine, and ephedrine).
Patients taking EMSAM should not undergo elective surgery requiring
general anesthesia or be given local anesthesia containing sympathomimetic
vasoconstrictors.
EMSAM should not be used in the presence of pheochromocytoma since such
tumors secrete pressor substances.
Adults with MDD or co-morbid depression in the setting of other
psychiatric illness being treated with antidepressants should be observed for
clinical worsening and suicidality, especially during the initial few months
of a course of drug therapy, or at times of dose changes, either increases or
decreases.
Risk of bipolar disorder should be ruled out prior to initiating
antidepressant therapy. EMSAM is not approved for the treatment of bipolar
depression.
Due to the potential for elevated blood pressure, the use of EMSAM with
buspirone is not recommended.
As with other MAOIs, postural hypotension can occur with EMSAM therapy.
Dose increases in the elderly should be made with caution and patients should
be observed closely for postural changes in blood pressure throughout
treatment.
EMSAM should be used with caution in patients with certain concomitant
systemic illnesses that can produce altered metabolism or hemodynamic
responses.
As with other psychoactive drugs, EMSAM may have the potential to impair
judgment, thinking, or motor skills. Patients should not drive or operate
hazardous machinery until they are certain EMSAM does not impair their ability
to engage in such activities.
The use of alcohol is not recommended while taking EMSAM.
EMSAM should not be used in combination with tyramine-containing
nutritional supplements.
EMSAM should be used in pregnancy only if the potential benefit justifies
the potential risk to the fetus. Caution should be exercised when
administering EMSAM to a nursing mother.
EMSAM is contraindicated in patients with known hypersensitivity to
selegiline or to any component of the transdermal system.
Treatment-emergent adverse events in short-term clinical trials that
occurred at a greater than or equal to 2 percent incidence with EMSAM and for
which the incidence was greater than placebo include: application site
reaction (24% vs 12%), headache (18% vs 17%), insomnia (12% vs 7%), diarrhea
(9% vs 7%), dry mouth (8% vs 6%), dyspepsia (4% vs 3%), rash (4% vs 2%),
pharyngitis (3% vs 2%), and sinusitis (3% vs 1%).
FULL PRESCRIBING INFORMATION including Boxed WARNING for EMSAM can be
found at http://www.bms.com.About Major Depression
According to the DSM-IV diagnosis, major depressive disorder is
characterized by one or more major depressive episodes, (i.e., at least two
weeks of depressed mood or loss of interest accompanied by at least four
additional symptoms of depression)(4) and impairs social and occupational or
other important areas of functioning.(4) Major depression affects
approximately 14 million American adults in a given year(5) and is the most
common mental health disorder after anxiety.(6) It is a leading cause of
disability and disease burden worldwide.(7)
The illness is one and a half to three times more common among people with
a family history than among the general population,(4) and studies indicate
that depressive episodes occur twice as frequently in women as in men.(4)
Today many patients with MDD do not achieve adequate symptom relief.(8)
If depression is not treated successfully, the chances that it will become
recurrent increase.(8) More than 80 percent of patients who have one episode
of MDD will have at least one subsequent episode.(9)Bristol-Myers Squibb and Somerset Pharmaceuticals, Inc.
EMSAM was developed by Somerset Pharmaceuticals, Inc. In December 2004,
Bristol-Myers Squibb and Somerset entered into an agreement that provides
Bristol-Myers Squibb with exclusive distribution rights to commercialize EMSAM
after approval in the United States and Canada.About Bristol-Myers Squibb
Bristol-Myers Squibb is a global pharmaceutical and related health care
products company whose mission is to extend and enhance human life. Visit
Bristol-Myers Squibb at http://www.bms.com.About Somerset Pharmaceuticals, Inc.
Somerset Pharmaceuticals, Inc. is a joint venture between Mylan
Laboratories Inc. (NYSE: MYL) and Watson Pharmaceuticals, Inc. (NYSE: WPI).
For more information about Somerset, visit http://www.somersetpharm.com.(1) Youdim, MBH. Therapeutic Applications of Selective and Non-Selective
Inhibitors of Monoamine Oxidase A and B that do not Cause Significant
Tyramine Potentiation, Neuro Toxicology, 2003: 25. P. 243-250
(2) Shulman KI, Walker SE. Psychiatric Annals. A Reevaluation of
Dietary Restrictions for Irreversible Monoamine Oxidase Inhibitors.
Psychiatric Annals, June 2001, 31:6;378-384.
(3) Kennedy SH, McKenna KF, Baker GB. Monamine Oxidase Inhibitors. In:
Sadock BJ, Sadock BA. Kaplan & Sadock's Comprehensive Textbook of
Psychiatry, 7th Edition. New York, NY: Lippincott, Williams &
Wilkins; 2000: 2398-2406.
(4) Diagnostic and Statistical Manual of Mental Disorders. Fourth ed.
Washington, DC. American Psychiatric Association; 1994.
(5) Kessler RC, Berglund P, Demler O, et al. The Epidemiology of Major
Depressive Disorder: Results from the National Comorbidity Survey
Replication (NCS-R). Journal of the American Medical Association
(JAMA), 2003; 289(23);3095-3105. P. 3099.
(6) Merck Manual of Medical Information - Second Home Edition. Whitehouse
Station, NJ: Merck Research Laboratories; Copyright (c) 1995-2005
Merck & Co.
(7) Ustun TB, et al. Global Burden of Depressive Disorders. British J
Psychiatry. 2004; 184. 386-392.
(8) Greden, JF. Unmet Need: What Justifies the Search for a New
Antidepressant? J Clin Psychiatry, 2002;63
(suppl. 2), 3-6.
(9) Hirschfeld RMA. Clinical Importance of Long-Term Antidepressant
Treatment. British J Psychiatry. 2001; 179 (suppl. 42): s4-s8.SOURCE Bristol-Myers Squibb Company; Somerset Pharmaceuticals,
Inc. Web Site: http://www.bms.com
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thread:613836
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