Ramelteon is a selective MT1 and MT2 agonist that is

approved for the medical treatment of insomnia. This drug has

no addiction liability (it is not a controlled substance), and it
appears to be distinctly more efficacious than melatonin (but
less efficacious than benzodiazepines) as a hypnotic. It is metabolized by P450 enzymes and should
not be used in individuals
taking CYP1A2 inhibitors. It has a half-life of 13 hours and an
active metabolite with a half-life of up to 5 hours. The toxicity of
ramelteon is as yet poorly defined, but prolactin levels were
elevated in one clinical trial.

Melatonin receptors are thought to be involved in maintaining circadian rhythms underlying the sleep-
wake cycle (see
Chapter 16 ). Ramelteon (Rozerem), a novel hypnotic drug
specifically useful for patients who have difficulty in falling
asleep, is an agonist at MT1 and MT2 melatonin receptors
located in the suprachiasmatic nuclei of the brain. The drug
has no direct effects on GABAergic neurotransmission in the
central nervous system. In polysomnography studies of
patients with chronic insomnia, ramelteon reduced the
latency of persistent sleep with no effects on sleep architecture and no rebound insomnia or significant
withdrawal
symptoms. Ramelteon has minimal potential for abuse, is not
a controlled substance, and regular use does not result in
dependence. The drug is rapidly absorbed after oral administration and undergoes extensive first-pass
metabolism, forming an active metabolite with longer half-life (25 hours) than
the parent drug. The CYP1A2 isoform of cytochrome P450 is
mainly responsible for the metabolism of ramelteon, but the
CYP2C9 isoform is also involved. The drug should not be used
in combination with inhibitors of CYP1A2 (eg, ciprofloxacin,
fluvoxamine, tacrine, zileuton) or CYP2C9 (eg, fluconazole)
and should be used with caution in patients with liver dysfunction. The CYP inducer rifampin markedly
reduces the
plasma levels of both ramelteon and its active metabolite.
Adverse effects of ramelteon include dizziness, somnolence,
fatigue, and endocrine changes as well as decreases in testosterone and increases in prolactin.
Ramelteon is an FDA pregnancy category C drug