Pharmacokinetic and Safety of Ramelteon Between Adolescents With Insomnia and Healthy Adults

Ramelteon is a treatment for insomnia approved for use in the United States (US) in July
2005 and in the Philippines and Indonesia in 2008. It is currently under development in the
European Union (EU) and Japan. Ramelteon is marketed in the US as ROZEREM® for the treatment
of insomnia characterized by difficulty with sleep onset in patients over 18 years of age.

In adolescents, the form of sleep onset and/or sleep maintenance insomnia, defined as
psychophysiologic insomnia, is similar to adults, and more appropriate for treatment with
pharmacological intervention when compared to insomnia in children younger than 12 years of
age. In psychophysiologic insomnia, the individual develops conditioned anxiety around
difficulty falling or staying asleep, which leads to heightened physiologic and emotional
arousal and further compromises the ability to sleep. In children over the age of 12,
insomnia is more likely to be persistent and have identifiable consequences. In addition,
there is less variability in normative sleep data for this age group than in younger
children.

Sleep disturbances are also common in children. Specifically, insomnia associated with ADHD
in children is very common with a reported prevalence of 28% in medication-free children
with ADHD.

This study is to characterize the pharmacokinetics (PK) and safety profile of a 4 or 8 mg
dose of ramelteon in adolescents who are between 12 to 17 years of age (prior to the 18th
birthday) with insomnia characterized by difficulty with sleep initiation, and in pediatrics
who are between 6 to 11 years of age who have insomnia associated with ADHD. These profiles
will be compared with those of healthy adult subjects aged 18 to 50 years who are matched by
race and gender receiving an 8 mg dose of ramelteon. This open-label study is designed in
accordance with the recommendations of the FDA and ICH guidances for pediatric PK studies.