Pharmacology Update: Ramelteon Tablets (Rozerem)
Pharmacology Update
Ramelteon Tablets (Rozerem™)
By William T. Elliott, MD, FACP, and James Chan, PhD, PharmD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Associate Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationships to this field of study.
The FDA has approved the first melatonin receptor agonist for the treatment of insomnia. Ramelteon differs from benzodiazepine and nonbenzo-diazepine sedative hypnotics in that it is a non-scheduled drug and it is approved for long term use. It is marketed by Takeda Pharmaceutical America, Inc as Rozerem™.
Indications
Ramelteon is indicated for the treatment of insomnia characterized by difficulty with sleep onset.1
Dosage
The recommended dose is 8 mg taken within 30 minutes of going to bed. It should not be taken with or immediately after a high fat meal as the absorption is significantly reduced. Ramelteon should not be used in patients with severe hepatic dysfunction and it should be used with caution in patients with moderate hepatic dysfunction.1
Potential Advantages
This is the first melatonin agonist approved and is mechanistically different from the barbiturates, benzodiazepine, and benzodiazepine-related (eg, zolpidem) agents. Ramelteon appears to be well tolerated and with no significant abuse potential, withdrawal, or rebound insomnia.1
Potential Disadvantages
Common side effects include somnolence (5% vs 3% for placebo), fatigue (4% vs 2%), and dizziness (5% vs 3%).1 Some evidence of fatigue was observed with chronic use and mean increase of 34% of prolactin levels have been reported in women.1
Comments
Ramelteon is the first melatonin receptor agonist approved. It has a 10-fold greater affinity for MT1 receptor and 100-fold greater affinity for MT2 receptor, associated with sleep promotion, compared to melatonin.1,2 It has low affinity for MT3 which has other systemic effects and no affinity for GABA receptors. Melatonin is regarded as an internal sleep facilitator and is believed to have a direct effect on sleep-inducing thermoregulatory mechanism.3 In placebo-controlled studies, ramelteon reduced sleep latency compared to placebo in subjects with chronic insomnia and transient insomnia.1 In subjects with chronic insomnia (n = 693), ages 64-69 yrs, ramelteon reduced sleep latency by about 8 minutes (78.5 min to 70.2 min) compared to placebo; P = 0.008.4 In a similarly designed study in younger subjects (ages 18-64 yrs), no difference was found between ramelteon and placebo.1 Ramelteon was studied in a model of transient insomnia using high doses (16 mg and 64 mg) (n = 370).5 Latency to sleep was 26.6 ± 21.0 min for placebo compared to 14.1 ± 15.1 min and 15.5 ± 15.4 min respectively for ramelteon 16 mg and 64 mg respectively. Total sleep times were 411.3 ± 41.7 min, 425.4 ± 37.6 min, and 422.4 ±34.8 min respectively. These were all statistically different at P < 0.05. Wake after sleep onset and time spent in each sleep stage were not significantly different. In a 35-day study, patients who received ramelteon reported more fatigued at week 1 and 3 but not at week 5 compared to placebo.1 A lower mean number of words recalled were observed at week 3. Elevations of serum prolactin levels have been reported in women. There are currently no published comparisons with other sedative hypnotics. The wholesale cost of ramelteon is $2.25 per 8 mg tablet which is priced similar to or lower than the nonbenzodiazepine drugs such as zolpidem (Ambien), zaleplon (Sonata), and eszopiclone (Lunesta).
Clinical Implications
Ramelteon is the first of the new class of agents to treat insomnia. The benefit of the drug appears modest, providing less than a 10-minute reduction in sleep latency with the FDA approved dose. It is not approved for increasing sleep duration. However the drug is unique in that it appears safe for long-term use. More clinical experience is needed to define the role of the agent in the treatment of insomnia.
References
1. Rozerem™ Product Information. Takeda Pharmaceuticals America, Inc. August 2005.
2. Anonymous. Ramelteon: TAK 375. Drugs R D. 2005;6(3):186-188.
3. Cajochen C, et al. Role of melatonin in the regulation of human circadian rhythms and sleep. J Neuroendocrinol. 2003;15:432-437.
4. Roth T, et al. AGS 2005 Annual Meeting Poster Abstract A-21. May 11-13, 2005.
5. Roth T, et al. Ramelteon (TAK-375), a selective MT1/MT2-receptor agonist, reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep environment. Sleep. 2005;28(3):303-307.
The FDA has approved the first melatonin receptor agonist for the treatment of insomnia. Ramelteon differs from benzodiazepine and nonbenzo-diazepine sedative hypnotics in that it is a non-scheduled drug and it is approved for long term use. It is marketed by Takeda Pharmaceutical America, Inc as Rozerem.Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.