The U.S. Food and Drug Administration late last month granted final
approval to ramelteon, the first insomnia medication in 35 years to offer a
unique mechanism of action that allows long-term use and is not designated as
a controlled substance by the Drug Enforcement Administration.
The drug will be marketed in the United States as Rozerem (rose-AIR-em) by
Takeda Pharmaceuticals North America Inc. It should be on pharmacy shelves in
September, a Takeda spokesperson confirmed. While pricing is expected to be"
competitive," it had not been set at press time.
Ramelteon was approved by the FDA "for the treatment of insomnia
characterized by difficulty with sleep onset" in those aged 18 and
"Rozerem represents a breakthrough in sleep medicine because it is
truly a novel medication in terms of how it works," said Louis Mini,
M.D., medical director for neuroscience at Takeda Pharmaceuticals North
America, a subsidiary of Takeda Pharmaceutical Company of Japan. "It
approaches the treatment of insomnia in a completely different way from all
other currently available prescription agents."
According to FDA approval documents, ramelteon's most significant
characteristic is its "highly selective and specific receptor-binding
profile." The medication has a very high affinity for two specific
melatonin receptors, MT1 and MT2. While melatonin
receptors are found throughout the body, MT1 and MT2 are
localized in the brain's supra-chiasmatic nucleus (SCN)—a small group of
neurons in the hypothalamus referred to as the brain's "master
clock." Ramelteon has very low or no detectable affinity for virtually
all other receptors in the central nervous system.
This highly selective binding is in stark contrast to nearly all other
available insomnia medications, which target some component of the
GABA-A-benzodiazepine receptor complex. Binding to the GABA-A complex results
in sedation due to central nervous system depression.
However, the GABA-A complex is widespread throughout the CNS. The resulting
widespread sedation from CNS depression is associated with adverse effects
commonly seen with many sleep medications, including memory problems,
cognitive blunting, and the general "sleeping pill hangover."
In contrast, the FDA-approved labeling for ramelteon indicates the drug has
no detectable affinity for the GABA-A complex. Rather, by targeting the
MT1 and MT2 receptors in the brain's SCN, the drug is
aimed at regulating the brain's intrinsic sleep-wake cycle.
"As the day goes on," Mini explained, "an individual's
need for sleep—or `sleep load'—increases, reaching a peak
somewhere around 9 p.m. or 10 p.m., for most who are sleeping
However, people do not generally fall asleep as their sleep load increases,
Mini said, because the SCN balances that load with an "alerting
signal" that promotes wakefulness.
"In individuals who are sleeping normally, the body begins to produce
melatonin in response to the onset of darkness," Mini continued.
Melatonin binds to receptors throughout the central nervous system, including
the MT1 and MT2 receptors in the SCN. "When
melatonin binds to [these two] receptors, the alerting-signal is dampened,
allowing the accumulated sleep load to do its job, and the individual falls
By binding specifically and selectively to the melatonin receptors in the
SCN, ramelteon is thought to achieve the same end point: a reduction of the
brain's normal alerting signal and the promotion of sleep.
"While we've learned from the advances of understanding the science
of melatonin, this drug itself is not melatonin," Mini emphasized. The
drug's chemical structure is different from melatonin; the drug is "more
selective, specific, and potent" in its binding to MT1 and
MT2 receptors than the natural hormone. This would suggest that the
new medication might benefit even those with sleep-onset insomnia who may have
tried melatonin but saw no benefit.
The drug, however, is not likely to benefit patients with insomnia
characterized by multiple night-time awakenings. In clinical trials, Mini told
Psychiatric News, "total sleep time was increased, but when it
came to awakening after sleep onset, we did not show statistical
Ramelteon was discovered by scientists at Takeda's headquarters in Japan in
1996. The development program for the drug has been "extensive,"
including more than 100 preclinical studies and "43 clinical studies
involving more than 4,200 patients," Mini said.
Takeda studied the drug in specific populations, including the elderly, who
tend to be especially prone to side effects related to CNS depression, such as
memory problems and respiratory depression. Mini, who practiced geriatric
psychiatry prior to joining Takeda, said clinical trials showed the drug was
indeed effective in elderly patients. In addition, there were no differences
in the safety profile of the drug in the trials with elderly patients compared
with those in adults aged 18 to 65.
The company also studied the drug in elderly patients with chronic
obstructive pulmonary disease and patients with sleep apnea. Again,
researchers found no differences in either efficacy or safety. The
FDA-approved labeling discusses the use of ramelteon in both of these special
In phase IV postmarketing studies, the company plans to look also at the
safety and efficacy of the drug in patients with cognitive impairments,
including those with Alzheimer's disease. In addition, the FDA is requiring
Takeda to undertake pediatric efficacy and safety trials.
The recommended dosing for ramelteon is 8 mg taken 30 minutes before
bedtime. The FDA chemical and medical reviews of the drug indicate that
ramelteon is rapidly absorbed from the stomach and extensively broken down by
first-pass metabolism in the liver. Ramelteon should not be taken with foods
high in fat, which significantly decrease the drug's absorption.
Because the drug is metabolized mostly in the liver, approved labeling
advises physicians to prescribe the drug with caution to those with moderate
liver impairment and not at all to those with severe liver failure. Since
ramelteon is principally metabolized in the liver by the CYP1A2 enzyme, it
should not be used in conjunction with any known strong inhibitor of the
enzyme, such as fluvoxamine (Luvox).
In clinical trials of ramelteon, the most often reported adverse effects
that occurred more frequently and at a statistically significantly higher rate
than placebo were somnolence, fatigue, and dizziness.
At extremely high doses (roughly 200 times the approved dosage) in animal
studies the drug was shown to be a developmental teratogen. The drug is
classified as Pregnancy Category C by the FDA and therefore should be used in
women who are pregnant "only if the potential benefit justifies the
potential risk to the fetus."
Physicians are also cautioned in the approved labeling that the drug was
associated with increased serum prolactin levels in women during clinical
trials. Prolactin levels increased on average 34 percent in women taking the
drug compared with a 4 percent decrease in those on placebo. No differences in
serum prolactin were seen in male patients during clinical trials.
Complete prescribing information on ramelteon is posted online at<www.rozerem.com>.▪