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Ramelteon

A Review of Its Use in Insomnia

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Summary

Abstract

Ramelteon (Rozerem™) is the first melatonin receptor agonist to be approved for the treatment of insomnia; it is not classified as a controlled substance. In patients with chronic insomnia, objectively assessed latency to persistent sleep (LPS) at week 1 was improved with oral ramelteon 8 mg administered 30 minutes before bedtime, compared with placebo, and this effect was maintained throughout the duration of 5-week and 6-month clinical studies. Subjectively assessed sleep latency (sSL) improved in some, but not all, studies. When a statistically significant improvement in sSL occurred at week 1, the effect was maintained throughout the duration of the 5-week studies, but not at all timepoints throughout a 6-month study. Improvements in objectively assessed total sleep time (TST) and sleep efficiency (SE) were only reported during the first week of treatment. Improvements in other objective or subjective measures of sleep were not consistent. Ramelteon was generally well tolerated, did not impair next-day cognitive or motor performance and was not associated with withdrawal symptoms, rebound insomnia or abuse potential. Thus, ramelteon provides a well tolerated option for the treatment of patients with insomnia characterized by difficulty in sleep onset.

Pharmacological Properties

Ramelteon is a highly selective melatonin MT1 and MT2 receptor agonist, with no appreciable affinity for the GABA receptor complex or receptors that bind neuropeptides, cytokines, opioids, dopamine or serotonin. Ramelteon enhanced re-entrainment of circadian rhythms to a new light-dark cycle in volunteers, according to measurements of endogenous melatonin secretion offset time. In patients with chronic insomnia, ramelteon was not associated with acute or next-day effects on cognitive or psychomotor function compared with placebo when assessed using standard tests, and had no effect on middle-of-the-night balance/body sway. Doses of ramelteon up to 20-fold greater than that recommended for the treatment of insomnia showed no potential for abuse in adults with a history of sedative abuse.

Ramelteon is rapidly absorbed, with a time to peak serum concentration of 0.75 hours. The total absorption of ramelteon is ≥84%; however, the absolute bioavailability is <2% due to extensive first-pass metabolism. Metabolism is via cytochrome P450 (CYP) isozymes, primarily CYP1A2. Fluvoxamine (a CYP1A2 inhibitor) should not be coadministered with ramelteon, and caution should be exercised with some other drug combinations. Eighty-four percent of the drug is excreted in the urine and ≈4% in the faeces; <0.1% is excreted as unchanged drug. The elimination half-life of ramelteon is ≈1.4 hours.

Therapeutic Efficacy

In patients with chronic insomnia, oral ramelteon 8 mg administered 30 minutes before bedtime improved LPS in the first week and throughout the duration of 5-week and 6-month randomized, double-blind studies. The difference between ramelteon 8 mg/night and placebo for LPS throughout the course of the 5-week study was 11–16 minutes. Ramelteon 8 mg/night improved sSL in some, but not all, studies. When a statistically significant improvement in sSL occurred at week 1, the effect persisted throughout the duration of the 5-week studies, but not at every timepoint throughout the 6-month study. TST, when monitored by polysomnography, was significantly greater with ramelteon 8 mg/night than with placebo only during the first week of the studies in patients with chronic insomnia. The changes in subjectively assessed TST were not consistent. Objectively measured SE was significantly higher in recipients of ramelteon 8 mg/night than with placebo only during the first week. There were no significant differences between ramelteon and placebo for other objective or subjective sleep parameters, including sleep quality, awake time and number of awakenings after sleep onset, and difficulty/ease of falling back to sleep.

In a first-night model of transient insomnia in volunteers, LPS was significantly shorter and TST was significantly longer with ramelteon 8 mg than placebo.

Tolerability

Ramelteon was generally well tolerated, with the majority of adverse events being of mild or moderate severity. According to data from a pooled analysis of phase I–III trials, the most common treatment-emergent adverse events in recipients of ramelteon 8 mg/night or placebo were headache (both 7%), somnolence (5% vs 3%), dizziness (5% vs 3%) and fatigue (4% vs 2%). Discontinuation due to an adverse event occurred in 6% of ramelteon recipients and 2% of placebo recipients. Increases in prolactin levels were reported in a 6-month trial and abnormalities in cortisol levels were reported in ramelteon recipients in an open-label 1-year trial in patients with chronic insomnia.

Ramelteon was not associated with withdrawal effects or rebound insomnia.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

References

  1. Ancoli-Israel S. Sleep problems in older adults: putting myths to bed. Geriatrics 1997; 52(1): 20–30

    PubMed  CAS  Google Scholar 

  2. American Academy of Sleep Medicine. The International Classification of Sleep Disorders, revised. Diagnostic and coding manual. Rochester (MN): American Academy of Sleep Medicine, 2001

    Google Scholar 

  3. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th edition, text revision. Washington, DC: American Psychiatric Association, 2000

    Book  Google Scholar 

  4. World Health Organization. The ICD-10 classification of mental and behavioural disorders. Geneva: World Health Organization, 1992

    Google Scholar 

  5. National Institutes of Health. NIH State-of-the-science conference statement on manifestations and management of chronic insomnia in adults. NIH Consens Sci Statements 2005; 22(2): 1–30

    Google Scholar 

  6. Roth T, Franklin M, Bramley TJ. The state of insomnia and emerging trends. Am J Managed Care 2007; 13 (5 Suppl.): SI17–20

    Google Scholar 

  7. Doghramji J. The epidemiology and diagnosis of insomnia. Am J Manag Care 2006; 12 (8 Suppl.): S214–20

    PubMed  Google Scholar 

  8. National Sleep Foundation. 2002 “Sleep in America” poll [online]. Available from URL: http://www.sleepfoundation.org/img/2002SleepInAmericaPoll.pdf [Accessed 2008 Apr 20]

  9. Curry DT, Eisenstein RD, Walsh JK. Pharmacologic management of insomnia: past, present, and future. Psychiatr Clin North Am 2006 Dec; 29(4): 871–93; abstract vii–viii

    Article  PubMed  Google Scholar 

  10. Turek FW, Gillette MU. Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists. Sleep Med 2004; 5(6): 523–32

    Article  PubMed  Google Scholar 

  11. Kato K, Hirai K, Nishiyama K, et al. Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology 2005 Feb; 48(2): 301–10

    Article  PubMed  CAS  Google Scholar 

  12. Nosjean O, Ferro M, Coge F. Identification of the melatonin-binding site MT3 as the quinone reductase 2. J Biol Chem 2000; 275(40): 31311–7

    Article  PubMed  CAS  Google Scholar 

  13. Ebrahim I. Ramelteon: a new approach to managing insomnia. Future Neurology 2008; 3(1): 9–18

    Article  CAS  Google Scholar 

  14. Takeda Pharmaceuticals America Inc. Rozerem™ (ramelteon) tablets: prescribing information [online]. Available from URL: http://www.rozerem.com/HCP/PI_1.aspx [Accessed 2008 Apr 7]

  15. Yukuhiro N, Kimura H, Nishikawa H, et al. Effects of ramelteon (TAK-375) on nocturnal sleep in freely moving monkeys. Brain Res 2004 Nov 19; 1027: 59–66

    Article  PubMed  CAS  Google Scholar 

  16. Miyamoto M, Nishikawa H, Doken Y, et al. The sleep-promoting action of ramelteon (TAK-375) in freely moving cats. Sleep 2004; 27(7): 1319–25

    PubMed  Google Scholar 

  17. Hirai K, Kita M, Ohta H, et al. Ramelteon (TAK-375) accelerates reentrainment of circadian rhythm after a phase advance of the light-dark cycle in rats. J Biol Rhythms 2005; 20(1): 27–37

    Article  PubMed  CAS  Google Scholar 

  18. Richardson G, Zee P, Wang-Weigand S, et al. Circadian phaseshifting effects of daily ramelteon in healthy adults [abstract no. 196]. Society for Research on Biological Rhythms 10th Biennial Meeting program and abstracts; 2006 May 21–25; Sandestin (FL), 134

  19. Greenblatt DJ, Harmatz JS, Karim A. Age and gender effects on the pharmacokinetics and pharmacodynamics of ramelteon, a hypnotic agent acting via melatonin receptors MT1 and MT2. J Clin Pharmacol 2007 Apr; 47(4): 485–96

    Article  PubMed  CAS  Google Scholar 

  20. Karim A, Tolbert D, Cao C. Disposition kinetics and tolerance of escalating single doses of ramelteon, a high-affinity MT1 and MT2 melatonin receptor agonist indicated for treatment of insomnia. J Clin Pharmacol 2006 Feb; 46(2): 140–8

    Article  PubMed  CAS  Google Scholar 

  21. Hajak G, Ebrahim I, Hibberd M. Effect of ramelteon and zopiclone on body sway at peak plasma levels in chronic insomnia [abstract no. NR611]. Conference Proceedings of the 160th Annual Meeting of the American Psychiatric Association; 2007 May 19–24; San Diego (CA), 261

  22. Wang-Weigand S, Zammit G, Peng X. Placebo-controlled, double-blind trial examining the effects of ramelteon vs placebo with zolpidem as a reference on balance in older adults after middle-of-night awakening [abstract no. NR604]. Proceedings of the 160th Annual Meeting of the American Psychiatric Association; 2007 May 19–24; San Diego (CA), 258

  23. Johnson MW, Suess PE, Griffiths RR. Ramelteon: a novel hypnotic lacking abuse liability and sedative adverse effects. Arch Gen Psychiatry 2006 Oct; 63(10): 1149–57

    Article  PubMed  CAS  Google Scholar 

  24. Ramakrishnan K, Scheid DC. Treatment options for insomnia. Am Fam Physician 2007 Aug 15; 76(4): 517–26

    PubMed  Google Scholar 

  25. Bhat A, Shafi F, El Solh AA. Pharmacotherapy of insomnia. Expert Opin Pharmacother 2008; 9(3): 351–62

    Article  PubMed  CAS  Google Scholar 

  26. Erman M, Seiden D, Zammit G, et al. An efficacy, safety, and dose-response study of ramelteon in patients with chronic primary insomnia. Sleep Med 2006 Jan; 7(1): 17–24

    Article  PubMed  Google Scholar 

  27. Roth T, Seiden D, Wang-Weigand S, et al. A 2-night, 3-period, crossover study of ramelteon’s efficacy and safety in older adults with chronic insomnia. Curr Med Res Opin 2007 May; 23(5): 1005–14

    Article  PubMed  CAS  Google Scholar 

  28. Zammit G, Erman M, Wang-Weigand S, et al. Evaluation of the efficacy and safety of ramelteon in subjects with chronic insomnia. J Clin Sleep Med 2007 Aug 15; 3(5): 495–504

    PubMed  Google Scholar 

  29. Zammit G, Schwartz H, Roth T, et al. Effect of ramelteon, a selective MT1/MT2 receptor agonist, in a first-night-effect model of transient insomnia [abstract no. 0701]. Sleep 2006; 29 (Suppl.): A238

    Google Scholar 

  30. 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(3): 303–7

    PubMed  Google Scholar 

  31. Wang-Weigand S, Mayer G, Roth-Schechter B. Long-term efficacy and safety of ramelteon 8 mg treatment in adults with chronic insomnia: results of a six-month, double-blind, placebo-controlled, polysomnography trial [abstract no. 525 plus poster]. 5th World Sleep Congress of the World Federation of Sleep Research and Sleep Medicine Societies; 2007 Sep 2–6; Cairns (QLD)

  32. Kryger M, Roth T, Wang-Weigand S, et al. The effects of ramelteon on respiration during sleep in subjects with moderate to severe chronic obstructive pulmonary disease. Sleep Breath. Epub 2008 Jun 27

  33. Kryger M, Wang-Weigand S, Zhang J, et al. Effect of ramelteon, a selective MT1/MT2-receptor agonist, on respiration during sleep in mild to moderate COPD. Sleep Breath 2008; 12(3): 243–50

    Article  PubMed  Google Scholar 

  34. Borja NL, Daniel KL. Ramelteon for the treatment of insomnia. Clin Ther 2006 Oct; 28(10): 1540–55

    Article  PubMed  CAS  Google Scholar 

  35. Pandi-Perumal SR, Srinivasan V, Poeggeler B, et al. Drug insight: the use of melatonergic agonists for the treatment of insomnia-focus on ramelteon. Nat Clin Pract Neurol 2007 Apr; 3(4): 221–8

    Article  PubMed  CAS  Google Scholar 

  36. Karim A, Tolbert D, Cao C. Effects of fluoxetine on the systemic exposure of ramelteon (TAK-375) [abstract no. NR844]. Proceedings of the 157 th Annual Meeting of the American Psychiatric Association; 2004 May 1–6; New York (NY), 317

  37. Karim Z, Bradford D, Siebert F, et al. Open-label assessment of the pharmacokinetics of ramelteon and donepezil coadministration in healthy adults [abstract no. NR606]. 160th Annual Meeting of the American Psychiatric Association; 2007 May 19–24; San Diego (CA), 259

  38. Karim A, Bradford D, Siebert F, et al. Effect of multiple oral doses of escitalopram on the systemic availability of ramelteon, an MT1 and MT2 receptor agonist, in healthy adults [abstract no. 0700]. Sleep 2006 May 20; 29 Suppl.: A237–8

    Google Scholar 

  39. Karim A, Bradford D, Zhao Z. Effect of multiple oral doses of venlafaxine on the systemic availability of ramelteon, an MT1/MT2 receptor agonist [abstract no. P01.139]. Int J Neuropsychopharmacol 2006 Jul 1; 9 Suppl. 1: S138

    Google Scholar 

  40. Karim A, Moore R, Zhao Z, et al. Open-label assessment of the pharmacokinetics of ramelteon 8 mg and zolpidem 10 mg coadministration in healthy adults [abstract no. 45-P]. 36th Annual Meeting of the American College of Clinical Pharmacology; 2007 Sep 9–11; San Francisco (CA)

  41. Karim A, Tolbert D, Cao C, et al. Study to assess the steadystate drug-drug interaction of omeprazole with ramelteon in healthy adults [abstract no. 0137]. Sleep 2005; 28 Suppl.: A46

    Google Scholar 

  42. Roth T, Seiden D, Sainati S, et al. Effects of ramelteon on patient-reported sleep latency in older adults with chronic insomnia. Sleep Med 2006 Jun; 7(4): 312–8

    Article  PubMed  Google Scholar 

  43. FDA. Medical review document for application for approval of ramelteon [online]. Available from URL: http://www.fda.gov/cder/foi/nda/2005/021782s000_Rozerem_medr.pdf [Accessed 2008 May 26]

  44. Mini LJ, Wang-Weigand S, Zhang J. Sleep-promoting effects of ramelteon: a subanalysis of adults with severe sleep-initiation difficulty [abstract no. NR610]. Proceedings of the 160th Annual Meeting of the American Psychiatric Association; 2007 May 19–24; San Diego (CA), 261

  45. Mini LJ, Wang-Weigand S, Zhang J. Self-reported efficacy and tolerability of ramelteon 8 mg in older adults experiencing severe sleep-onset difficulty. Am J Geriatr Pharmacother 2007 Sep; 5(3): 177–84

    Article  PubMed  CAS  Google Scholar 

  46. Jhaveri M, Seal B, Pollack M, et al. Will insomnia treatments produce overall cost savings to commercial managed-care plans? A predictive analysis in the United States. Curr Med Res Opin 2007 Jun; 23(6): 1431–43

    Article  PubMed  CAS  Google Scholar 

  47. Richardson G, Wang-Weigand S, Zhang J, et al. Long-term safety of ramelteon treatment in adults with chronic insomnia: a 1-year study [abstract no. 0685]. Sleep 2006; 29 Suppl.: A233

    Google Scholar 

  48. Richardson GS, Wang-Weigand S, Sainati S, et al. Long-term effects of ramelteon on endocrine function in patients with chronic insomnia in a double-blind, placebo-controlled phase III study [abstract no. P111-38]. Clin Pharmacol Ther 2006 Feb 1; 79(2): 68

    Article  Google Scholar 

  49. Nichols J, Alper C, Milkin T. Strategies for the management of insomnia: an update on pharmacologic therapies. Formulary 2007; 42(2): 86–98

    CAS  Google Scholar 

  50. Silber MH. Clinical practice: chronic insomnia. N Engl J Med 2005 Aug 25; 353(8): 803–10

    Article  PubMed  CAS  Google Scholar 

  51. Taylor JR, Vazquez CM, Campbell KM. Pharmacologic management of chronic insomnia. South Med J 2006; 99(12): 1373–7

    Article  PubMed  Google Scholar 

  52. Pfizer. Halcion — triazolam tablets, USP CIV [online]. Available from URL: http://www.pfizer.com/files/products/uspi_halcion.pdf [Accessed 2008 May 1]

  53. Mallinckrodt Inc. Restoril® — temazepam capsules USP; prescribing information [online]. Available from URL: http://www.restoril.com/pdf/restoril_prod_pi.pdf [Accessed 2008 May 1]

  54. Estazolam tablets: prescribing information [online]. Available from URL: http://www.drugs.com/ppa/estazolam.html [Accessed 2008 May 1]

  55. Dolder C, Nelson M, McKinsey J. Use of non-benzodiazepine hypnotics in the elderly: are all agents the same? CNS Drugs 2007; 21(5): 389–405

    Article  PubMed  CAS  Google Scholar 

  56. Buscemi N, Vandermeer B, Hooton N, et al. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. BMJ 2006; 332(7538): 385–93

    Article  PubMed  CAS  Google Scholar 

  57. Brzezinski A, Vangel MG, Wurtman RJ, et al. Effects of exogenous melatonin on sleep; a meta-analysis. Sleep Med Rev 2005; 9(1): 41–50

    Article  PubMed  Google Scholar 

  58. Gerdin MJ, Masana MI, Rivera-Bermúdez MA. Melatonin desensitizes endogenous MT2 melatonin receptors in the rat suprachiasmatic nucleus: relevance for defining the periods of sensitivity of the mammalian circadian clock to melatonin. FASEB J 2004; 18(14): 1646–56

    Article  PubMed  CAS  Google Scholar 

  59. Pandi-Perumal SR, Srinivasan V, Spence DW, et al. Role of the melatonin system in the control of sleep: therapeutic implications. CNS Drugs 2007; 21(12): 995–1018

    Article  PubMed  CAS  Google Scholar 

  60. National Institutes of Health. Safety of ramelteon in elderly subjects [online]. Available from URL: http://clinicaltrials.gov [Accessed 2008 Apr 17]

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Authors and Affiliations

  1. Wolters Kluwer Health ¦ Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, Auckland, 0754, New Zealand

    Dene Simpson & Monique P. Curran

  2. Wolters Kluwer Health, Conshohocken, Pennsylvania, USA

    Dene Simpson & Monique P. Curran

Authors
  1. Dene Simpson
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  2. Monique P. Curran
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Correspondence to Monique P. Curran.

Additional information

Various sections of the manuscript reviewed by: I.O. Ebrahim, The London Sleep Centre, London, England; M.W. Johnson, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; T.L. Levien, Washington State University Spokane, Spokane, Washington, USA; S.R. Pandi-Perumal, College of Physicians and Surgeons of Columbia University, New York, New York, USA; G.S. Richardson, Henry Ford Hospital, Sleep Disorders and Research Center, Detroit, Michigan, USA; R.J. Wurtman, Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, Cambridge, Massachusetts, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘ramelteon’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and AdisBase search term was ‘ramelteon’. Searches were last updated 6 August 2008.

Selection: Studies in patients with insomnia who received ramelteon. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Ramelteon, insomnia, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

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Simpson, D., Curran, M.P. Ramelteon. Drugs 68, 1901–1919 (2008). https://doi.org/10.2165/00003495-200868130-00011

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