Ramelteon (Rozerem): Roth et al.

1 Mar
2010

A double-blind study by Roth and colleagues evaluated the efficacy of ramel-teon in treating transient insomnia in healthy adults ranging from 35 to 60 years of age. Subjects received 16 mg, 64 mg, or placebo 30 minutes before bedtime. The study enrolled 375 patients from 14 sleep research centers in the U.S. The investigators used the “first night effect” model, which is characteristic of transient insomnia; this refers to insomnia that often occurs when someone is assessed in a sleep laboratory.

To be eligible for enrollment, participants had to report a customary total sleep duration of 6.5 to 8.5 hours, a usual sleep latency of 30 minutes or less, and a habitual bedtime between 8:30 p.m. and midnight. They also had to be within 20% of their ideal body weight and in good overall health, as determined by a medical history, a physical examination, clinical laboratory values, and a 12-lead ECG. pharmacy united kingdom

Patients were excluded from the study if they were pregnant or nursing, had an Epworth Sleepiness Scale score above 10, had changed their sleep schedule within the past three months, had flown across three or more time zones within the past seven days, had signs and symptoms of a primary sleep disorder, or had any physical or psychiatric disorder that could be associated with a disturbance in sleep.

All prescription medications and over-the-counter medications were discontinued for an equivalent of five half-lives before ramelteon or placebo was given.

Subjects were placed into two groups according to their reported sleep duration: 6.5 to 7.5 hours or 7.5 to 8.5 hours. They were then randomly assigned to one of three groups: ramelteon 64 mg (n = 126), ramelteon 16 mg (n = 126), or placebo (n = 123).

The subjects were instructed to refrain from alcohol and products containing caffeine for the six hours before their arrival at the sleep laboratory. They were to arrive 1.5 to 2 hours before their normal bedtime.

Polysomnographic readings began 30 minutes before sleep and continued for eight hours. Thirty minutes after the readings were terminated, the subjects completed a post-sleep questionnaire that included subjective information regarding sleep latency, total sleep time, number of awakenings, and sleep quality. A DSST was also administered.

The primary efficacy outcome measure was mean latency to persistent sleep. Secondary outcome measures included total sleep time, wake-up time after sleep onset, the percentage of sleep time in each sleep stage, and the number of awakenings.
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All 375 subjects enrolled completed the study. There were no significant differences among the three treatment groups in terms of race, sex, or age. Both dosage levels of ramelteon resulted in statistically significant decreases in mean latency to persistent sleep as follows: 24.6 minutes to persistent sleep with placebo, 14.1 minutes with a ramelteon dose of 16 mg, and 15.5 minutes with 64 mg (P< 0.001).

Total sleep times were 411.3 minutes with placebo, 425.4 minutes with ramel-teon 16 mg, and 422.4 minutes with a dose of 64 mg (P < 0.05).

Differences in wake-up times after sleep with ramelteon and placebo were not statistically significant. The subjective number of awakenings and the subjective ease of falling back to sleep did not differ with ramelteon or placebo.

No serious ADEs were reported, and increased dosages of the study drug did not show an increased number of ADEs. Of the 375 participants, 63 reported at least one ADE as follows: in 21 patients taking placebo, in 20 patients taking ramelteon 16 mg, and in 22 patients taking ramelteon 64 mg.

Headache, the most common ADE, occurred in two patients taking placebo, in nine patients taking 16 mg, and in eight patients taking 64 mg. Less common ADEs were fatigue, nausea, somnolence, and dizziness. Assessment of vital signs, laboratory values, and ECGs between the two treated groups revealed no statistically significant differences.

The study authors concluded that ramelteon’s mechanism of action might offer a novel way to treat insomnia. They noted a flat dose-response curve from the four-fold increase in the ramelteon dose, resulting in a 1.5-minute difference on the primary outcome measure (latency to persistent sleep). In terms of this response, ramelteon did not appear to produce dose-dependent sedation; it affected only sleep promotion.

The investigators suggest the need for further studies of patients with chronic insomnia, because the data in the current study might portray unrealistic results from healthy patients in a simulated environment.

Roth et al.

Roth and associates conducted a randomized, double-blind phase 3 study to determine the efficacy of ramelteon in promoting sleep in 829 elderly patients with a diagnosis of chronic insomnia, as defined by DSM-IV criteria, for at least three months. Patients received placebo, ramelteon 4 mg, or ramelteon 8 mg for five weeks. Sleep was assessed with polysomnography as well as with a post-sleep questionnaire. The primary endpoint was the mean latency time to sleep.

A statistically significant difference was noted between sleep latency times of those subjects taking placebo and subjects receiving ramelteon 4 mg and 8 mg. The approximate reduction in sleep latency between active treatment and placebo was eight minutes at week one (70.2 minutes in the ramelteon groups vs. 78.5 minutes with placebo; P = 0.008). The reduction continued to improve through to week five (57.7 minutes in the ramelteon groups vs. 70.6 minutes with placebo; P< 0.001).

At the first week, total sleep times were improved (i.e., increased) with each dose of ramelteon, compared with placebo: 324.6 minutes with 4 mg vs. 313.9 minutes with placebo (P = 0.004) and 321.1 minutes with 8 mg vs. 313.9 minutes with placebo (P = 0.055). There was no evidence of significant rebound or withdrawal effects after ramelteon therapy was discontinued.

ADEs were reported to be mild and similar to those experienced by the placebo treatment group. The investigators concluded that ramelteon promoted sleep in elderly patients with chronic insomnia, as determined by statistically significant decreases in sleep latency over a period of five weeks.
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ACQUISITI ON COSTS

The average wholesale price (AWP) of a one-month supply (30 8-mg tablets) of ramelteon (Rozerem) is $96.67. This price may vary among different health care systems. The AWPs of the other leading agents indicated for insomnia for a 30-day supply (30 tablets) are as follows:

  • zolpidem tartrate (Ambien) 10 mg, $135.79
  • zolpidem (Genpharm, Inc.), 10 mg, $115.49 (generic equivalent)
  • zaleplon (Sonata) 10 mg, $111.20
  • eszopiclone (Lunesta) 2 mg, $126.77

Although the AWP of ramelteon is lower than that of some of the other insomnia agents, a comparison of prices may be irrelevant because of ramelteon’s novel mechanism of action. The statistically significant improvement in sleep, in terms of decreased latency and increased total sleep time, averaged 10 to 15 minutes between treatment and placebo. The cost of $2.00 to $3.00 per day for a 15-minute difference in sleep onset and total sleep time might be an important consideration for some patients and an easy choice for others.

CONCLUSION

Ramelteon appears to have advantages over previous medications for treating insomnia. It is the first non-scheduled prescription drug indicated for insomnia. It is also noteworthy that no study has been completed or reported comparing the efficacy of melatonin versus ramel-teon, and it is therefore possible that one agent might not offer any clinical advantage over the other.

The studies that are available to assess the efficacy of ramelteon also show a desirable side-effect profile. The absence of tolerance, dependence, and toxicity help to prevent ADEs associated with other medications for insomnia. A low incidence of side effects makes it especially favorable for elderly people. The rapid onset of action of ramelteon suggests that it should have a place for the treatment of primary or transient insomnia as a safe alternative to other available medications.

True insomnia is rare. Physicians and pharmacists should carefully evaluate all patients and their presenting symptoms before recommending any hypnotic agent, because insomnia can be a sign of another pre-existing condition that, if addressed, might help resolve the secondary insomnia. generic cialis tadalafil

For patients whose transient or chronic insomnia is refractory to non-pharmacological interventions and is not secondary to an underlying medical or psychiatric condition, ramelteon may be an alternative treatment option to be considered and utilized.

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