Clinical and Research News
New Sleep Drug Binds To Melatonin Receptors
Psychiatric News
Volume 40 Number 16 page 14-21

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 older.

"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 normally."

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 asleep."

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 significance."


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 populations.

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>.

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