U.S. Food and Drug Administration Approves EMSAM(R) (selegiline transdermal system), the First Transdermal Patch for the Treatment of Major Depressive Disorder

PRINCETON, N.J. and TAMPA, Fla., Feb. 28 /PRNewswire-FirstCall/ -- Bristol-Myers Squibb Company and Somerset Pharmaceuticals, Inc., a joint venture between Mylan Laboratories Inc. and Watson Pharmaceuticals, Inc., , 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. and Watson Pharmaceuticals, Inc. . 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.

First Call Analyst: FCMN Contact: david.m.rosen@bms.com