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New Drug Reviews

Ramelteon (Rozerem) for Insomnia



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Am Fam Physician. 2006 Apr 15;73(8):1437-1438.

Synopsis

Ramelteon (Rozerem) is a highly selective melatonin receptor type 1 and type 2 agonist,1,2 unlike nonprescription melatonin, which is nonselective for all three melatonin receptors.3 The U.S. Food and Drug Administration approved ramelteon 8-mg tablets for the treatment of insomnia characterized by difficulty with sleep onset. Ramelteon is the only prescription sleep aid not designated as a Schedule IV controlled substance.

Name Starting dosage Dose form Approximate monthly cost*

Ramelteon (Rozerem)

8 mg orally 30 minutes before going to bed

8-mg tablets

$82 (for 30 8-mg tablets)


*—Average wholesale cost based on Red Book, Montvale, N.J.: Medical Economics Data, 2005.

Name Starting dosage Dose form Approximate monthly cost*

Ramelteon (Rozerem)

8 mg orally 30 minutes before going to bed

8-mg tablets

$82 (for 30 8-mg tablets)


*—Average wholesale cost based on Red Book, Montvale, N.J.: Medical Economics Data, 2005.

Safety

No major safety issues have been identified with ramelteon. After one year of study participation, 3.1 percent of patients reported one or more serious adverse events, but less than 10 percent of those events were attributed to ramelteon.4 Ramelteon should not be used by patients taking fluvoxamine (Luvox), which can inhibit the metabolism of ramelteon, or by patients who have severe hepatic impairment. Use of ketoconazole (Nizoral) or fluconazole (Diflucan) increases blood levels of ramelteon, which may increase the risk of side effects or the therapeutic effect.5 Ramelteon does not have a significant additive effect when taken with alcohol. It has not been studied in children and therefore should not be used by adolescents or children. Ramelteon is pregnancy category C; it is not recommended for nursing mothers.

Tolerability

Ramelteon generally is well tolerated. During clinical studies, the discontinuation rate for ramelteon was 5 percent compared with 2 percent for placebo.5 Ramelteon does not produce residual “hangover” effects. In studies lasting 35 days, ramelteon did not cause rebound insomnia, and there was no evidence of withdrawal on discontinuation.5

Effectiveness

Ramelteon has not been compared directly with other hypnotics or melatonin. The manufacturer conducted five unpublished placebo-controlled studies of effectiveness.5 In two studies using polysomnography to assess effectiveness, a faster onset of persistent sleep was found with ramelteon than with placebo. However, when patient evaluation (i.e., completion of postsleep questionnaires or sleep diaries) was used to assess effectiveness, a greater improvement with ramelteon than with placebo was found only in some studies.5 Patient evaluation is a more subjective measurement, but it also is more reflective of longer-term effects.

In patients with transient insomnia, improvements in sleep architecture with ramelteon were demonstrated using polysomnography, but evaluation with postsleep questionnaires showed no difference between ramelteon and placebo.5,6 Ramelteon has not been studied in patients with insomnia caused by depression or anxiety, in shift workers, or for the prevention or minimization of jet lag.

Price

A one-month supply of ramelteon 8-mg tablets costs approximately $82. This is comparable to the cost of zaleplon (Sonata) and of zolpidem (Ambien) and is much higher than that of melatonin.

Simplicity

Ramelteon (8 mg) should be taken 30 minutes before going to bed, with or without food, although it is not recommended with or immediately after consumption of a high-fat meal. Fluvoxamine is the only drug that should not be used in combination with ramelteon.

Bottom Line

Ramelteon is safe and effective for decreasing the time to persistent sleep in patients with chronic insomnia. It does not have the potential for abuse or dependence that sedative hypnotics have and is not a controlled substance. No studies have compared ramelteon with other hypnotics or melatonin, and patient evaluation using postsleep questionnaires has not confirmed consistent benefit.

Curt R. Ward, M.D., M.B.A., is associate program director of the St. Vincent Family Medicine Residency Program, St. Vincent Hospital, Indianapolis, Ind.

REFERENCES

1. Kato K, Hirai K, Nishiyama K, Uchikawa O, Fukatsu K, Ohkawa S, et al. Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology. 2005;48:301–10.

2. Turek FW, Gillette MU. Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists. Sleep Med. 2004;5:523–32.

3. Melatonin. Natural Medicines Comprehensive Database. Accessed online December 16, 2005, at: http://www.naturaldatabase.com.

4. Internal study report (TL-375-022). Lincolnshire, Ill.: Takeda Pharmaceuticals America, Inc.

5. Rozerem (ramelteon) tablets. Product information. Lincolnshire, Ill.: Takeda Pharmaceuticals America, Inc., 2005. Accessed online January 24, 2006, at: http://www.rozerem.com/PI_1.aspx.

6. Roth T, Stubbs C, Walsh JK. 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;28:303–7.

STEPS drug updates cover Safety, Tolerability, Effectiveness, Price, and Simplicity. Each update provides an independent review of a new medication by authors who have no financial association with the drug manufacturer.

The series coordinator is Allen F. Shaughnessy, Pharm.D., Tufts University Family Medicine Residency Program, Boston, Mass.


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