Ramelteon for the treatment of insomnia

New

Drug

Ramelteon for the Treatment of Insomnia Nancy L. Borja, PharmD; and Karen L Daniel, PharmD, CDE Nova Southeastern University College of Pharmacy, Fort Lauderdale, Florida ABSTRACT

Background: Insomnia is a common sleep disorder with a significant potential for deleterious effects on activities of daily living, productivity, and overall quality of life. Ramelteon, a highly selective agonist for melatonin subtypes I and 2 receptors, is a hypnotic agent approved by the US Food and Drug Administration (FDA) for the treatment of insomnia characterized by difficulty falling asleep. Objectiv~ This article reviews the pharmacokinetic properties, efficacy, and tolerability of ramelteon in the treatment of insomnia characterized by difficulty falling asleep. Methods: Relevant articles were identified through searches of MEDLINE (1966 to July 2006), International Pharmaceutical Abstracts (January 1970 to July 2006), EMBASE Drugs and Pharmacology (1980 to third quarter 2006), and Current Contents/Clinical Medicine (2005 week 32 to 2006 week 31). Search terms included ramelteon, TAK-375, melatonin agonist, melatonin receptor agonist, insomnia, and sleep

disorders~drugtherapy (MESH). Results: A literature search revealed 12 randomized, controlled clinical trials that examined the efficacy or tolerability of ramelteon. In addition, 17 studies were reviewed for pharmacology and pharmacokinetic data. The references of the clinical trials and recent review articles were examined to ensure the comprehensiveness of the literature search. In 2 trials of patients with primary insomnia, patients treated with ramelteon 4 to 32 mg had significant reductions in latency to persistent sleep (LPS) compared with placebo (P < 0.001). Additionally, improvements in total sleep time (TST) were observed (P < 0.001), although increases in TST were noted only on nights 1-2 of the second study. Similarly, improvement in sleep efficiency was reported only on nights 1-2 of the second trial (P < 0.001). In elderly patients with primary insomnia, significant reductions in subjective LPS were observed with ramelteon 4 and 8 mg (P = 0.008); however, average subjective LPS

was >70 minutes. Mean reported TST was significantly increased in the 4-mg group (P = 0.004). A second study in elderly patients found decreases in LPS with ramelteon 4 mg (P < 0.001) and 8 mg (P < 0.01), as well as significant increases in TST (P < 0.05 and P < 0.01, respectively). Sleep efficiency improved for patients treated with 4 mg (P < 0.05) and 8 mg (P < 0.01). Overall, the mean decrease in LPS reported in trials of ramelteon ranged from 10 to 19 minutes, and the mean increase in TST was 8 to 22 minutes. The most common adverse events observed with ramelteon included headache (7%), dizziness (5%), somnolence (5%), fatigue (4%), and nausea (3%). No evidence of cognitive impairment, rebound insomnia, withdrawal effects, or abuse potential was noted. Conclusions: Based on this review, ramelteon, the first FDA-approved melatonin receptor agonist, represents a pharmacologic option for the treatment of insomnia characterized by difficulty falling asleep. In patients with insomnia, treatment with ramelteon was generally well tolerated and resulted in modest but statistically significant decreases in LPS. In the absence of published trials comparing ramelteon with other sedative-hypnotic agents, it is not yet possible to determine its efficacy relative to other therapeutic options for insomnia. (Clin Ther. 2006;28:1540-1555) Copyright © 2006 Excerpta Medica, Inc. Key words: ramelteon, TAK-375, melatonin receptor agonist, insomnia.

INTRODUCTION

Insomnia is a common sleep disorder that affects >70 million Americans.1 Insomnia is defined as diffiAccepted for publication September 3, 2006. doi:l 0.1016/j.clinthera.2006.10.016 0149-2918/06/$19.00 Printed in the USA. Reproduction in whole or part is not permitted. Cop/right © 2006 Excerpta Medica, Inc.

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culty initiating sleep, difficulty maintaining sleep, or experiencing nonrestorative sleep.2-s Based on the duration of symptoms, insomnia may be classified as transient, short-term, or chronic. Transient insomnia occurs for a period of a few nights, and short-term insomnia is characterized as insomnia lasting up to 4 weeks. 4,~ In general, transient and short-term insomnia are related to situational factors such as temporary stress, jet lag, or transitory medical or psychological problems. 1,s Insomnia lasting at least 1 month is categorized as chronic insomnia, and is often the result of persistent medical conditions or psychological disorders, such as sleep apnea, restless leg syndrome, menopause, chronic pain, anxiety, depression, or substance abuse. 2-s In the absence of causative medical or substance abuse disorders, insomnia resulting in significant impairment in social or occupational functioning for at least 1 month is consistent with a diagnosis of primary insomnia. 2 According to a survey conducted by the National Sleep Foundation in 2002, -58% of adults in the United States experience some symptoms of insomnia at least a few times per weekJ Other sources estimate that insomnia occurs in -30% to 45% of adults. 2-4 The prevalence of primary insomnia is reported to be 1% to 10% in the general population, ranging up to 25% in the elderly.2 A significant number of individuals with insomnia report detrimental effects on activities of daily living (ADLs), including decreased attention and concentration, diminished motivation, lack of energy, lower productivity, and increased irritability. 2,4,7 Direct costs of insomnia are estimated to be approximately (US, 1994) $14 billion each year, and indirect costs due to work loss, accidents, and injuries may reach $28 billion. 1 Because of its high prevalence and the potential for adverse consequences on ADLs and productivity, insomnia is a significant health issue J, s Ramelteon is a hypnotic agent approved by the US Food and Drug Administration (FDA) in 2005 for the treatment of insomnia characterized difficulty falling asleep. 6,s Ramelteon, (S)-N-[2-(1,6,7,8-tetrahydro-2Hindeno-[5,4-b]furan-8-yl)ethyl]propionamide, is the first FDA-approved selective melatonin receptor agonist, s$ with the chemical formula Cl~H21NO 2 (Figure) and a molecular weight of 259.34 Da. s Of all the prescription products approved by the FDA for insomnia, ramelteon is the only agent that is not a controlled substance. 6 This article evaluates the role of ramelteon in

by

o NH~.,,/CHa

Figure. Chemical structure of ramelteon. 8

the treatment of insomnia. An overview of current therapy for insomnia is provided, and clinical data on the pharmacokinetic properties, efficacy, and tolerability of ramelteon are reviewed. MATERIALS A N D METHODS

Relevant articles were identified through searches of MEDLINE (1966 to July 2006), International Pharmaceutical Abstracts (January 1970 to July 2006), EMBASE Drugs and Pharmacology (1980 to third quarter 2006), and Current Contents/Clinical Medicine (2005 week 32 to 2006 week 31). Search terms included ramelteon, TAK-37S, melatonin agonist, melatonin receptor agonist, insomnia, and sleep disorders~drug therapy (MESH). In MEDLINE, a search with insomnia, using limit terms review articles (n = 1488) and practice guideline (n = 9) was conducted. The most recent review articles (2003 or later), and articles with a thorough overview of nonpharmacologic and pharmacologic therapies were used for the discussion of current insomnia treatment options. Studies published in English and involving the pharmacokinetic properties, efficacy, and tolerability of ramelteon were evaluated.

RESULTS Overview of Current Therapy for Insomnia Current treatment for insomnia includes both nonpharmacologic and pharmacologic therapies. Appropriate selection of anti-insomniac therapy should be based on a number of factors, including the age of the patient, concurrent medical conditions, current medications, and previous anti-insomniac treatment, s

Nonpharmacologic options for patients with chronic insomnia are based on behavioral therapy and cognitive-behavioral therapy (CBT). Types of CBT include stimulus control therapy, sleep-restriction therapy, relaxation therapy, cognitive therapy, and sleep-hygiene education. 1° Examples of sleep hygiene include maintaining a regular sleep-wake schedule; avoiding excessive liquids and/or heavy evening meals; establishing a regular exercise routine but not exercising within 4 hours of bedtime; and minimizing the use of caffeine, tobacco, or other stimulants,s Alternative activities, such as tai chi and yoga, have also been used to facilitate relaxation. Some insomniac patients use alcohol to help induce sleep; however, generally this is not recommended because alcohol reduces the quality of sleep and may cause awakening during the night.3 Nine prescription medications, including ramelteon, benzodiazepines (BZDs), and non-BZDs are FDA approved for the treatment of insomnia.4 Other pharmacologic agents used for the treatment of insomnia include antidepressants, antihistamines, antipsychotics, barbiturates, and alternative medications (eg, melatonin, valerian root). Table I compares 4 medication classes that are used for sleep management: antidepressants, antihistamines, BZDs, and non-BZDs, wq3 The lack of randomized controlled trials and head-to-head studies and the short duration of most anti-insomniac trials contribute to the deficiency of treatment algorithms and practice guidelines for the management of insomnia. Currently, BZD receptor agonists are the agents most commonly prescribed for the management of insomnia. 14 This class is further divided into BZDs and non-BZDs. Both BZDs and non-BZDs bind to the BZD component of the yoaminobutyric acid (GABA)Areceptor complex14; however, the non-BZDs may bind selectively to 0tl or 0G receptor subunits of the complex. 11 These agents act by facilitating the ability of GABA to cause neuronal inhibition by opening of the chloride channel.7 BZDs FDA approved for insomnia include estazolam, flurazepam, quazepam, temazepam, and triazolam. BZDs alter the architecture of sleep by increasing the amount of time spent in stage 2 sleep, but they diminish the time spent in stage 3-4 sleep. 13 Overall, BZDs decrease latency to persistent sleep (LPS) and increase total sleep time (TST). Their efficacy in treating short-term insomnia and the availability of generic agents make this class of hyp-

notic agents an attractive choice for the treatment of insomnia.3,s,l°dl The risk for adverse events, such as daytime sedation and potential for abuse, contributes to the concerns clinicians have when prescribing these medications.6,13 A comparison of the non-BZD hypnotic agents zolpidem, zaleplon, and eszopiclone is shown in Table II. ls-19 Unlike the BZDs, the non-BZDs are less likely to change sleep patterns because they have a minimal effect on the percentage of time spent in stage 3-4 sleep. 14 All 3 agents have FDA-approved labeling for insomnia and should be initiated at the lowest available dose in the elderly population. 1s-is Zolpidem and zaleplon are indicated for the short-term management of insomnia, and it is generally recommended that these agents be prescribed for no more than 1 month at a time. ls,17 A controlled-release formulation of zolpidem is not subject to the same limitation of duration of therapy.16 Eszopiclone has been found to have efficacy in clinical trials up to 6 months and is also FDA approved for use without a specific time limit. 3,18 Major limitations to the use of non-BZDs are COSt19 and abuse potential. 11 Sedation is a common adverse effect of certain antidepressants such as trazodone and the tricyclic class, which makes these medications a viable option for the treatment of insomnia. Additionally, in many cases insomnia is secondary to depression, and an antidepressant with sedating qualities may be used to treat both conditions. Trazodone, a serotonin agonist at higher doses (>150 mg/d) and a serotonin antagonist at lower doses (25-50 mg/d), is the antidepressant most commonly prescribed for insomnia management,a2° The sedative effects of trazodone and its ability to improve sleep parameters are most pronounced within the first 2 weeks of treatment initiation. No published data are available regarding the long-term use of trazodone in the treatment of insomnia. Other antidepressants that have been prescribed for insomnia include amitriptyline and mirtazapine2°; however, data concerning these medications in chronic insomnia are lacking. Antihistamines such as diphenhydramine and doxylamine are common over-the-counter medications used for insomnia.13 These histamine1 (H 0 receptor antagonists are known to cause sedation, drowsiness, and cognitive impairment. Increased dosages of antihistamines do not cause an increase in response rates. 13 Due to the high prevalence of sedative and anticholin-

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ergic effects with antihistamines, this class should not be considered as primary agents for elderly patients with insomnia,a,la Antipsychotics such as quetiapine and olanzapine have been studied in the treatment of insomnia; however, there are insufficient studies to determine their value for short- or long-term therapy. Adverse effects of these agents, such as the metabolic syndrome, weight gain, and hyperglycemia, render these agents unfavorable for the treatment of insomnia.11 Barbiturates such as pentobarbital and secobarbital have fallen out of favor for the management of insomnia due to risks for overdose, tolerance, and drug interactions. At high doses they can cause respiratory depression, and the risks for abuse and misuse of these medications are higher compared with those for newer agents.21 Alternative medications, such as melatonin and valerian root, are available. Supplemental melatonin, in a controlled-release 2-mg formulation, has been found to improve the subjective sleep quality of elderly patients who were melatonin deficient.1a-z2 Melatonin may also positively impact the sleep quality of individuals who are not melatonin deficient, but it has been found to have minimal impact on LPS or TST in these patients.22 Concerns with melatonin include a lack of specificity for melatonin subtypes 1 and 2 (MT 1 and MT2) receptors, a short tl/2, a variation of preparations due to lack of regulation by the FDA, and limited evidence supporting the usefulness of melatonin for the treatment of insomnia,a,6 Valerian root has sedativehypnotic properties, possibly due to a mechanism involving inhibition of GABA transaminase, the enzyme that breaks down and inactivates GABA. 12 As with melatonin, valerian root preparations are not regulated by the FDA. a Agents under development include the non-BZD GABAA receptor agonists gaboxadol and indiplon.4,7 Other therapeutic targets for future development are GABAB, o2 8, serotonin (5-HT2A), H 1 antihistamine, and H a antihistamine receptors, la Mechanism o f Action Three subtypes of mammalian melatonin receptors have been identified and are classified as MT 1, MT2, and MTa. 4,6,7 However, only the MT 1 and MT 2 subtypes are known to play a role in the regulation of sleep. Activation of these receptors leads to an inhibition of adenylate cyclase and a resultant decrease in

cyclic adenosine monophosphate (cAMP) production. 4'7 Ramelteon works by selectively binding and exerting agonist activity at MT 1 and MT 2 receptors in the suprachiasmatic nucleus (SCN), a small area of the hypothalamus,s,23 The SCN acts as the internal clock of the body and is responsible for the generation of the circadian rhythm, which plays an integral role in the sleep-wake cycle.784 Activation of the MT 1 receptor is believed to regulate sleepiness and facilitate sleep onset, while the MT 2 receptor may mediate phase-shifting effects of melatonin on the circadian rhythm.4,7~-s Studies of receptor binding have revealed that ramelteon is a highly selective agonist at MT 1 and MT 2 receptors, with little affinity for the MT 3 receptor. 9,26-29 In an animal study using chick forebrain, ramelteon exhibited a 15-fold greater affinity for the MT 1 receptor than melatonin.26 In contrast, ramelteon had a 100-fold lower affinity for hamster brain MT 2 receptors than melatonin.26,a° When using Chinese hamster ovary cells that express human MT 1 receptors, ramelteon inhibited forskolin-stimulated cAMP production with a 4-fold higher potency than endogenous melatonin.2~,a° Compared with melatonin, ramelteon has a selectivity for MT 1 receptors >1000-fold over that of MT 2 receptors.27 Increased affinity and selectivity for MT 1 receptors suggests that ramelteon may target sleep onset more specifically than melatonin and may be a more suitable medication for insomnia characterized by difficulty falling asleep.7 Ramelteon has no appreciable affinity for BZD, dopamine, opiate, or serotonin receptor sites.2s In addition, it has not been found to have affinity for receptors that bind acetylcholine, norepinephrine, neuropeptides, or cytokines,s The active metabolite of ramelteon, M-II, has no significant affinity for any other receptors, except for a weak affinity for the serotonin 5-HT2B receptor (median inhibitory concentration, 1.75 mM). 2s,29 The weak affinity of M-H for the 5-HT2B receptor is unlikely of clinical importance due to the low serum concentration of the parent compound necessary for the activation of MT 1 receptors.2s Pharmacokinetic Properties Following oral administration, ramelteon is rapidly absorbed, with a Tm~ of <1 hourS,al-3s; however, the absolute bioavailability is low (<2%) due to exten-

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sive first-pass hepatic metabolism. Pharmacokinetic parameters of ramelteon are summarized in Table lII. In a study in 6 healthy male volunteers, a single 16-mg oral dose of (14C)-ramelteon was rapidly absorbed, with a Tmax of 0.3 hour and an elimination tla of 1.2 hours.S1,32 Of the total radioactivity administered, 84% was recovered in the urine and 4% was eliminated in the feces,31,32with metabolites of ramelteon accounting for the majority of radioactivity recovered. The rate of recovery of urinary radioactivity suggested at least 84% absorption of ramelteon following oral administration.31,32 Serum concentrations of ramelteon were low compared with those of its metabolites (actual values not reported), and urinary excretion of the parent compound was negligible (<0.1%). 31,32 Based on those results, it may be concluded that ramelteon undergoes extensive first-pass metabolism. In a crossover study to determine the absolute bioavailability of oral ramelteon, 18 healthy male subjects received a single 16-mg oral dose of ramelteon and a 5-minute, 2-mg IV infusion in random order. 3¢3yThe 2 treatments were separated by a washout period of at least 1 week. Serum samples were collected over 24 hours following ramelteon administration, and the

absolute bioavailability of ramelteon was calculated based on the geometric ratio of AUC0~ between the tablet and IV formulations. The absolute bioavailability of the oral formulation was <2% (range, 0.5%12%).3~ 7 Based on this finding and the results of the previous study, it may again be concluded that ramelteon undergoes extensive first-pass metabolism.3¢37 Karim et al 3s conducted a dose-ascending study in 60 subjects aged 35 to 65 years to further characterize the pharmacokinetic profile of ramelteon. Healthy adult subjects were randomly assigned to receive a single oral dose of ramelteon 4, 8, 16, 32, or 64 mg, or placebo, following a 10-hour fast. Blood samples for pharmacokinetic analyses were collected for 24 hours after ramelteon administration. The group randomized to the lowest dose of ramelteon was treated first, and subsequent groups were treated in an ascending fashion. Eight subjects were randomized to each of the 5 dose groups of ramelteon, and 20 subjects were randomized to placebo. AUC and Cm~,,for ramelteon exhibited dose-proportional pharmacokinetic properties. Mean AUC0_oovalues were 1.71, 6.95, 9.88, 22.5, and 36.1 ng • h/mL for the 4-, 8-, 16-, 32-, and 64-mg doses of ramelteon, respectively, and Cm~, values were 1.15, 5.73, 6.92, 17.4, and 25.9 ng/mL, respectively.

Table III. Selected pharmacokinetic parameters o f r a m e l t e o n after oral administration. Study/Dose* Karim et a138f 4mg 8mg 16mg 32 mg 64 mg Greenblacc and Harrnacz4° 16 mg

Greenblat~ et a141~ 16 mg

Study Population 6M, 6M, 6M, 6 M, 6 M,

2F 2F 2F 2F 2F

tData are mean (%CV).

~Data are mean (SD).

1.71 (114) 6.95 (108)

Cmax,ng/mL

1.15 (109) 5.73 (97)

Tmax, h

tl/2, h

0.78 (43) 0.75 (18)

0.83 (42) 1.36 (36) 1.28 (33) 1.59 (37) 1.90 (53)

9.88 (78) 22.50 (80) 36.10 (71)

6.92 (77) 17.40 (76) 25.90 (77)

0.78 (20) 0.88 (34) 0.94 (31)

12 M 12 M (elderly)

7.7 17.0

12 F

12.9

12 F (elderly)

19.8

5.9 12.0 9.5 11.4

NA NA NA NA

2.2

NA NA

1.57 (0.78) 2.60 (1.14)

12 M, 12 F 12 M, 12 F (elderly)

female; NA = not available. *All data reported are for single-doseoral administration. M = male; F =

AUC, ng. h/mL

10.5 (12.8) 18.7 (19.4)

6.9 (Z6) 11.6 (13.8)

1.2 1.6 1.3

Special Populations Elderly

Tmax values for all doses remained <1 hour (range,

0.75-0.94 hour). The mean elimination tlrz values were short and dose dependent, ranging from 0.83 hour with the 4-mg dose to 1.90 hours with the 64-mg dose. Karim et a139 also examined the effects of food on the pharmacokinetic properties of ramelteon. In a crossover study, 24 healthy subjects were randomized to receive a single 16-mg oral dose of ramelteon 30 minutes following breakfast or following an overnight fast. The 2 treatment periods were separated by a 5-day washout period, and pharmacokinetic samples were collected for 24 hours after each treatment. When ramelteon was administered following a high-fat breakfast, the AUC0_~ of ramelteon increased by 31%. In addition, the Cm~ decreased by 22% and the mean Tmax was delayed by 55 minutes (P < 0.001 for Tmax).8,39 Because Tmax is substantially delayed following a high-fat meal, ramelteon should not be used in conjunction with or immediately following a highfat meal s Ramelteon is -82% protein bound, with the majority being bound to albumin,s After IV administration, ramelteon has a mean volume of distribution of 73.6 L, indicating significant tissue distribution,s Ramelteon is hepatically metabolized primarily via oxidation to hydroxyl and carbonyl groups.S,32 Secondary metabolism of ramelteon produces glucuronide conjugates.S,32 The major hepatic isozyme responsible for metabolism of ramelteon is cytochrome 1)450 (CYP) 1A2. CYPIA2 has implications for drug interactions and will be discussed in detail later in the text. In addition, the CYP3A4 isozymes and CYP2C subfamily are involved to a lesser extent, s Ramelteon has 4 principal metabolites: M-I, MqI, M-Ill, and M-IV. M-II is the only active metabolite and is the most prevalent of the 4 metabolites. After oral administration, M-II concentrations are much higher than ramelteon, resulting in a systemic exposure that is 20- to 100-fold greater than the parent compound,s Ramelteon is rapidly excreted, with an elimination tlr2 of I to 2.6 hours, s Approximately 84% is excreted as metabolites in the urine and 4% is eliminated via the feces,s,32,3~Less than 0.1% of the parent compound is excreted unchanged in the urine or feces,s,31,32,36 The elimination tla of M-II is 2 to 5 hours and is not dose dependent,s

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Greenblatt et al4°,41 evaluated the effects of age and sex on the pharmacokinetic properties of ramelteon. A total of 48 healthy subjects (12 men and 12 women aged 18-34 years, and 12 men and 12 women aged 63-79 years) received a single 1g-rag oral dose of ramelteon following a light breakfast. 4°,41 Pharmacokinetic blood sampling to measure plasma concentrations of ramelteon and M-II was performed over the next 24 hours. Compared with that in young men, ramelteon had a similar mean AUC in elderly men (17.0 vs 7.7 n g . h/mL) and a similar elimination tlr2 (1.6 vs 1.2 hours).4° Elderly women had a similar AUC (19.8 vs 12.9 ng. h/mL) but a prolonged elimination tlr2 (2.2 vs 1.3 hours; P < 0.05). On evaluation of rameheon in all of the elderly subjects compared with younger adults, the AUC, Cm~, and elimination tl/2 of ramelteon were significantly greater in the elderly (AUC, 18.7 [19.4] vs 10.5 [12.8] ng. h/mL [P = 0.011]; Cm~x, 11.6 [13.8] vs 6.9 [7.6] ng/mL [P = 0.024]; tl/2, 2.60 [1.14] vs 1.57 [0.778] hours [P = 0.004]). 41 Overall, the total systemic exposure (AUC0_oo)in elderly subjects was 97% higher and the Cmax was 86% greater compared with those in the younger subjects,s Results were similar for the active metabolite M-II, revealing elevated AUC, Cmax, and tl/2 values in elderly patients (AUC, 482.6 [143.5] vs 375.9 [132.9] ng • h/mL [P = 0.009]; Cm~x, 124.9 [32.0] vs 110.2 [29.7] ng/mL [NS]; tl/2, 3.21 [0.67] vs 2.42 [0.57] hours [P < 0.001]). 41 The dose used in the trial was greater than the 8-mg recommended dose, and although mean systemic exposure and Cm~, were increased in the elderly, the incidences of adverse events were similar between the elderly and young groups.4°,41 While no dosage adjustments are recommended for the geriatric population, the prudent practitioner should monitor these patients closely for the development of adverse effects,s

Hepatic Impairment Karim et a142 also investigated the effects of hepatic impairment on the pharmacokinetic properties of single and multiple doses of ramelteon. A total of 48 patients with varying levels of hepatic impairment were divided into groups based on Child-Pugh score. All patients received a single 16-rag oral dose of ramelteon, and pharmacokinetic samples were collected for 48 hours following ramelteon administration. After a

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2-day washout period, the patients received ramelteon 16 mg/d for 5 days, again followed by sampling for 48 hours. For single doses of ramelteon, AUC and Cm~, were found to be elevated in patients with mild and moderate hepatic impairment (mild, AUC, 6.99 vs 24.2 ng. h/mL and Cm~, 4.4 VS21.1 ng/mL; moderate, AUC, 13.6 vs 109 ng • h/mL and Cm~, 10.7 VS 60.9 ng/mL). Similar data were observed for multiple doses of ramelteon, with the systemic exposure of ramelteon increased by as much as 10-fold; however, the increase in ramelteon systemic exposure did not correlate well with the degree of hepatic dysfunction. Because of the wide therapeutic window of ramelteon, no dosage adjustments are recommended in patients with mild to moderate hepatic dysfunction, although caution should be used in patients with moderate hepatic impairment,s,42 A review of the literature did not identify any published data on the use of ramelteon in patients with severe hepatic impairment; ramelteon use should be avoided in these patients, s Renal Impairment In a similar study, Tolbert et a143 investigated the effects of renal impairment on the pharmacokinetic properties of single and multiple doses of ramelteon. Fifty patients were divided into groups based on the degree of renal dysfunction (healthy = creatinine clearance [CrC1] >80 mL/min, mild = CrCI 50-80 mL/min, moderate = CrCI 30-<50 mL/min, severe = CrC1 <30 mL/min, hemodialysis). As in the previous study, all patients received a single 16-mg oral dose of ramelteon followed by a 2-day washout period. Patients then received ramelteon 16 mg/d for 5 days. In each case, pharmacokinetic samples were collected for 48 hours after the end of the dosing period. Overall, no significant changes were observed in AUC or Cm~ for the renally impaired patients compared with those in the healthy subjects. No correlation was noted between the degree of renal dysfunction and systemic ramelteon exposure following single or multiple doses of ramelteon. Based on these data, no dosage adjustments are necessary for patients with renal impairment or patients who require hemodialysis,s,43

Efficacy and Tolerability Several clinical trials have evaluated the efficacy and tolerability of rameheon compared with placebo in the treatment of transient and primary insomnia.~'~"~.s A summary of the trials is provided in Table IV. To date,

there have been no published trials comparing ramelteon with other therapeutic agents for the management of insomnia. Roth et a144 evaluated the efficacy of ramelteon in the treatment of transient insomnia in 375 healthy volunteers aged 35 to 60 years. To simulate a model of transient insomnia associated with sleep in an unfamiliar environment, the investigators conducted a 1-night study in a sleep laboratory. Eligibility criteria included a usual sleep duration of 6.5 to 8.5 hours, ability to fall asleep within 30 minutes, and a habitual bedtime between 8:30 PM and midnight. Participants also had to be in good overall health and weigh within 20% of ideal body weight. Women were excluded if they were pregnant or nursing. Subjects were also excluded if they had previously slept in a sleep laboratory, had an Epworth Sleepiness Scale49 score >10 (scale for daytime sleepiness; >10 is considered sleepy), had an altered sleeping schedule within 3 months, had flown across 3 or more time zones within the past 7 days, or had any signs or symptoms related to a primary sleep disorder. Volunteers were stratified into 2 treatment groups based on reported sleep duration and were randomized to receive a single oral dose of ramelteon 16 mg (n = 126) or 64 mg (n = 126) or placebo (n = 123). All previous medications (actual medications were not reported) were discontinued 5 half-lives before administration of study medication, and the study drug was administered 30 minutes before scheduled bedtime. Primary outcome measures included polysomnograplay (PSG) recordings to determine the mean LPS. Secondary measures included TST, wake time after sleep onset (WASO), percentage of sleep time per sleep stage, and the number of nighttime awakenings. All study patients completed a postsleep questionnaire to assess subjective sleep latency, subjective TST, number of awakenings, and sleep quality. A Digit Symbol Substitution Test (DSST) was used to assess residual drug effects. Statistical analysis consisted of 2-way analysis of variance, followed by pairwise comparisons to evaluate active treatment arms versus placebo. The effects of ramelteon 16- and 64-mg doses were not direcdy compared. All subjects completed the study. In both ramelteon treatment groups, mean LPS was significantly decreased compared with placebo (P < 0.001), with mean LPS values of 14.1, 15.5, and 24.6 minutes for ramelteon 16 mg, ramelteon 64 mg, and placebo, re-

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spectively. Mean TST was significantly improved in the ramelteon arms versus placebo (425.4 and 422.4 vs 411.3 minutes; P = 0.007 and P = 0.033, respectively). With the exception of subjective sleep latency in the ramelteon 16-mg group, none of the secondary outcomes were significantly different in either ramelteon group compared with placebo. Mean DSST scores were not significantly different between groups. Subjects in the 64-mg group had significant decreases in level of alertness (P = 0.020) and ability to concentrate (P = 0.043) on the postsleep questionnaire. The numbers of reported adverse events were similar between all groups. Headache was the most common (6.7%) adverse event reported in patients receiving either dose of ramelteon. Other adverse events included fatigue (3.2%), somnolence (3.6%), nausea (2.0%), and dizziness (1.6%). Although patients treated with ramelteon had significant improvements in LPS and TST in this simulated model of transient insomnia, the patients did not have a diagnosis of insomnia, and the differences in LPS and TST were generally 15 minutes or less. A double-blind, placebo-controlled study evaluated the use of ramelteon in patients aged 18 to 64 years with primary insomnia (N = 103). 46 Eligible patients had experienced insomnia for >3 months before the study and mean LPS >20 minutes, and had a mean wake time >60 minutes on 2 consecutive screening nights in a sleep laboratory. Each patient was randomized to a 5-treatment schedule that included rameheon 4, 8, 16, and 32 mg and placebo. Each treatment was administered 30 minutes before normal bedtime on 2 consecutive nights, with a washout period of 5 to 12 days between treatments. PSG monitoring was performed to determine LPS, TST, WASO, and sleep efficiency (ratio of TST to total time spent in bed). Other measures included a visual analog scale WAS) for mood and feeling, DSST, memory-recall test, and postsleep questionnaire. Reduction in mean LPS in all ramelteon groups was significant compared with that in the placebo group (all, P < 0.001), with mean LPS values of 24.0, 24.3, 24.0, 22.9, and 37.7 minutes in the ramelteon 4-, 8-, 16-, and 32-mg groups and the placebo group, respectively. Additionally, significant increases in TST were observed with all doses of ramelteon (all, P = 0.001 for overall effect) compared with placebo. Although the increase in TST was found to be statistically significant, the mean TST increased by 11 to 18 minutes in all groups treated with ramelteon compared with pla-

cebo. Patients who received ramelteon spent a lower mean percentage of time in the non-rapid eye movement stage compared with those receiving placebo. The 16-mg group reported a subjective decrease in LPS (P < 0.05) compared with placebo. Other measures, such as the VAS, DSST, memory-recall tests, and subjective levels of alertness and ability to concentrate, were not statistically or clinically significant. Patients reported headache (5.3%), somnolence (1.9%), and pharyngolaryngeal pain (1.9%) as the most common adverse events; however, no differences in adverse events were found among the active-treatment groups and compared with placebo. Zammit et a147 conducted a 35-night double-blind study to evaluate the efficacy of ramelteon in patients with primary insomnia as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. 2 A total of 405 patients (mean age, 39.3 years) were randomized to receive ramelteon 8 or 16 mg or placebo each night. Patients were evaluated in the sleep laboratory on nights 1-2, 15-16, and 29-30. On days 36-37, patients were given placebo and evaluated in the sleep laboratory for the assessment of possible withdrawal effects and rebound insomnia. PSG was used to determine LPS, TST, and sleep efficiency. Patients also completed a postsleep questionnaire. Nights not spent in the laboratory were evaluated using a sleep diary. Mean LPS values for ramelteon 8 and 16 mg were significandy reduced compared with placebo on nights 1-2 (32.2 and 28.9 vs 47.9 minutes; P < 0.001), nights 15-16 (32.6 and 27.9 vs 45.5 minutes; P < 0.001), and nights 29-30 (31.5 and 29.5 vs 42.5 minutes; P = 0.003). Patients treated with ramelteon 8 and 16 mg had significant improvements in TST and sleep efficiency on nights 1-2 (TST, 394.2 and 397.6 vs 375.2 minutes [P < 0.001]; sleep efficiency, 82.3% and 83.4% vs 78.3% [P < 0.001]). Differences in TST and sleep efficiency were not noted on the other nights of sleep laboratory observation. Rebound insomnia and withdrawal effects were not observed. Adverse-event rates were not provided but were reported to be similar between all groups. Seiden et al4s conducted a double-blind, placebocontrolled study of ramelteon use in elderly patients with primary insomnia. The study enrolled 829 patients (aged 63-94 years, mean age, 72.4 years), of whom 693 patients completed the trial. Patients were randomized to rameheon 4 mg, 8 mg, or placebo be-

fore bedtime for 5 weeks. Prior to starting treatment with the study medication, patients completed an initial 7-night placebo lead-in period. After 5 weeks of assigned treatment, the study concluded with a 7-night placebo run-out period to assess rebound insomnia or withdrawal effects. Patients completed a sleep diary and Benzodiazepine Withdrawal Symptom Questionnaire, so The primary end point was patient-reported sleep latency within the first week. In the first week of treatment, mean subjective sleep latency was significandy reduced in patients who received ramelteon 4 and 8 mg compared with that in those who received placebo (4 vs 8 mg, 70.2 vs 78.5 minutes; P = 0.008). Although treatment with ramelteon was associated with statistically significant reductions in subjective sleep latency, the mean difference in sleep latency compared with placebo was 8 minutes, and subjective time to sleep onset was 70 minutes. The investigators did not provide individual data for the 4- and 8-mg groups at later time points but reported significant effects on sleep latency at weeks 3 (P = 0.013) and 5 (P < 0.001) for the 4- and 8-mg groups combined. Mean TST was increased in the 4-mg ramelteon group compared with placebo (4 rag, 313.9 vs 324.6 minutes [P = 0.004]; 8 mg, 313.9 vs 321.1 minutes [P = NS]), although much of the change in TST was probably attributable to the decrease in mean sleep latency. Rebound insomnia after discontinuation of ramelteon was not reported, and no withdrawal effects were observed. Adverse event rates were not provided but were reported to be similar between all treatment groups. In a randomized, double-blind, 3-way crossover study, Roth et al4s evaluated the use of ramelteon in 100 elderly patients with primary insomnia. Patients included in the trial were between 65 and 83 years of age (mean, 70.7 years) and had a diagnosis of primary insomnia for at least 3 months, a bedtime between 8:30 PM and midnight, and a mean sleep latency >_20 minutes on 2 consecutive nights. Patients were randomized to receive ramelteon 4 or 8 nag or placebo, given 30 minutes before bedtime on 2 consecutive nights. Treatments were separated by a 5- to 12-day washout period. The primary outcome was the least squares mean sleep latency of 2-night PSG recordings. Secondary outcomes included next-day effects on psychomotor and memory skills, and patient level of alertness and ability to concentrate. The DSST, memoryrecall tests, and postsleep questionnaires were used to

analyze these measures. Compared with placebo, significant reductions in mean sleep latency were seen in both the 4- and 8-mg ramelteon groups (P < 0.001 and P < 0.010, respectively). TST and sleep efficiency also were significantly improved in these groups (TST: 4 mg, P = 0.036; 8 mg, P = 0.007; sleep efficiency: 4 mg, P < 0.05; 8 mg, P < 0.01). During the treatment period, residual effects of ramelteon were not observed. Nausea (3.5%) and headache (3.5%) were the most commonly reported adverse events in both the 4- and 8-mg treatment groups.

Dosage and Administration Although doses used in clinical trials ranged from 4 to 64 mg, ramelteon is available only as an 8-mg tablet, s The recommended dosage is 8 mg administered orally within 30 minutes of bedtime. Ramelteon should not be used in conjunction with or immediately following a high-fat meal. Patients with mild or moderate hepatic impairment may use ramelteon with caution, but those with severe impairment should not use ramelteon. No dosage adjustments are recommended for patients with renal impairment, including patients with severe renal impairment or those who require hemodialysis. Ramelteon is classified as pregnancy category C and should be used in pregnancy only if the benefits clearly outweigh the risks to the fetus, s No published data are available regarding the use of ramelteon in pediatric patients or patients with severe sleep apnea or severe chronic obstructive pulmonary disease (COPD); therefore, no dosage recommendations exist for these populations. Adverse Events Ramelteon has been found to be generally well tolerated in clinical trials, with most adverse events classified as mild or moderate. 6,s,as,37,4°,41,44,46 Adverse events most commonly seen with ramelteon 8 mg included headache (7%), somnolence (5%), dizziness (5%), fatigue (4%), and nausea (3%). In clinical studies with ramelteon, 5% of patients discontinued treatment due to adverse effects. Patients were most likely to discontinue treatment due to headache, somnolence, fatigue, or dizziness,s Following the administration of ramelteon, patients did not report rebound insomnia or withdrawal effects.44,4~,49 Compared with placebo, patients receiving ramelteon did not exhibit any evidence of cognitive impairment as observed in several clinical trials using tools such as the DSST, memory tasks, and VAS.3s,44,46In patients with mild to moderate COPD or

those with mild to moderate obstructive sleep apnea, no significant respiratory depressant effects or exacerbations of sleep apnea were seen with ramelteon treatment, sl-s2 Two studies were conducted to evaluate the effects of ramelteon on endocrine function,s,s3 In the first study, 99 healthy volunteers were randomized to receive ramelteon 16 mg or placebo for 28 nights,s3 Blood samples were drawn at baseline and days 14, 29, and 42 to analyze levels of adrenocorticotropic hormone, cortisol, estradiol, follicle-stimulating hormone, luteinizing hormone, prolactin, testosterone, thyroid-stimulating hormone, thyroxine, and triiodothyronine. The investigators found no significant differences between ramelteon and placebo in any of the hormone levels measured. The major limitation of that study was the short duration. In the second endocrine function study, 122 patients with chronic insomnia were randomized to receive ramelteon 16 mg or placebo for 6 months, s The effects of ramelteon on the thyroid, adrenal, and reproductive axes were evaluated. Increases in serum prolactin levels occurred in 32% of patients who received ramelteon compared with 19% of patients who received placebo. The mean change from baseline in prolactin level was significantly greater in women in the ramelteon group compared with that in women in the placebo group (P = 0.003). The mechanism for increased prolactin is not understood at this time. Also, both endocrine function studies used ramelteon 16 mg, which is greater than the recommended dose. Abuse Potential The abuse potential and effects on behavior of ramelteon were compared with those of triazolam in a double-blind, crossover study by Griffiths et al.s4 That study was the only available publication we found that compared the abuse potential of ramelteon with those of another agent; however, efficacy was not evaluated. Fourteen adult patients with known histories of sedative drug abuse received single oral doses of ramelteon 16, 80, and 160 mg; triazolam 0.25, 0.50, and 0.75 mg; and placebo. The method of study drug assignment (ie, randomization) was not stated. Each of the 7 treatments was separated by a washout period. A subjective questionnaire was used to measure abuse potential. Behavioral and cognitive performance was measured using a Word Recall/Recognition Task, Enter and Recall Task, Balance Task, DSST, and Circular Lights performance. Compared with placebo, patients treated with

doses of ramelteon up to 20-fold the recommended dose had no differences on questionnaire items such as "drug liking, .... good effects,.... drug strength," and "street value." In addition, ramelteon was found to have no significant effect on behavioral and cognitive performance. Consistent with the known potential for abuse, triazolam 0.50 and 0.75 mg were associated with increased "drug liking" on questionnaires and impaired task performance on behavioral assessments.

Drug-Drug Interactions Because CYP1A2 is the major isozyme responsible for hepatic metabolism of ramelteon, medications that induce or inhibit the activity of the isozyme may cause significant alterations in ramelteon metabolism and systemic exposure. The isozymes CYP2C and CYP3A4 affect the metabolism of ramelteon to a minor degree. Some medications that are strong CYP1A2 inhibitors indude amiodarone, ciprofloxacin, and fluvoxamine,ss To determine the potential for a pharmacokinetic interaction between fluvoxamine, a selective serotonin reuptake inhibitor, and ramelteon, subjects were administered fluvoxamine 100 mg BID for 3 days prior to receiving a single dose of ramelteon 16 rag.s The concurrent use of these medications resulted in a 190fold increase in the AUC of ramelteon, as well as a 70fold increase in Cm~,,. Therefore, ramelteon should not be used in patients receiving fluvoxamine,s Studies have not adequately addressed the potential drugdrug interactions with the combination of ramelteon and other CYP1A2 inhibitors, but ramelteon should be used with caution and close monitoring in patients receiving these agents,s Other medications reported to increase levels of ramelteon in clinical trials, such as fluoxetine (CYP2D6 inhibitor) and ketoconazole (CYP3A4 inhibitor), did not cause clinically significant drug-drug interactions, although they increased exposure to ramelteon and the metabolite M-II, suggesting a need for close monitoring in these patients, as well.s,st,s7 In contrast, rifampin, a strong inducer of the CYP enzyme system, significantly decreased total exposure to ramelteon and M-II following administration of rifampin 600 mg/d for 11 days. Thus, the efficacy of ramelteon may be compromised in the presence of rifampin. Drugs with a narrow therapeutic index were also assessed in clinical trials to evaluate the potential for interactions. Digoxin (pglycoprotein substrate), warfarin (CYP2C9 [S]/CYPIA2 [R] substrate), and theophylline (CYPIA2 substrate)

had no clinically significant effect on ramelteon or vice versa, s,ss,59 Other medications studied with similar findings include omeprazole,c'° dextromethorphan,~1 and

www.sleepfou ndation.org/hottopics/index, ph p?secid9&id-215. Accessedjanuary 17, 2006. 2. American Psychiatric Association, Task Force on DSM-/V.

midazolam. ~z Pharmacoeconomic Considerations

Our literature search found no published studies that evaluated the cost-effectiveness of rameheon in the treatment of insomnia. The average wholesale price of a 30-day supply of ramelteon 8 mg administered daily was $81.00.19 In comparison, the cost of a 30-day supply of the conventional recommended adult doses of the non-BZDs zolpidem, zaleplon, and eszopiclone were $101.84, $102.82, and $121.14, respectively.19 The cost of rameheon was less than that of the non-BZDs; however, because it is the first drug in its class and no pharmacoeconomic studies are available, the cost-effectiveness of ramelteon in the treatment of insomnia remains to be determined. CONCLUSIONS

Ramelteon, the first FDA-approved melatonin receptor agonist, represents a pharmacologic option for the treatment of insomnia characterized by difficulty falling asleep. In clinical studies of patients with primary insomnia, treatment with ramelteon was associated with small but statistically significant decreases in sleep latency at doses ranging from 4 to 32 mg. Effects on TST and sleep efficiency were less pronounced and were not consistently observed in all clinical studies. In general, ramelteon was well tolerated, with the main adverse effects consisting of headache, somnolence, dizziness, fatigue, and nausea. No evidence of cognitive impairment, rebound insomnia, withdrawal effects, or abuse potential have been noted. Elevated prolactin levels were associated with administration of rameheon in 1 trial. With a lack of published trials comparing ramelteon with other sedative-hypnotic agents, it is not yet possible to determine its efficacy relative to other therapeutic options for insomnia. ACKNOWLEDGMENT

The authors thank David Gazze, PhD, of Nova Southeastern University College of Pharmacy, Fort Lauderdale, Florida, for his review of the manuscript.

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Address correspondence to: Karen L. Daniel, PharmD, CDE, Nova Southeastern University College of Pharmacy, 3200 South University Drive, Fort Lauderdale, FL 33328-2018. E-mail: [email protected]