Lundbeck has entered the sleep disorder market in Eastern Europe with three consecutive launches of first in class insomnia medication, Circadin® in Poland, Hungary and Czech Republic. Circadin®, a sustained-release melatonin, is indicated as monotherapy for the short-term treatment of primary insomnia in patients who are aged 55 or over.1

Primary insomnia, or insomnia with no underlying cause or medical condition, affects up to 10% of the general population, increasing to 25% in the elderly.2 Melatonin is the naturally occurring hormone that is key to regulating the sleep-wake cycle (or circadian rhythm).3 The production of melatonin in the body decreases as we age and this is thought to be linked to the increasing prevalence of insomnia among the elderly.

Circadin®, the first melatonin agent approved by the European Medicines Agency (EMEA) represents a new therapeutic principle in insomnia treatment. It's sustained-release formulation was specifically designed to ensure gradual melatonin release throughout the night, mimicking the body's natural release of melatonin resulting in the resetting of natural circadian rhythms and the encouragement of restorative, quality sleep.1 Unlike existing sleep medications, Circadin is not associated with problems such as dependency and poor next day functioning.4

Data have shown that insomnia can have a negative impact on many areas of patients' lives, including health, relationships, family life and work life. Sleep deprivation is associated with psychological disorders, including depression as well as decreased immune function and cardiovascular disease.5,6,7,8,9

"Insomnia is a debilitating condition that can have a devastating impact on a person's general health, well-being and quality of life with huge societal and economic implications and yet is still under-diagnosed and under-treated," said Vice President Dierk Schoch, head of Strategic Marketing. "Circadin is an exciting new direction in insomnia treatment and the continued launches across Europe and our future plans for Circadin in Asian and South American markets demonstrate our commitment to tackling insomnia globally."

The importance of quality sleep

Traditionally insomnia has been diagnosed on the basis of quantity of sleep - i.e. how long it takes to get to sleep or how long a person sleeps for. While it is important not to ignore quantity of sleep, this is a matter of individual need. What matters to all patients, regardless of the amount of sleep they need, is quality of sleep. It is the quality of sleep which results in morning alertness, improved functioning the following day and better quality of life. Circadin® is the first sleep drug with proven efficacy on all these parameters.4

Efficacy of Circadin® in clinical trials

Circadin® has proved to be an effective treatment in clinical studies for over 55s with primary insomnia.10

The trials showed that almost half of patients taking Circadin® experienced a significant improvement in quality of sleep, and nearly 40% improved on morning alertness, as measured by the Leeds Sleep Evaluation Questionnaire.10

This is important in the treatment of insomnia because improvements in sleep quality, rather than quantity, translate into greater improvements to next day functioning and quality of life.10 In fact 70% of patients responding to Circadin® on both quality of sleep and morning alertness reported a significant improvement in quality of life as measured by the WHO-5 well-being scale.2

Other study endpoints included sleep latency (or time to get to sleep), and a clinically significant reduction in time was found in the Circadin® group, similar to that of traditional sleep medications.2

Circadin® mode of action avoids side effects associated with traditional sleep treatments2

Although much of the outcomes of insomnia derive from the extent to which it impairs daytime functioning, insomnia drugs have been approved on the basis of improvements in sleep induction and/or maintenance but not in sleep quality and next day performance.11 Paradoxically current sleep treatments are associated with adverse reactions such as daytime sedation (or 'hang over'), impaired memory, driving skills and concentration. Furthermore, abrupt withdrawal of benzodiazepine hypnotics is associated with a return of insomnia worse than before (rebound insomnia), and they are also known to carry a risk of dependency.12, 6

However, clinical studies with Circadin® have not shown any risk of rebound insomnia nor any impairment on memory or psychomotor functioning at any point after dosing.1

Circadin® has a positive safety profile and in clinical studies the incidence of adverse events with Circadin® was low and even less than with placebo.1 Adverse effects were generally mild and infrequent and those reported included headache, sore throat, back pain and generalised feelings of weakness.1

About insomnia

Insomnia is the most common sleep disorder and is characterised by difficulty falling asleep, difficulty in maintaining sleep, non-restorative sleep or of poor sleep resulting in poor next day functioning.2 It is estimated that between 30 and 45% percent of the world's population suffers from insomnia.2 The condition can present as primary or secondary insomnia. Primary insomnia is where no other reason for the condition is identified; secondary insomnia occurs when a physical or mental condition or problem causes an inability to sleep (for example pain, anxiety). Some experts recommend using the term "comorbid insomnia" rather than secondary insomnia because13, 14 of the difficulty in establishing causality.14 The prevalence of primary insomnia increases with age and affects up to 25 percent of the elderly population.2 The increase in prevalence is associated with the decrease in melatonin that occurs with age.

About melatonin

Melatonin is a naturally occurring hormone that regulates the circadian rhythm in humans and animals. It is the signal of night and day, and of sleep and awake time.8 Circadian rhythm is often referred to as the 'body clock'. In the evening, the retina of the eye responds to the fading light and signals a small gland in the brain called the pineal gland to release melatonin. Melatonin levels peak in the middle of the night, and then slowly decline until morning, ensuring restorative sleep throughout the night.15

As a person grows older, the night-time production of melatonin tends to decrease, and the levels of melatonin in elderly people with insomnia are lower than in healthy persons. As the prevalence of insomnia increases with age, it appears that insomnia in elderly people may be caused by this reduced melatonin secretion, as opposed to simply age alone.16 Circadin® mimics this pattern of melatonin release throughout the night to promote restorative sleep with no evidence of impairment on next day functioning.11

About Circadin®

Circadin® was approved via the central procedure of the European Commission on 29th June 2007, and indicated as monotherapy for the short-term treatment of primary insomnia characterised by poor quality of sleep in patients who are aged 55 or over. Circadin® is the approved trade name in the whole EU. Lundbeck holds commercialisation rights to Spain, Germany, UK, Italy, France, Ireland, Portugal, Poland, Hungary, Romania, Czech Republic, Slovak Republic, Slovenia, Bulgaria, Cyprus, Malta and Liechtenstein, representing 75% of the market potential in Europe. Lundbeck also holds exclusive rights to commercialise Circadin® in Asia, Latin America and other major markets such as Australia and Turkey. Following regulatory filing and approval Lundbeck expects to market Circadin® in the first markets outside Europe in 2009.

Nycomed holds the commercialisation rights to the remaining markets in Europe. At the end of February 2008, Circadin® had been launched by Nycomed in Austria, Belgium, Denmark, Estonia, Finland, Greece, Iceland, Latvia, Lithuania, and Norway.

About Lundbeck

H. Lundbeck A/S is an international pharmaceutical company engaged in the research and development, production, marketing and sale of drugs for the treatment of psychiatric and neurological disorders. In 2006, the company's revenue was DKK 9.2 billion (approximately EUR 1.2 billion or USD 1.6 billion). The number of employees is approximately 5,300 globally. For further information, please visit lundbeck.

References

1. Circadin®, Summary of Product Characteristics emea.europa.eu/humandocs/PDFs/EPAR/Circadin®/H-695-en6.pdf last accessed 16 April 2008.

2. Wade et al. Prolonged-release melatonin for the treatment of insomnia: Targeting quality of sleep and morning alertness. Ageing Health 2008; 4(1): 11-21

3. Zisapel et al. Sleep and sleep disturbances; biological basis and clinical implications. Cell Mol Life Sci 2007; 64: 1174-1186

4. Wade et al. Efficacy of prolonged release melatonin in insomnia patients ages 55-80 years: quality of sleep and next day alertness. Curr Med Opin 2007:23(10); 2597-2605

5. L├ęger D, Poursain B, Neubauer D et al. An international survey of sleeping problems in the general population. Curr Med Res Opin 2008; 24(1): 307-317

6. Taylor DJ, Lichstein KL, Durrence HH. Insomnia as a health risk factor. Behav Sleep Med 2003; 1: 227-247

7. Ohayon MM, Zulley J. Correlates of global sleep dissatisfaction in the German population. Sleep 2001; 24: 780-787

8. Okuji Y, Matsuura M, Kawasaki N et al. Prevalence of insomnia in various psychiatric diagnostic categories. Psychiatry Clin Neurosci 2002; 56: 239-240

9. Katz DA, McHorney CA. Clinical correlates of insomnia in patients with chronic illness. Arch Intern Med 1998; 158: 1099-107

10. Lemoineet al. Prolonged release melatonin improves sleep quality and morning alertness in insomnia patients aged 55 and older and has no withdrawal effects. J Sleep Res 2007; 16: 372-380

11. Krystal, A. D. Treating the health, quality of life, and functional impairments in insomnia. J. Clin. Sleep. Med., 2007, 3: 63-72

12. Waldhauser F, Weiszenbacher G, Tatzer E et al. Alteration in nocturnal serum melatonin levels in humans with growth and ageing. J Clin Endocrinol Metab 1988; 66(3): 648-652

13. National Institutes of Health, National Institutes of Health State of the Science Conference statement on Manifestations and Management of Chronic Insomnia in Adults, Sleep, 2005; 66:10-13

14. Buysse D. J., Chronic Insomnia, Am. J. Psichiatry 165:6; June 2008

15. Lewey et al. Light suppresses melatonin secretions in humans. Science 1980; 210(4775): 1267-1269

16. Mahlberg R et al. Normative data on the daily profile of urinary 6-sulfatoxymelatonin in healthy subjects between the ages of 20 and 84. Psychoneuroendocrinology. 2006 Jun;21(5):634-41. Epub 2006 Apr 3.

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