U.S. Regulators Approve Cymbalta® For Treatment Of Generalised Anxiety Disorder

The U.S. Food and Drug Administration (FDA) has approved the antidepressant Cymbalta® (duloxetine HCl) for the treatment of generalised anxiety disorder (GAD), Eli Lilly and Company (NYSE: LLY) and Boehringer Ingelheim announced today.

The approval is based on the results of three randomized, double-blind, placebo-controlled studies in which the safety and efficacy of duloxetine in the treatment of GAD was studied in more than 800 non-depressed adults. In all studies, duloxetine significantly improved core anxiety symptoms as measured by the Hamilton Anxiety Scale (HAMA), compared with placebo.[i], [ii], [iii] In addition, duloxetine patients reported greater improvement in functional impairment associated with the illness, including improved ability to perform everyday activities at work, home, and in social situations.[iv], [v]

Duloxetine, a member of a class of drugs commonly referred to as serotonin and norepinephrine reuptake inhibitors (SNRI),[vi] was approved by Mexico for the treatment of GAD in October 2006. Lilly and Boehringer Ingelheim, which partner in the development and commercialization of duloxetine for neuroscience indications in most countries outside the United States and Japan, are evaluating further submissions in other regions, including Europe.

More than 7 million Europeans may have generalised anxiety disorder. [vii],[viii] Worldwide prevalence is not known. While anxiety is a symptom of many mental health disorders, including depression, GAD is more than simple anxiety. The essential feature of the disorder is excessive anxiety and worry about a number of events and activities (such as work or school performance), occurring for a majority of days for at least six months.[ix] Because GAD presents with a variety of symptoms, both anxious and physical, it can be difficult to diagnose[x] and may have a negative impact on a person's quality of life[xi] and ability to work.[xii] Symptoms can include exaggerated worry or chronic anxiety and irritability, which can lead to poor concentration and procrastination, as well as physical symptoms such as muscle tension, fatigue and nausea. Episodes of generalised anxiety disorder may be brought on, or worsened by, stressful life events. The illness also tends to be chronic with periods of exacerbation and remission.

In a pooled analysis of the three clinical trials supporting the approval, on average, patients treated with duloxetine for generalised anxiety disorder experienced a 46 percent improvement in anxiety symptoms compared with 32 percent for those who took placebo, as measured by the Hamilton Anxiety Scale (p<=0.001).[xiii], [xiv], [xv] In addition, patients in these studies experienced a 46 percent improvement in function, as measured by the Sheehan Disability Scale, compared with 26 percent for those who took placebo (p<=0.001).[xvi], [xvii] The most common side effects in these studies included nausea, fatigue, dry mouth, drowsiness, constipation, insomnia, decreased appetite, hyperhidrosis, decreased libido, vomiting, ejaculation delay and erectile dysfunction.

About Duloxetine

Duloxetine is believed to potentiate both serotonin and norepinephrine/noradrenaline in the brain and the spinal cord, impacting nerve signaling. Based on pre-clinical studies, duloxetine is a balanced and potent reuptake inhibitor of serotonin and norepinephrine/noradrenaline. While the mechanism of action of duloxetine in humans is not fully known, scientists believe its effect on pain perception is due to increasing the activity of serotonin and noradrenaline in the central nervous system.

Duloxetine is approved for the treatment of depression and diabetic peripheral neuropathic pain in many countries and is approved in some countries for the treatment of stress urinary incontinence. Duloxetine is approved only for adults 18 and over. In children and teens, antidepressants can increase the risk of suicidal thoughts or actions. Patients should call their doctor right away if they experience worsening depression symptoms, unusual changes in behavior or thoughts of suicide, especially at the beginning of treatment or after a change in dose.

The most commonly reported adverse reactions in patients with depression treated with duloxetine in clinical trials were headache, nausea, dry mouth and constipation. However, the majority of common adverse reactions were mild to moderate, they usually started early in therapy and most tended to subside even as therapy was continued. The most commonly observed adverse reactions in patients with diabetic neuropathic pain treated with duloxetine were: nausea; somnolence; dizziness; and headache.

Duloxetine is contraindicated in patients who are allergic to it, who have liver disease resulting in hepatic impairment, who are taking a monoamine oxidase inhibitor (MAOI), fluvoxamine, ciprofloxacin or enoxacine or who have severe kidney disease.

Eli Lilly and Company and Boehringer Ingelheim

In November 2002, Eli Lilly and Company and Boehringer Ingelheim signed a long-term agreement to jointly develop and commercialize duloxetine hydrochloride. This partnership covers neuroscience indications in most countries outside of the United States and Japan, with few exceptions.

About Eli Lilly and Company

Lilly, a leading innovation-driven corporation, is developing a growing portfolio of best-in-class pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Ind., Lilly provides answers - through medicines and information - for some of the world's most urgent medical needs. Additional information about Lilly is available at http://www.lilly.com.

About Boehringer Ingelheim

The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 143 affiliates in 47 countries and almost 37,500 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine. In 2005, Boehringer Ingelheim posted net sales of 9.5 billion euro while spending almost one fifth of net sales in its largest business segment Prescription Medicines on research and development. For more information please visit http://www.boehringer-ingelheim.com.

Duloxetine for major depressive episodes is marketed by Lilly and Boehringer Ingelheim in all countries included in the partnership under the brand name Cymbalta, except for Greece, Italy and Spain. In Greece, Italy and Spain Lilly markets the product as Cymbalta and Boehringer Ingelheim markets the product as Xeristar®. In the United States, Cymbalta is marketed by Lilly and Quintiles. In Japan, duloxetine will be co-developed and co-marketed by Lilly and Shionogi & Co., Ltd.

Duloxetine for stress urinary incontinence is marketed by Lilly under the brand name Yentreve.®

[i] Koponen H., et al. Efficacy of Duloxetine for the Treatment of Generalized Anxiety Disorder: Implications for Primary Care Physicians. Primary Care Companion to The Journal of Clinical Psychiatry. In press 2007.
[ii] Rynn M., et al. Efficacy and Safety of Duloxetine in the Treatment of Generalized Anxiety Disorder: A Flexible-Dose, Progressive-Titration, Placebo-Controlled Trial. Depression and Anxiety. In press 2007.
[iii] Hartford J., et al. Duloxetine as an SNRI Treatment for Generalized Anxiety Disorder: Results from a Placebo- and Active-Controlled Trial. International Clinical Psychopharmacology. In press 2007.
[iv] Endicott J., et al. Duloxetine Treatment for Role Functioning Improvement in Generalized Anxiety Disorder: Three Independent Studies. The Journal of Clinical Psychiatry. In press 2007.
[v] Allgulander C., et al. Pharmacotherapy of Generalized Anxiety Disorder: Results of Duloxetine Treatment from a Pooled Analysis of 3 Clinical Trials. Current Medical Research and Opinion. In press 2007.
[vi] Bymaster, FP et al. "The Dual Transporter Inhibitor Duloxetine: A Review of its Preclinical Pharmacology, Pharmacokinetic Profile, and Clinical Results in Depression." Current Pharmaceutical Design. 2005; 11: 1475-1493.
[vii] Lieb R, Becker E and Altamura C. The epidemiology of generalised anxiety disorder in Europe. European Neuropsychopharmacology 2005 Aug;15(4):445-52.
[viii] National Institute of Economic and Social Research. Summarized from the National Institute Economic Review,194, 28 October 2005.
[ix] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, p 472.
[x] Gliatto, Michael, F. "Generalised Anxiety Disorder." American Family Physicians, Vol. 62/No. 7, October 1, 2000.
[xi] Mendlowicz, Maura V. and Stein, Murray B. "Quality of Life in Individuals with Anxiety Disorders." American Journal of Psychiatry, Vol. 157/No. 5, May 2000, pp 677-678
[xii] Eric R. Henning, M.A., Cynthia L. Turk, Ph.D. , Douglas S. Mennin, Ph.D. , David M. Fresco, Ph.D., Richard G. Heimberg, Ph.D. Impairment and quality of life in individuals with generalised anxiety disorder. Depression and Anxiety 2006 Nov:1091-4269
[xiii] Koponen H., et al. Efficacy of Duloxetine for the Treatment of Generalized Anxiety Disorder: Implications for Primary Care Physicians. Primary Care Companion to The Journal of Clinical Psychiatry. In press 2007.
[xiv] Rynn M., et al. Efficacy and Safety of Duloxetine in the Treatment of Generalized Anxiety Disorder: A Flexible-Dose, Progressive-Titration, Placebo-Controlled Trial. Depression and Anxiety. In press 2007.
[xv] Hartford J., et al. Duloxetine as an SNRI Treatment for Generalized Anxiety Disorder: Results from a Placebo- and Active-Controlled Trial. International Clinical Psychopharmacology. In press 2007.
[xvi] Endicott J., et al. Duloxetine Treatment for Role Functioning Improvement in Generalized Anxiety Disorder: Three Independent Studies. The Journal of Clinical Psychiatry. In press 2007.
[xvii] Allgulander C., et al. Pharmacotherapy of Generalized Anxiety Disorder: Results of Duloxetine Treatment from a Pooled Analysis of 3 Clinical Trials. Current Medical Research and Opinion. In press 2007.