Rozerem Insert pdf/2008 - American Pharmacists Association

For a brief summary of prescribing information for ROZEREM, please see the ROZEREM ad on pages 9 and 10. 

To view the complete prescribing information, visit www.ROZEREM.com.

Here’s what you’ll fi nd 

in this therapeutic review . . . 

Understanding Insomnia 

The prevalence and characteristics of insomnia, 

how it is diagnosed, and its impact on patients ............................................. 1 

Treatment of Insomnia 

A brief overview of available treatments 

for patients with insomnia ............................................................................. 1 

The Pharmacist’s Guide to Assessing 

Patients With Insomnia 

When to assess patients for insomnia and the 

types of questions to ask ................................................................................. 3 

What Pharmacists Should Know 

About ROZEREM ® (ramelteon) 

The efficacy and safety of ROZEREM* ......................................................... 4 

* For important safety information, please see the ROZEREM ad on pages 9 and 10. 

Supporting Appropriate Use of ROZEREM 

Important information for educating patients about 

the appropriate use of ROZEREM, in a practical, 

straightforward, question-and-answer format ............................................... 6 

Resources 

Useful sources on insomnia and its treatment .............................................. 7 

References ................................................................................................... 8 

Reviewer: 

Disclosure: 

Michelle Kasperowicz, RPh 

Pharmacist 

Shop Rite Pharmacy, Woodbridge, New Jersey 

This publication was prepared by Judy Crespi-Lofton, MS, of JCL Communications on behalf of the 

American Pharmacists Association. 

This program was developed by the American Pharmacists Association and supported by a grant from Takeda. 

The publication went through a full medical and legal review by Takeda. 

©2008 by the American Pharmacists Association. All rights reserved. Printed in the U.S.A.

UNDERSTANDING INSOMNIA 

(ramelteon) 

Insomnia 

1 , 2 

is defined as unsatisfactory sleep that impacts daytime functioning in a patient who has the opportunity to sleep. 

It may be characterized as difficulty falling asleep (i.e., long sleep-onset latency), difficulty staying asleep (i.e., nocturnal awakening), 

or nonrestorative sleep. 3 Insomnia is very common in the United States, affecting at least one-third of adults. Roughly 

10% to 15% of adults have chronic insomnia 2 (lasting 30 days or longer) 4 ; another 25% to 35% experience occasional insomnia. 5, 6 

Causes of Insomnia 

There are many possible causes of insomnia. Acute 

insomnia (less than 30 days) is generally triggered by 

situational factors, such as grief or stress (e.g., from 

relationships, job responsibilities, financial concerns). 1 

Chronic insomnia, on the other hand, often coexists 

with another condition, such as chronic pain, a psychiatric 

disorder, or a variety of medical conditions 1 (e.g., 

pulmonary or gastrointestinal disorders, heart disease 

or allergies). 2 Other sleep disorders can also contribute 

to insomnia, such as obstructive sleep apnea, restless leg 

syndrome, or narcolepsy. 4 In addition, chronic insomnia 

may be caused by many medications (Table 1). 1 When 

insomnia coexists with another condition, it is considered 

“comorbid insomnia.” If no coexisting disorder can be 

identified, the term “primary insomnia” is used. 4 

Chronic insomnia may last for a short period (a 

few months) or may persist for decades. It can go into 

remission and recur at a later time, or be continual. 4 

Effects of Insomnia 

Insomnia can hinder daytime function and impair 

memory and cognitive functioning. 4 Daytime fatigue 

from insomnia also may result in safety issues or poor 

performance at work, and can be a driving hazard. 2 

Insomnia can trigger or worsen many medical 

conditions. Chronic insomnia appears to be 

particularly associated with the development of 

depression. 2 

TREATMENT OF INSOMNIA 

A 

number of strategies are used in the treatment of 

insomnia, including both nonpharmacologic and pharmacologic 

approaches. 2 

Nonpharmacologic approaches, some of which may 

overlap, include: 

− Cognitive behavioral therapy, which has been 

shown to be effective in randomized controlled 

trials and is recommended for the treatment 

of insomnia in most patients. Such therapy 

can include increasing patients’ understanding 

of sleep, improving and maintaining sleep 

hygiene, stimulus control, and adopting sleep 

restrictions (Table 2). 2 

− Relaxation training, which includes progressive 

muscle relaxation, meditation and yoga, can 

help patients with insomnia break the cycle of 

worrying about being tired the next day, which 

Diagnosing Insomnia 

The diagnosis of insomnia is usually based on the 

report of symptoms by the patient or caregiver. A variety 

of tools, such as sleep diaries and post-sleep questionnaires, 

may be used to aid the diagnosis, although no specific 

test is required to make a diagnosis and there are no 

standardized diaries or questionnaires. A multichannel 

polysomnography (sometimes performed in a sleep 

laboratory) can also be used to precisely monitor a patient’s 

sleep patterns, but can be expensive and disruptive, which 

limits its usefulness in diagnosing insomnia. 4 

A medical history and physical examination to identify 

any comorbid conditions that contribute to insomnia should 

be performed during a diagnostic evaluation. 4 

Table 1. Medications That May Cause Insomnia 1 

■ Anticholinergic agents 

■ Antidepressants (SSRIs, bupropion, MAOIs) 

■ Antiepileptics (lamotrigine, phenytoin) 

■ Antineoplastics 

■ Beta blockers 

■ Bronchodilators (beta agonists) 

■ CNS stimulants (methylphenidate, dextroamphetamine) 

■ Nicotine 

■ Steroids 

■ Oral contraceptives 

■ Progesterone 

■ Thyroid replacement hormone 

■ Miscellaneous (diuretics, atorvastatin, levodopa, quinidine) 

can lead to the inability to fall asleep. 2 

− Exercise, which has also been shown to be 

effective for treating insomnia, 1 as long as it is 

not done too close to bedtime. 2 

Pharmacologic therapies may be used if nonpharmacologic 

therapies fail, when immediate symptom response is desired, 

when insomnia produces severe impairment, or when insomnia 

persists after treatment of an underlying medical condition. 1 

Sleep aids available over-the-counter, including drug products 

containing diphenhydramine, 7,8 are used by almost 25% of 

patients with insomnia; however, there are several drawbacks 

associated with these products. Their efficacy is weak, and 

they may reduce sleep quality and can cause residual daytime 

drowsiness 1 and functional impairment. 9 Tolerance to their 

sleep-inducing effects develops quickly, making over-the-counter 

sleep aids poorly suited to treat insomnia that lasts for more than 

a few nights. 9 These agents also are associated with anticholin- 

Rozerem ® (ramelteon) 1

Table 2. Good Sleep Hygiene Measures 2,34 

Establish a regular sleep 

schedule 

Create a relaxing sleep 

environment 

Practice stimulus control— 

train your body to associate 

the bed with sleep 

Avoid stimulants close 

to bedtime 

· Avoid daytime naps 

· Go to bed and get up at the same time every day, including weekends (whenever possible) 

· Establish a relaxing bedtime routine 

· Make sure your bed is comfortable 

· Keep your room at a comfortable temperature 

· Minimize light and noise 

· Remove clocks, or position them so they cannot be seen from the bed 

· Avoid activities, such as watching television or paying bills, in bed 

· If you wake up during the night and cannot fall back asleep within 20 minutes, get up and 

engage in a quiet activity until you feel sleepy again 

· Avoid: Caffeine, Nicotine, Vigorous exercise 

ergic effects, including dry mouth, blurred vision, urinary 

retention, constipation, and risk of increased intraocular 

pressure in patients with narrow angle glaucoma. 4 

Several herbals and dietary supplements, including 

valerian and melatonin, are used as sleep aids. 1 In general, 

these products have insufficient evidence of benefit, 

and little is known about the safety of these products, 

especially for long-term use. 1,4 

Alcohol is also used by a substantial proportion of 

adults to help them sleep. 10 One general population 

survey found that 13% of adults 18 to 45 years of age 

reported using alcohol as a sleep aid in the past year; 

5% reported using a combination of alcohol and medications 

intended to treat insomnia. In other surveys, up 

to 28% of patients have reported using alcohol to help 

them sleep. 10 Although alcohol can reduce sleep-onset 

latency, it reduces the quality of sleep 4 and can actually 

increase daytime sleepiness and promote future sleep 

disturbances. 10 Furthermore, the use of alcohol as a 

sleep aid should be limited due to alcohol’s potential 

for abuse. 

Prescription products that are indicated for the 

treatment of insomnia include benzodiazepines, nonbenzodiazepines, 

and melatonin receptor agonists. 11 

Benzodiazepines, such as flurazepam, temazepam, 

and triazolam, improve sleep onset and reduce nocturnal 

awakening, increasing total sleep time, by binding to 

GABA receptors in the brain. 1 Residual daytime sleepiness 

11 resulting in reduced function may be a problem 

following the use of these products. 11,12 In addition, 

some may produce physical dependence, resulting in 

withdrawal symptoms and rebound insomnia when 

they are discontinued. With benzodiazepines, this may 

occur after only 1 to 2 weeks’ use. Benzodiazepines 

have an abuse potential and are scheduled drugs. 11,12 

In patients with sleep-related breathing disorders (e.g., 

obstructive sleep apnea), benzodiazepines also may 

have the potential to worsen hypoxia. 9 

Non-benzodiazepines, such as eszopiclone, zolpidem, 

or zolpidem CR, 1 are more selective in their affinities 

for different subtypes of GABA receptors. 11 They 

have fewer adverse effects than benzodiazepines but can 

cause memory impairment, 1 rebound insomnia, withdrawal 

symptoms, dizziness, drowsiness, and headache. 

They may also have potential for abuse. 13 

ROZEREM ® (ramelteon) is the only nonscheduled 

prescription medication approved for the treatment of 

insomnia characterized by difficulty with sleep onset. 14 

The prescribing information should be carefully consulted 

for detailed information about the benefits and 

risks of each medication to select the most appropriate 

product for a patient. 

Considerations for Treating Insomnia in Older Adults 

Insomnia has been found to occur at 

higher rates in the elderly. In one 

study, more than 50% of 9,000 adults 

65 years of age and older reported at 

least one chronic sleep complaint. 9 

This increased prevalence may be at 

least partially attributed to declining 

health and institutionalization, 4 but 

also appears to result from changes 

in circadian rhythms associated with 

aging. Circadian sleep-wake rhythms 

appear to be less pronounced in the elderly, 

which can reduce the quality of 

sleep and increase daytime sleepiness. 

These circadian rhythm changes may 

be due in part to decreased melatonin 

secretion. In addition, many medical 

conditions that may trigger insomnia 

become more prevalent as people age. 9 

Chronic insomnia in the elderly 

may increase the likelihood of cognitive 

dysfunction, falls, depression, 

potential early institutionalization, 

decreased quality of life, and increased 

mortality. 9 

Treatment of insomnia in the 

elderly generally follows the same recommendations 

for younger patients. 

However, extra caution is warranted 

due to altered pharmacokinetics and 

pharmacodynamics, and the increased 

likelihood that patients will be taking 

other medications. 9 

Cognitive behavioral therapy 

approaches to insomnia have been 

shown to be as effective in the elderly 

as in younger adults. If medications 

are prescribed for treatment of insomnia 

in the elderly, any neurologic, 

cognitive, hepatic, or renal changes 

that may be present should be taken 

into account when selecting a dosage. 

In addition, elderly patients may be 

more sensitive to the hypnotic effects 

of insomnia medications. 9 Residual 

daytime drowsiness associated with 

some prescription agents 11 may be of 

particular concern in the elderly. 9 

2 TODAY IN PHARMACY DRUG THERAPY

the pharmacist’s guide 

to assessing patients 

with insomnia 

the majority of patients with difficulty sleeping do 

not consult a health care professional for help. 10 

Pharmacists, who are the most accessible health care 

providers, can question patients about their sleep habits 

when providing patient care services, provide education 

as appropriate, and refer patients for additional evaluation 

when necessary. In addition, patients with conditions 

that are commonly associated with insomnia, such as 

depression, can be questioned about their sleep quality as 

part of regular patient counseling. 1 Questions assessing 

the quality of patients’ sleep can also be asked of patients 

who seek guidance on the purchase of over-the-counter 

sleep aids and dietary supplements. 

Patients who report difficulty sleeping should be 

asked about the nature of their insomnia, including when 

they began experiencing problems, whether they have 

difficulty falling and/or staying asleep, or whether sleep 

is nonrestorative. 4 It 

is important to keep in 

mind that daytime fatigue 

resulting from inadequate 

sleep is not considered 

insomnia if the patient 

does not allow himself or 

herself, through choice 

or life circumstance, the 

opportunity to obtain an 

adequate night’s sleep, 

usually 7 to 8 hours. 2 

Pharmacists can provide good sleep hygiene measures 

and recommendations to patients on improving their 

sleep schedule, bedtime routine, or sleep environment. 1 

However, it is important to tailor recommendations to a 

patient’s specific situation. For example, it would not be 

practical to advise a shift worker to maintain a regular 

sleep-wake schedule. 

Pharmacists can further work in conjunction with 

other health care providers to look carefully at a patient’s 

history to determine whether any predisposing factors are 

present, including a complete review of comorbid medical 

conditions. The patient assessment should also determine 

whether other sleep disorders that could contribute to 

insomnia, such as obstructive sleep apnea, restless leg 

syndrome, or narcolepsy, are present. 4 Pharmacists can 

work with the patient’s health care provider to ensure 

that any underlying causes of insomnia that are identified 

are addressed in the treatment plan. (For example, if the 

patient cannot sleep due to chronic pain, it is important to 

ensure that the patient’s pain is controlled.) In addition, 

pharmacists can examine the patient’s medications to 

determine whether any could be triggering insomnia, 1 and 

work with the patient’s prescriber to determine whether 

any modifications are possible. 

 

 

 

 

 

 

 

 

 

 

Questions 

to ask 

“Do you go to bed and wake 

up at the same time each 

day, including weekends” 

“Is your sleep environment 

cool, dry, quiet, and 

comfortable” 

“Do you avoid alcohol 

or foods/drinks high in 

caffeine close to bedtime” 

“Do you use your bed 

primarily for sleep” 

“Do you exercise at least 

three hours before bedtime 

and fall asleep easily that 

night” 

“Do you sleep on a 

comfortable mattress or 

pillow” 

“Do you have a regular 

relaxing routine to help 

wind down from the day 

BEFORE getting into bed” 

“Do you finish eating at 

least two to three hours 

before your regular 

bedtime” 

“Do you avoid cigarettes 

and other tobacco products 

close to bedtime” 

“Do you avoid taking naps 

during the day” 

Rozerem ® (ramelteon) 

3

WHAT PHARMACISTS SHOULD KNOW 

ABOUT ROZEREM ® (ramelteon) 

ROZEREM is a melatonin receptor 

agonist that was approved by the 

U.S. Food and Drug Administration 

(FDA) in July 2005 for the treatment 

of insomnia characterized by difficulty 

with sleep onset. It is the first and only 

prescription insomnia medication that 

has not been designated as a controlled 

substance (i.e., it is “nonscheduled”) 14 

and has shown no evidence of abuse 

potential, 12 withdrawal, 14 middle-of-thenight 

balance impairment, 15 or rebound 

insomnia in clinical studies. 14 It also 

does not work by depressing the general 

central nervous system (CNS), 14,16 but 

instead works with the brain’s normal 

sleep-wake cycle. 14 

Melatonin plays an important role 

in working with the sleep-wake cycle 

by helping to regulate the suprachiasmatic 

nucleus (SCN), 17 a region of the 

hypothalamus involved in circadian 

rhythms. 18 Melatonin acts at melatonin 

receptors in the SCN called MT 1 

and 

MT 2 

. 19 The MT 1 

receptors in the SCN are 

associated with normal sleep induction, 

while the MT 2 

receptors are associated 

with maintaining circadian rhythm. 18,20 

Melatonin is secreted from the 

pineal gland and helps control the 

function of the SCN. The synthesis and 

secretion of melatonin is affected by 

exposure of the eyes to light and follows 

a circadian pattern—low during the day 

(in daylight) and high during the night 

(in darkness). It is believed that melatonin 

inhibits activity in the SCN that 

produces wakefulness. Therefore, high 

melatonin concentrations contribute to 

the creation of a state that allows sleep. 17 

ROZEREM targets the MT 1 

and 

MT 2 

receptors in the brain. The activity 

at these receptors in the SCN is believed 

to promote sleep. 14,21 

Efficacy 

The efficacy of ROZEREM in 

decreasing the mean latency to persistent 

sleep (LPS) has been demonstrated 

in clinical trials using dosages ranging 

Table 3. Clinical Studies Demonstrating the Efficacy of ROZEREM 

from 4 mg to 64 mg in both younger (18 

to 64 years of age) and older (at least 65 

years of age) adults. 14,22 Several studies 

also have demonstrated efficacy and 

increased total sleep time. 14,23 Efficacy 

has been demonstrated in the treatment 

of both acute insomnia and chronic insomnia, 

for up to five weeks of treatment 

in adults (Table 3). 14,24,25,26 No evidence 

of rebound insomnia (worsening of insomnia 

after stopping use of a sleep aid) 

or withdrawal effects were seen in any of 

these clinical studies. 14 

Special Populations 

Additional clinical trials have 

been conducted to assess the safety of 

ROZEREM with sleep-related breathing 

disorders. In one study, the safety of a 

single bedtime dose of ROZEREM 16 mg 

compared with placebo was studied in 26 

patients with mild-to-moderate chronic 

obstructive pulmonary disease (COPD) 

in a double-blind, randomized, crossover 

trial. ROZEREM had no statistically sig- 

Patient Population and 

Study Intervention 

375 healthy adults 35–60 years of 

age in a novel sleep environment 

Single dose of ROZEREM 16 mg, 

64 mg, or placebo 

107 patients with chronic 

insomnia, 18–64 years of age 

Two days of treatment with each 

of the following in a randomized 

dosing sequence: ROZEREM 4 mg, 

8 mg, 16 mg, 32 mg, and placebo 

405 adults with chronic insomnia 

Five weeks’ treatment with 

ROZEREM 8 mg, 16 mg, or 

placebo 

829 older adults with chronic 

insomnia, ≥65 years of age 

Five weeks’ treatment with 

ROZEREM 4 mg, 8 mg, or placebo 

100 older adults with chronic 

insomnia 65–83 years of age 

(crossover) 

Two days of treatment with 

ROZEREM 4 mg, 8 mg, or placebo 

in a randomized dosing sequence 

(crossover) 

Objective 

To evaluate the efficacy of ROZEREM 

for the treatment of transient insomnia 

in healthy adults 

To evaluate the efficacy, safety, and 

dose response of ROZEREM in patients 

with chronic primary insomnia 

To evaluate safety and efficacy of 

ROZEREM in subjects with chronic 

primary insomnia 

To assess the safety and efficacy of 

ROZEREM for chronic insomnia treatment 

in older adults 

To assess the efficacy and safety of 

ROZEREM for insomnia treatment in 

older adults (crossover) 

Results 

Both dosages of ROZEREM significantly reduced objective LPS and 

increased objective TST. Only the 16 mg dose significantly reduced 

subjective sleep latency and increased subjective TST, using a postsleep 

questionnaire. 22 

All dosages of ROZEREM significantly reduced objective LPS and 

increased objective TST. Subjective sleep latency was significantly 

reduced only at the 16 mg dose, based on a post-sleep questionnaire. 

Several assessments revealed no next-day residual effects at any 

dose. 23 

Both dosages of ROZEREM significantly reduced objective LPS 

throughout the five weeks of treatment. Objective TST was increased 

for both dosages at week 1, and continued to be significantly 

longer than placebo at week 3 for the 16 mg dose. Further, 

based on a post-sleep questionnaire, both dosages of ROZEREM 

significantly reduced subjective sleep onset and increased subjective 

TST throughout the five weeks of treatment with the 8 mg 

dose. The 16 mg dose showed significant reduction in subjective 

sleep onset at weeks 1 and 3 and increased TST at week 1. No 

evidence seen of next-day residual effects, withdrawal symptoms, 

or rebound insomnia after completion of treatment. 25 

Patient-reported data were collected using sleep diaries. Both 

dosages of ROZEREM significantly reduced subjective sleep latency 

throughout the five weeks of treatment, except for the 4 mg dose at 

week 3. Subjective TST was increased at week 1 and week 3 

(4 mg). No differences were seen across 5 weeks for 8 mg. No 

evidence of rebound insomnia or withdrawal symptoms. 24 

Both dosages of ROZEREM significantly reduced LPS and improved 

TST (objective only). For subjective sleep latency, using a 

post-sleep questionnaire, only the 4 mg dose showed significant 

reductions. No evidence seen of adverse next-day psychomotor or 

cognitive effects. 32 

LPS = latency to persistent sleep; TST = total sleep time. 

4 TODAY IN PHARMACY DRUG THERAPY

nificant effect on any measure of arterial 

oxygen percent saturation (SaO 2 

). The 

mean percent SaO 2 

for the entire night 

was 92.9% in both treatment groups. 

The mean apnea-hypopnea index was 

also similar in both treatment groups. 27,28 

ROZEREM has also been studied in patients 

with severe COPD 29 ; however, the 

FDA has not yet evaluated these studies 

and ROZEREM is not currently recommended 

for this patient population. 14 

A similar study was conducted to 

assess the safety of ROZEREM in patients 

with mild-to-moderate obstructive 

sleep apnea. Twenty-six adults received 

a single bedtime dose of ROZEREM 

16 mg in a double-blind, randomized, 

crossover trial. The apnea-hypopnea 

index was similar in both treatment 

groups. ROZEREM had no effect on the 

number of central, obstructive, or mixed 

apnea episodes, nor was there any significant 

effect on mean SaO 2 

. 30 Although 

ROZEREM did not exacerbate sleep 

apnea, it has not been studied in patients 

with severe sleep apnea and is not recommended 

for this patient population. 14 

Safety and Precautions 

ROZEREM is well tolerated, with 

rates of adverse events reported in clinical 

trials similar to those seen with placebo. 

The most common adverse events 

seen with ROZEREM that had at least 

a 2% incidence difference from placebo 

were somnolence, dizziness, and fatigue 

(Table 4). Further, in clinical studies, 

ROZEREM has been shown to promote 

sleep without the risks of abuse potential, 

withdrawal, middle-of-the-night balance 

impairment, or rebound insomnia. 14,15 

Two studies have assessed the 

effects of ROZEREM on endocrine function. 

In the first study, no differences 

were found between ROZEREM 16 mg 

and placebo after 28 days of treatment 

in 99 healthy volunteers. Hormone 

levels assessed included adrenocorticotropic 

hormone, cortisol, estradiol, 

follicle-stimulating hormone, luteinizing 

hormone, prolactin, testosterone, 

thyroid-stimulating hormone, thyroxine, 

and tri-iodothyronine. 31 

In the second study, 6 months of 

treatment with ROZEREM 16 mg or 

placebo were compared in 122 patients 

with chronic insomnia. In this study, 

prolactin levels were significantly 

increased in women who received 

ROZEREM. The mechanism for this 

effect remains unclear. 31 

ROZEREM was found to decrease 

circulating testosterone levels in the rat. 14 

It is not known how the effects 

Table 4. Treatment-Emergent Adverse Events 

in Phase 1–3 Clinical Trials of ROZEREM 14 

Adverse Event 

noted on reproductive hormones 

(decreased testosterone and increased 

prolactin) might affect the reproductive 

axis in adolescents and children. The 

safety and efficacy of ROZEREM has not 

been studied in these patients. Patients 

should consult a health care provider if 

they experience amenorrhea, galactorrhea, 

decreased libido, or problems with 

fertility. In addition, patients should 

consult a health care provider if they 

have worsening insomnia or experience 

any new symptoms of concern. 14 

ROZEREM has a “Pregnancy 

Category C” labeling. There are no 

adequate and well-controlled studies 

of ROZEREM in pregnant women. 

ROZEREM should be used during 

pregnancy only if the potential benefit 

justifies the potential risk to the fetus. 14 

As ROZEREM is metabolized 

by the liver, it should not be used 

in patients with severe hepatic 

impairment, and should be used with 

caution in patients with moderate 

hepatic impairment. 14 

Placebo (%) 

n=1,370 

ROZEREM 8 mg (%) 

n=1,250 

Headache NOS 7 7 

Somnolence 3 5 

Fatigue 2 4 

Dizziness 3 5 

Nausea 2 3 

Insomnia exacerbated 2 3 

Upper respiratory tract 

infection NOS 

2 3 

Diarrhea NOS 2 2 

Myalgia 1 2 

Depression 1 2 

Dysgeusia 1 2 

Arthralgia 1 2 

Influenza 0 1 

Blood cortisol decreased 0 1 

Potential for Abuse 

Available evidence indicates that 

ROZEREM is unlikely to be abused. A 

clinical trial in subjects with a history of 

poly-drug abuse found no indication 

of abuse potential for subjects receiving 

ROZEREM, even at doses up to 20 times 

the recommended therapeutic dose. 12 

Binding affinity of ROZEREM to receptors 

associated with abuse and impairment 

(e.g., dopamine receptors, opiate 

receptors) is minimal. 21 (Preclinical 

studies in monkeys found no signs of a 

reinforcing effect.) No signs of physical 

dependence or withdrawal symptoms 

have been noted in clinical studies lasting 

up to 5 weeks. Likewise, no signs of 

memory or psychomotor impairment 

have been noted. 12 

Dosage and Administration 

The recommended dose of 

ROZEREM is 8 mg taken within 30 

minutes of going to bed. After taking 

ROZEREM, patients should limit their 

activities to those required to get ready 

for bed and avoid potentially hazardous 

situations. A high-fat meal may delay 

the onset of effect of ROZEREM, 

and increase total exposure to the 

drug. Therefore, it is recommended 

that ROZEREM not be taken with or 

immediately after a high-fat meal. 14 

ROZEREM is primarily metabolized 

by CYP1A2. Fluvoxamine, which 

is a strong CYP1A2 inhibitor, should 

not be used in combination with 

ROZEREM. Caution should be used 

if ROZEREM is combined with other 

CYP1A2 inhibitors. 14 

Alcohol has not been shown to alter 

the pharmacokinetics of ROZEREM, 

but may have an additive effect on 

measures of alcohol performance. Because 

of these additive effects, patients 

should be cautioned not to consume 

alcohol when using ROZEREM. 14 


SUPPORTING APPROPRIATE USE OF ROZEREM 

As with any medication, ROZEREM should 

be used appropriately. Pharmacists can 

help patients use ROZEREM appropriately 

by educating them about the use of this product. 

Pharmacists can review the patient’s medical and 

prescription history to check for any potential drugdrug 

interactions. 

Patient education should emphasize that 

ROZEREM should be taken within 30 minutes of 

bedtime, and that activity should be limited after taking 

ROZEREM. In addition, patients should be instructed 

to avoid consuming a high-fat meal in conjunction with 

ROZEREM. 14 

Pharmacists may educate patients that they may 

begin to derive benefit from ROZEREM the first night 

that they take it, and that studies have shown sustained 

efficacy up to five weeks. Furthermore, pharmacists 

can educate patients that no signs of rebound insomnia 

or withdrawal symptoms have been noted when 

patients discontinue ROZEREM. 14 

Questions you may have about ROZEREM 

Q. Which patients might ROZEREM be appropriate for 

A. In clinical trials, ROZEREM has been shown to significantly 

reduce latency to persistent sleep. Therefore, it 

is likely to benefit patients whose insomnia is characterized 

by long sleep-onset latency (i.e., patients who 

have trouble falling asleep). Efficacy has been demonstrated 

in adults 18 to 64 years of age, 14,25 and older 

adults 65 to 83 years of age. 32 ROZEREM has not been 

studied in children or adolescents. 14 

Q. When should patients take ROZEREM 

A. Patients should take ROZEREM 30 minutes before bedtime. 

Patients should be instructed to avoid consuming 

a high-fat meal in conjunction with ROZEREM. 14 

Q. What adverse events are associated with ROZEREM 

A. The most common adverse events seen with 

ROZEREM that had at least a 2% incidence difference 

from placebo were somnolence, dizziness, and 

fatigue. 14 Patients should be educated to report any 

new symptoms that occur to a health care provider. 

Q. What drug interactions have been noted with 

ROZEREM 

A. ROZEREM is primarily metabolized by the CYP1A2 

isozyme. Fluvoxamine is a strong CYP1A2 inhibitor, 

and coadministration with ROZEREM should 

be avoided. Although they do not appear to interact 

pharmacokinetically, coadministration of alcohol and 

ROZEREM should be avoided as well. 14 

Q. Why is ROZEREM nonscheduled 

A. The clinical development program for ROZEREM 

did not find any evidence suggesting that ROZEREM 

might be abused. 12,14 Binding affinity studies showed 

no interaction with receptors involved with abuse 

and addiction, 10,21 and preclinical studies revealed no 

indications of abuse potential in monkeys. 12 

Q. Are there any patients who shouldn’t use 

ROZEREM 

A. ROZEREM should not be used in patients with 

hypersensitivity to any components of the 

formulation, severe hepatic impairment, or in 

combination with fluvoxamine. Hypnotics should 

be administered with caution to patients exhibiting 

signs and symptoms of depression. ROZEREM has 

not been studied in patients with severe sleep apnea, 

or in children or adolescents. The effects in these 

populations are unknown. 14 Further, ROZEREM 

has been studied in patients with severe COPD 29 ; 

however, the FDA has not yet evaluated these studies 

and ROZEREM is not currently recommended for this 

patient population. 

Questions your patients may have about ROZEREM 

Q. How does ROZEREM work 

A. ROZEREM targets the MT 1 

and MT 2 

receptors 14 

in the brain. The activity at these receptors in the 

suprachiasmatic nucleus (SCN), also referred to as 

the body’s “master clock,” 18 is believed to promote 

sleep. 14,21 The MT 1 

receptors in the SCN are associated 

with normal sleep induction, while the MT 2 

receptors 

are associated with maintaining circadian rhythm. 18,20 

Q. How long will it take for ROZEREM to start to work 

A. ROZEREM may help you fall asleep faster the first 

night you take it. It usually helps patients fall asleep 

within 30 minutes. Because it works so quickly, you 

should limit your activities after taking it. 14 

Q. If I start taking ROZEREM, will I always need it to 

fall asleep 

A. In studies in which patients used ROZEREM daily for 

up to five weeks, there were no signs that it was harder 

to fall asleep after patients stopped using the drug. 14 

Q. How is ROZEREM different from melatonin dietary 

supplements 

A. ROZEREM is much more potent at melatonin binding 

sites in the brain than melatonin itself. 21 In addition, it 

is important to be aware that melatonin supplements 

that you may see in the pharmacy aisles are marketed 

as dietary supplements, 1 which are not as strictly 

regulated by the FDA. 4 On the other hand, ROZEREM 

is a prescription product and has undergone FDA’s 

thorough analysis and approval process. This 

approval shows that efficacy and safety have been 

adequately demonstrated. 14 

Q. Should I use an over-the-counter sleep aid along with 

ROZEREM 

A. No. Even though these therapies are available, taking 

two products together may increase the risk of having 

6 

TODAY IN PHARMACY DRUG THERAPY

side effects. In clinical trials, ROZEREM, when 

taken alone, was shown to be effective for treating 

insomnia. 14 If you do not feel that ROZEREM is 

working for you, it is best to discuss it with your 

health care team and follow their recommendations. 

Please note that clinical studies have not been 

conducted between ROZEREM and other 

prescription sleep aids. 

Q. What else can I do when I have insomnia 

A. There are many things that you can do to help you 

get a good night’s sleep, including the use of good 

“sleep hygiene.” Sleep hygiene includes, but is not 

limited to: establishing a regular sleep schedule, creating 

a relaxing sleep environment, only using the 

bed for sleep, and avoiding stimulants and exercise 

too close to bed time. 33 Relaxation training, sleep 

restriction (limiting the amount of time you spend 

in bed), and exercise may also help. 1 Consult your 

health care provider for additional details about 

improving your sleep hygiene, or if these measures 

are insufficient. 

RESOURCES 

This list of selected resources on insomnia information is for your reference and is not a complete list of 

available resources. These resources are not intended to replace discussion with or a medical evaluation by a 

health care provider. 

American Academy of Sleep Medicine 

http://www.aasmnet.org/ 

The American Academy of Sleep Medicine offers 

educational opportunities, resources, and professional 

training to help sleep specialists and other medical 

professionals provide exceptional health care for people 

with sleep-related problems. 

It also provides a dedicated patient education Web site 

at www.sleepeducation.com, as well as a search tool 

for local sleep centers at www.sleepcenters.org. 

American Insomnia Association 

http://www.americaninsomniaassociation.org 

The American Insomnia Association is a patient-based 

organization dedicated to assisting and providing 

resources to individuals who suffer from insomnia. It 

advocates and promotes awareness, education, and 

research of insomnia disorders and encourages the 

formation of local support groups. 

Online Resources 

National Center on Sleep Disorders Research 

http://www.nhlbi.nih.gov/about/ncsdr/index.htm 

The National Center on Sleep Disorders Research 

coordinates government-supported sleep research, 

training, and education. It also provides both 

professional education materials and information for 

patients and the public. It is a part of the National 

Heart, Lung, and Blood Institute. 

National Sleep Foundation 

http://www.sleepfoundation.org 

The National Sleep Foundation (NSF) is dedicated 

to improving the quality of life for Americans who 

suffer from sleep problems. In addition, NSF alerts the 

public, health care providers, and policymakers to the 

importance of adequate sleep. NSF programs include 

public education and awareness initiatives, government 

relations and advocacy efforts, research support, 

including annual public opinion surveys on sleeprelated 

issues, and outreach to health care providers. 

Books for Patients 

Hauri P, Linde S. No More Sleepless Nights. Revised 

edition. John Wiley and Sons, New York; 1996. 

Provides a step-by-step program that allows readers to 

learn how to get to the root of their sleep problems and 

provides strategies for treating them. 

Jacobs GD, Benson H. Say Goodnight to Insomnia. Henry 

Holt & Company; New York, NY: 2000. 

Describes a six-week treatment program that allows 

patients to establish sleep-promoting habits and lifestyle 

practices; change negative, stressful thoughts about 

sleep; implement relaxation and stress-reduction techniques; 

and enhance peace of mind. 

Morin CM. Insomnia: Psychological Assessment and 

Management. Guilford Press; New York, NY: 1993. 

Offers a complete, multifaceted cognitive-behavioral 

treatment program for chronic insomnia. 

Szuba MP, Dinges DF, Kloss JD. Insomnia: Principles and 

Management. Cambridge University Press: New York, 

NY; 2003. 

Provides an evidence-based approach to discuss the 

Books for Health Care Providers 

classification and principles of insomnia as well as 

available treatments. 

Treatment of Late-Life Insomnia. Lichstein KL, Morin CM 

(eds.). Sage Publishers; Thousand Oaks, CA; 2000. 

Provides an overview of the main issues health care 

practitioners need to know in order to address geriatric 

insomnia; includes recent research on assessment 

methodologies, diagnostic issues, differential diagnosis, 

and treatment modalities. 


8 

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on Manifestations and Management of Chronic 

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of enforcement policy. Federal Register Docket 

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adulthood. Sleep 1998:21:178-186. 

11. Tariq S and Pulisetty S. Pharmacotherapy for 

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12. Johnson M, Suess P, Griffiths R. Ramelteon. 

A novel hypnotic lacking abuse liability and 

sedative adverse effects. Arch Gen Psychiatry 

2006;63:1149–57. 

13. Wagner J and Wagner M. Non-benzodiazepines 

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Reviews 2000;4:551-581. 

14. ROZEREM Prescribing Information. 

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double-blind trial examining the 

effects of ramelteon vs placebo with zolpidem 

as a reference on balance in older adults after 

middle-of-the-night awakening. Abstract. American 

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role of GABA A 

— benzodiazepine receptor in 

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17. Vela-Bueno A and Olavarrieta-Bernardino S. 

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18. Dubocovich M, Rivera-Bermudez M, Gerdin M, 

et al. Molecular pharmacology, regulation and 

function of mammalian melatonin receptors. 

Frontiers in Bioscience 2003;8:d1093-1108. 

19. Pandi-Perumal S, 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;3:221–8. 

TODAY IN PHARMACY DRUG THERAPY 

20. Liu C, Weaver D, Jin X, et al. Molecular dissection 

of two distinct actions of melatonin on 

the suprachiasmatic circadian clock. Neuron 

1997;19;91-102. 

21. Kato K, Hirai K, Nishiyama K, et al. Neurochemical 

properties of ramelteon (TAK-375), a 

selective MT 1 

/MT 2 

receptor agonist. Neuropharmacology 

2005;48:301–10. 

22. Roth T, Stubbs C, Walsh J. Ramelteon (TAK-375), 

a selective MT 1 

/MT 2 

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latency to persistent sleep in a model of transient 

insomnia related to a novel sleep environment. 

Sleep 2005;28:303–7. 

23. 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;7:17–24. 

24. 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;7:312–8. 

25. Zammit G, Erman M, Wang-Weigand S, et 

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ramelteon in subjects with chronic insomnia. 

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ramelteon, a selective MT 1 

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receptor, 

agonist in a first-night-effect model of transient 

insomnia. Abstract. Annual Meeting of 

Associated Professional Sleep Societies 2006. 

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of ramelteon, a selective MT 1 

/MT 2 

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on respiration during sleep in mild to moderate 

COPD. Sleep Breath 2007;s11325-007-0156-4. 

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safety study of ramelteon (TAK 375) in subjects 

with mild to moderate COPD. Annual Meeting 

of the American Thoracic Society 2006. 

29. Kryger M, Roth T, Wang-Weigand S, Zhang J. 

The effects of ramelteon on respiration during 

sleep in subjects with moderate to severe chronic 

obstructive pulmonary disease. Sleep Breath [published 

online ahead of print June 27, 2008]. 

30. Kryger M, Wang-Weigand S, Roth T. Safety of 

ramelteon in individuals with mild to moderate 

obstructive sleep apnea. Sleep Breath 

2007;11:159–64. 

31. Borja N, Daniel K. Ramelteon for the treatment 

of insomnia. Clin Ther 2006;28:1540–55. 

32. Roth T, Seiden D, Wang-Weigand S, Zhang J. A 

2-night, 3-period, crossover study of ramelteon’s 

efficacy and safety in older adults with chronic 

insomnia. Curr Med Res Opin 2007;23:1005–14. 

33. National Sleep Foundation. Sleep Hygiene. 

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org/site/c.huIXKjM0IxF/b.2422637/k.5B7E/ 

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org/site/c.huIXKjM0IxF/b.2419247/k.BCB0/ 

Healthy_Sleep_Tips.htm. Accessed June 6, 2008.

Brief Summary of Prescribing Information 

ROZEREM 

(ramelteon) Tablets 

INDICATIONS AND USAGE 

ROZEREM is indicated for the treatment of insomnia characterized by 

difficulty with sleep onset. 

CONTRAINDICATIONS 

ROZEREM is contraindicated in patients with a hypersensitivity to ramelteon 

or any components of the ROZEREM formulation. 

WARNINGS 

Since sleep disturbances may be the presenting manifestation of a physical 

and/or psychiatric disorder, symptomatic treatment of insomnia should be 

initiated only after a careful evaluation of the patient. The failure of insomnia to 

remit after a reasonable period of treatment may indicate the presence of a 

primary psychiatric and/or medical illness that should be evaluated. Worsening 

of insomnia, or the emergence of new cognitive or behavioral abnormalities, 

may be the result of an unrecognized underlying psychiatric or physical 

disorder and requires further evaluation of the patient. As with other hypnotics, 

exacerbation of insomnia and emergence of cognitive and behavioral abnormalities 

were seen with ROZEREM during the clinical development program. 

ROZEREM should not be used by patients with severe hepatic impairment. 

ROZEREM should not be used in combination with fluvoxamine (see 

PRECAUTIONS: Drug Interactions). 

A variety of cognitive and behavior changes have been reported to occur 

in association with the use of hypnotics. In primarily depressed patients, 

worsening of depression, including suicidal ideation, has been reported in 

association with the use of hypnotics. 

Patients should avoid engaging in hazardous activities that require concentration 

(such as operating a motor vehicle or heavy machinery) after taking ROZEREM. 

After taking ROZEREM, patients should confine their activities to those 

necessary to prepare for bed. 

PRECAUTIONS 

General 

ROZEREM has not been studied in subjects with severe sleep apnea or 

severe COPD and is not recommended for use in those populations. 

Patients should be advised to exercise caution if they consume alcohol in 

combination with ROZEREM. 

Use in Adolescents and Children 

ROZEREM has been associated with an effect on reproductive hormones in 

adults, e.g., decreased testosterone levels and increased prolactin levels. It is 

not known what effect chronic or even chronic intermittent use of ROZEREM 

may have on the reproductive axis in developing humans (see Pediatric Use). 

Information for Patients 

Patients should be advised to take ROZEREM within 30 minutes prior to going 

to bed and should confine their activities to those necessary to prepare for bed. 

Patients should be advised to avoid engaging in hazardous activities (such 

as operating a motor vehicle or heavy machinery) after taking ROZEREM. 

Patients should be advised that they should not take ROZEREM with or 

immediately after a high-fat meal. 

Patients should be advised to consult their health care provider if they 

experience worsening of insomnia or any new behavioral signs or 

symptoms of concern. 

Patients should consult their health care provider if they experience one of 

the following: cessation of menses or galactorrhea in females, decreased 

libido, or problems with fertility. 

Laboratory Tests 

No standard monitoring is required. 

For patients presenting with unexplained amenorrhea, galactorrhea, 

decreased libido, or problems with fertility, assessment of prolactin levels 

and testosterone levels should be considered as appropriate. 

Drug Interactions 

ROZEREM has a highly variable intersubject pharmacokinetic profile (approximately 

100% coefficient of variation in C max and AUC). As noted above, 

CYP1A2 is the major isozyme involved in the metabolism of ROZEREM; the 

CYP2C subfamily and CYP3A4 isozymes are also involved to a minor degree. 

Effects of Other Drugs on ROZEREM Metabolism 

Fluvoxamine (strong CYP1A2 inhibitor): When fluvoxamine 100 mg twice 

daily was administered for 3 days prior to single-dose co-administration of 

ROZEREM 16 mg and fluvoxamine, the AUC 0-inf for ramelteon increased 

approximately 190-fold, and the C max increased approximately 70-fold, 

compared to ROZEREM administered alone. ROZEREM should not be used 

in combination with fluvoxamine (see WARNINGS). Other less potent CYP1A2 

inhibitors have not been adequately studied. ROZEREM should be administered 

with caution to patients taking less strong CYP1A2 inhibitors. 

Rifampin (strong CYP enzyme inducer): Administration of rifampin 600 mg 

once daily for 11 days resulted in a mean decrease of approximately 80% 

(40% to 90%) in total exposure to ramelteon and metabolite M-II, (both 

AUC 0-inf and C max) after a single 32 mg dose of ROZEREM. Efficacy may be 

reduced when ROZEREM is used in combination with strong CYP enzyme 

inducers such as rifampin. 

Ketoconazole (strong CYP3A4 inhibitor): The AUC 0-inf and C max of ramelteon 

increased by approximately 84% and 36%, respectively, when a single 

16 mg dose of ROZEREM was administered on the fourth day of ketoconazole 

200 mg twice daily administration, compared to administration of ROZEREM 

alone. Similar increases were seen in M-II pharmacokinetic variables. 

ROZEREM should be administered with caution in subjects taking strong 

CYP3A4 inhibitors such as ketoconazole. 

Fluconazole (strong CYP2C9 inhibitor): The total and peak systemic exposure 

(AUC 0-inf and C max) of ramelteon after a single 16 mg dose of ROZEREM was 

increased by approximately 150% when administered with fluconazole. 

Similar increases were also seen in M-II exposure. ROZEREM should be 

administered with caution in subjects taking strong CYP2C9 inhibitors such 

as fluconazole. 

Interaction studies of concomitant administration of ROZEREM with fluoxetine 

(CYP2D6 inhibitor), omeprazole (CYP1A2 inducer/CYP2C19 inhibitor), 

theophylline (CYP1A2 substrate), and dextromethorphan (CYP2D6 substrate) 

did not produce clinically meaningful changes in either peak or total 

exposures to ramelteon or the M-II metabolite. 

Effects of ROZEREM on Metabolism of Other Drugs 

Concomitant administration of ROZEREM with omeprazole (CYP2C19 

substrate), dextromethorphan (CYP2D6 substrate), midazolam (CYP3A4 

substrate), theophylline (CYP1A2 substrate), digoxin (p-glycoprotein substrate), 

and warfarin (CYP2C9 [S]/CYP1A2 [R] substrate) did not produce clinically 

meaningful changes in peak and total exposures to these drugs. 

Effect of Alcohol on Rozerem 

Alcohol: With single-dose, daytime co-administration of ROZEREM 32 mg and 

alcohol (0.6 g/kg), there were no clinically meaningful or statistically significant 

effects on peak or total exposure to ROZEREM. However, an additive effect was 

seen on some measures of psychomotor performance (i.e., the Digit Symbol 

Substitution Test, the Psychomotor Vigilance Task Test, and a Visual Analog 

Scale of Sedation) at some post-dose time points. No additive effect was seen 

on the Delayed Word Recognition Test. Because alcohol by itself impairs 

performance, and the intended effect of ROZEREM is to promote sleep, 

patients should be cautioned not to consume alcohol when using ROZEREM. 

Drug/Laboratory Test Interactions 

ROZEREM is not known to interfere with commonly used clinical laboratory 

tests. In addition, in vitro data indicate that ramelteon does not cause 

false-positive results for benzodiazepines, opiates, barbiturates, cocaine, 

cannabinoids, or amphetamines in two standard urine drug screening 

methods in vitro. 

Carcinogenesis, Mutagenesis, and Impairment of Fertility 

Carcinogenesis 

In a two-year carcinogenicity study, B6C3F 1 mice were administered 

ramelteon at doses of 0, 30, 100, 300, or 1000 mg/kg/day by oral gavage. 

Male mice exhibited a dose-related increase in the incidence of hepatic 

tumors at dose levels ≥ 100 mg/kg/day including hepatic adenoma, hepatic 

carcinoma, and hepatoblastoma. Female mice developed a dose-related 

increase in the incidence of hepatic adenomas at dose levels ≥ 300 mg/kg/day 

and hepatic carcinoma at the 1000 mg/kg/day dose level. The no-effect level 

for hepatic tumors in male mice was 30 mg/kg/day (103-times and 3-times 

the therapeutic exposure to ramelteon and the active metabolite M-II, 

respectively, at the maximum recommended human dose [MRHD] based on 

an area under the concentration-time curve [AUC] comparison). The no-effect 

level for hepatic tumors in female mice was 100 mg/kg/day (827-times and 

12-times the therapeutic exposure to ramelteon and M-II, respectively, at 

the MRHD based on AUC). 

In a two-year carcinogenicity study conducted in the Sprague-Dawley rat, 

male and female rats were administered ramelteon at doses of 0,15, 60, 

250 or 1000 mg/kg/day by oral gavage. Male rats exhibited a dose-related 

increase in the incidence of hepatic adenoma and benign Leydig cell tumors 

of the testis at dose levels ≥ 250 mg/kg/day and hepatic carcinoma at the 

1000 mg/kg/day dose level. Female rats exhibited a dose-related increase in 

the incidence of hepatic adenoma at dose levels ≥ 60 mg/kg/day and 

hepatic carcinoma at the 1000 mg/kg/day dose level. The no-effect level for 

hepatic tumors and benign Leydig cell tumors in male rats was 

60 mg/kg/day (1,429-times and 12-times the therapeutic exposure to 

ramelteon and M-II, respectively, at the MRHD based on AUC).The no-effect 

level for hepatic tumors in female rats was 15 mg/kg/day (472-times and 

16-times the therapeutic exposure to ramelteon and M-II, respectively, at 

the MRHD based on AUC). 

The development of hepatic tumors in rodents following chronic treatment 

with non-genotoxic compounds may be secondary to microsomal enzyme 

induction, a mechanism for tumor generation not thought to occur in humans. 

Leydig cell tumor development following treatment with non-genotoxic 

compounds in rodents has been linked to reductions in circulating 

testosterone levels with compensatory increases in luteinizing hormone 

release, which is a known proliferative stimulus to Leydig cells in the rat 

testis. Rat Leydig cells are more sensitive to the stimulatory effects of 

luteinizing hormone than human Leydig cells. In mechanistic studies 

conducted in the rat, daily ramelteon administration at 250 and 

1000 mg/kg/day for 4 weeks was associated with a reduction in plasma 

testosterone levels. In the same study, luteinizing hormone levels were 

elevated over a 24-hour period after the last ramelteon treatment; however, 

the durability of this luteinizing hormone finding and its support for the 

proposed mechanistic explanation was not clearly established. 

Although the rodent tumors observed following ramelteon treatment 

occurred at plasma levels of ramelteon and M-II in excess of mean clinical 

plasma concentrations at the MRHD, the relevance of both rodent hepatic 

tumors and benign rat Leydig cell tumors to humans is not known. 

Mutagenesis 

Ramelteon was not genotoxic in the following: in vitro bacterial reverse 

mutation (Ames) assay; in vitro mammalian cell gene mutation assay 

using the mouse lymphoma TK + /- cell line; in vivo/in vitro unscheduled 

DNA synthesis assay in rat hepatocytes; and in in vivo micronucleus 

assays conducted in mouse and rat. Ramelteon was positive in the 

chromosomal aberration assay in Chinese hamster lung cells in the 

presence of S9 metabolic activation. 

Separate studies indicated that the concentration of the M-II metabolite 

formed by the rat liver S9 fraction used in the in vitro genetic toxicology 

studies described above, exceeded the concentration of ramelteon; 

therefore, the genotoxic potential of the M-II metabolite was also 

assessed in these studies. 

Impairment of Fertility 

Ramelteon was administered to male and female Sprague-Dawley rats in an 

initial fertility and early embryonic development study at dose levels of 6, 

60, or 600 mg/kg/day. No effects on male or female mating or fertility were 

observed with a ramelteon dose up to 600 mg/kg/day (786-times higher 

than the MRHD on a mg/m 2 basis). Irregular estrus cycles, reduction in the 

number of implants, and reduction in the number of live embryos were 

noted with dosing females at ≥ 60 mg/kg/day (79-times higher than the 

MRHD on a mg/m 2 basis). A reduction in the number of corpora lutea 

occurred at the 600 mg/kg/day dose level. Administration of ramelteon up to 

600 mg/kg/day to male rats for 7 weeks had no effect on sperm quality and 

when the treated male rats were mated with untreated female rats there was 

no effect on implants or embryos. In a repeat of this study using oral administration 

of ramelteon at 20, 60 or 200 mg/kg/day for the same study duration, 

females demonstrated irregular estrus cycles with doses ≥ 60 mg/kg/day, but 

no effects were seen on implantation or embryo viability. The no-effect dose 

for fertility endpoints was 20 mg/kg/day in females (26-times the MRHD 

on a mg/m 2 basis) and 600 mg/kg/day in males (786-times higher than 

the MRHD on a mg/m 2 basis) when considering all studies. 

Pregnancy: Pregnancy Category C 

Ramelteon has been shown to be a developmental teratogen in the rat 

when given in doses 197 times higher than the maximum recommended 

human dose [MRHD] on a mg/m 2 basis. There are no adequate and wellcontrolled 

studies in pregnant women. Ramelteon should be used during 

pregnancy only if the potential benefit justifies the potential risk to the fetus. 

The effects of ramelteon on embryo-fetal development were assessed in 

both the rat and rabbit. Pregnant rats were administered ramelteon by oral 

gavage at doses of 0,10,40,150, or 600 mg/kg/day during gestation days 

6 -17, which is the period of organogenesis in this species. Evidence of 

maternal toxicity and fetal teratogenicity was observed at doses greater 

than or equal to 150 mg/kg/day. Maternal toxicity was chiefly characterized 

by decreased body weight and, at 600 mg/kg/day, ataxia and decreased 

spontaneous movement. At maternally toxic doses (150 mg/kg/day or 

greater), the fetuses demonstrated visceral malformations consisting of 

diaphragmatic hernia and minor anatomical variations of the skeleton 

(irregularly shaped scapula). At 600 mg/kg/day, reductions in fetal body 

weights and malformations including cysts on the external genitalia were 

additionally observed. The no-effect level for teratogenicity in this study was 

40 mg/kg/day (1,892-times and 45-times higher than the therapeutic 

exposure to ramelteon and the active metabolite M-II, respectively, at the 

MRHD based on an area under the concentration-time curve [AUC] 

comparison). Pregnant rabbits were administered ramelteon by oral gavage 

at doses of 0,12, 60, or 300 mg/kg/day during gestation days 6-18, which 

is the period of organogenesis in this species. Although maternal toxicity 

was apparent with a ramelteon dose of 300 mg/kg/day, no evidence of 

fetal effects or teratogenicity was associated with any dose level. The 

no-effect level for teratogenicity was, therefore, 300 mg/kg/day (11,862-times 

and 99-times higher than the therapeutic exposure to ramelteon and M-II, 

respectively, at the MRHD based on AUC). 

The effects of ramelteon on pre- and post-natal development in the rat were 

studied by administration of ramelteon to the pregnant rat by oral gavage 

at doses of 0, 30,100, or 300 mg/kg/day from day 6 of gestation through 

parturition to postnatal (lactation) day 21, at which time offspring were 

weaned. Maternal toxicity was noted at doses of 100 mg/kg/day or 

greater and consisted of reduced body weight gain and increased adrenal 

gland weight. Reduced body weight during the post-weaning period was 

also noticed in the offspring of the groups given 100 mg/kg/day and 

higher. Offspring in the 300 mg/kg/day group demonstrated physical and 

developmental delays including delayed eruption of the lower incisors, a 

delayed acquisition of the righting reflex, and an alteration of emotional 

response. These delays are often observed in the presence of reduced 

offspring body weight but may still be indicative of developmental delay. 

An apparent decrease in the viability of offspring in the 300 mg/kg/day 

group was likely due to altered maternal behavior and function observed 

at this dose level. Offspring of the 300 mg/kg/day group also showed 

evidence of diaphragmatic hernia, a finding observed in the embryo-fetal 

development study previously described. There were no effects on the 

reproductive capacity of offspring and the resulting progeny were not 

different from those of vehicle-treated offspring. The no-effect level for 

pre- and post-natal development in this study was 30 mg/kg/day (39-times 

higher than the MRHD on a mg/m 2 basis). 

Labor and Delivery 

The potential effects of ROZEREM on the duration of labor and/or delivery, 

for either the mother or the fetus, have not been studied. ROZEREM has 

no established use in labor and delivery. 

Nursing Mothers 

Ramelteon is secreted into the milk of lactating rats. It is not known 

whether this drug is excreted in human milk. No clinical studies in nursing 

mothers have been performed. The use of ROZEREM in nursing mothers 

is not recommended. 

Pediatric Use 

Safety and effectiveness of ROZEREM in pediatric patients have not been 

established. Further study is needed prior to determining that this product 

may be used safely in pre-pubescent and pubescent patients. 

Geriatric Use 

A total of 654 subjects in double-blind, placebo-controlled, efficacy trials 

who received ROZEREM were at least 65 years of age; of these, 199 were 

75 years of age or older. No overall differences in safety or efficacy were 

observed between elderly and younger adult subjects. 

ADVERSE REACTIONS 

Overview 

The data described in this section reflect exposure to ROZEREM in 4251 subjects, 

including 346 exposed for 6 months or longer, and 473 subjects for one year. 

Adverse Reactions Resulting in Discontinuation of Treatment 

Six percent of the 3594 individual subjects exposed to ROZEREM in clinical 

studies discontinued treatment owing to an adverse event, compared with 

2% of the 1370 subjects receiving placebo. The most frequent adverse 

events leading to discontinuation in subjects receiving ROZEREM were 

somnolence (0.8%), dizziness (0.5%), nausea (0.3%), fatigue (0.3%), 

headache (0.3%), and insomnia (0.3%). 

ROZEREM Most Commonly Observed Adverse Events in Phase 1-3 trials 

The incidence of adverse events during the Phase 1 through 3 trials 

(% placebo, n=1370; % ramelteon [8 mg], n=1250) were: headache NOS 

(7%, 7%), somnolence (3%, 5%),fatigue (2%, 4%),dizziness (3%, 5%), 

nausea (2%, 3%), insomnia exacerbated (2%, 3%), upper respiratory tract 

infection NOS (2%, 3%), diarrhea NOS (2%, 2%), myalgia (1%, 2%), 

depression (1%, 2%), dysgeusia (1%, 2%), arthralgia (1%, 2%), influenza 

(0, 1%), blood cortisol decreased (0, 1%). 

Because clinical trials are conducted under widely varying conditions, 

adverse reaction rates observed in the clinical trials of a drug cannot be 

directly compared to rates in clinical trials of other drugs, and may not 

reflect the rates observed in practice. The adverse reaction information from 

clinical trials does, however, provide a basis for identifying the adverse 

events that appear to be related to drug use and for approximating rates. 

DRUG ABUSE AND DEPENDENCE 

ROZEREM is not a controlled substance. 

Human Data: See the CLINICAL TRIALS section, Studies Pertinent to 

Safety Concerns for Sleep-Promoting Agents, in the Complete 

Prescribing Information. 

Animal Data: Ramelteon did not produce any signals from animal behavioral 

studies indicating that the drug produces rewarding effects. Monkeys did 

not self-administer ramelteon and the drug did not induce a conditioned 

place preference in rats. There was no generalization between ramelteon 

and midazolam. Ramelteon did not affect rotorod performance, an indicator 

of disruption of motor function, and it did not potentiate the ability of 

diazepam to interfere with rotorod performance. 

Discontinuation of ramelteon in animals or in humans after chronic 

administration did not produce withdrawal signs. Ramelteon does not 

appear to produce physical dependence. 

OVERDOSAGE 

Signs and Symptoms 

No cases of ROZEREM overdose have been reported during clinical development. 

ROZEREM was administered in single doses up to 160 mg in an abuse 

liability trial. No safety or tolerability concerns were seen. 

Recommended Treatment 

General symptomatic and supportive measures should be used, along with 

immediate gastric lavage where appropriate. Intravenous fluids should be 

administered as needed. As in all cases of drug overdose, respiration, pulse, 

blood pressure, and other appropriate vital signs should be monitored, and 

general supportive measures employed. 

Hemodialysis does not effectively reduce exposure to ROZEREM. Therefore, 

the use of dialysis in the treatment of overdosage is not appropriate. 

Poison Control Center 

As with the management of all overdosage, the possibility of multiple drug 

ingestion should be considered. The physician may contact a poison control 

center for current information on the management of overdosage. 

Rx only 

Manufactured by: 

Takeda Pharmaceutical Company Limited 

540-8645 Osaka, JAPAN 

Manufactured in: 

Takeda Ireland Ltd. 

Kilruddery, County Wicklow, Republic of Ireland 

Marketed by: 

Takeda Pharmaceuticals America, Inc. 

One Takeda Parkway 

Deerfield, IL 60015 

ROZEREM is a trademark of Takeda Pharmaceutical Company Limited 

and used under license by Takeda Pharmaceuticals America, Inc. 

©2005, Takeda Pharmaceuticals America, Inc. 

05-1124 Revised: Apr., 2006 

L-RAM-00029

Rozerem delivers 

efficacy and safety, 

night after night † 

NONSCHEDULED ROZEREM— 

ZERO 

EVIDENCE OF ABUSE, DEPENDENCE, 

OR WITHDRAWAL IN CLINICAL STUDIES* 

• Rozerem significantly reduced objective time to 

fall asleep from the first night and demonstrated 

sustained efficacy through 5 weeks 3,5 

• Rozerem is the only prescription insomnia 

medication that works with the body’s sleepwake 

cycle to promote sleep and has not been 

associated with sedation 1,6-10 

• Clinical studies have shown no evidence of 

potential abuse, dependence, or withdrawal* 

• A single 8-mg dose can be used safely in a variety 

of patients, including older adults, patients with 

mild-to-moderate COPD, and patients for whom 

substance abuse may be a concern 1 

*Rozerem is not a controlled substance. A clinical abuse liability study showed 

no differences indicative of abuse potential between Rozerem and placebo at 

doses up to 20 times the recommended dose (N=14). Three 35-day insomnia 

studies showed no evidence of rebound insomnia or withdrawal symptoms 

with Rozerem compared to placebo (N=2082). 1,2 

†Sustained efficacy has been shown over 5 weeks in clinical studies in adults 

and older patients. 3,4 

References: 1. Rozerem package insert, Takeda Pharmaceuticals America, Inc. 

2. Johnson MW, Suess PE, Griffiths RR. Ramelteon: a novel hypnotic lacking 

abuse liability and sedative adverse effects. Arch Gen Psychiatry. 

2006;63:1149-1157. 3. Zammit G, Erman M, Wang-Weigand S, Sainati S, 

Zhang J, Roth T. Evaluation of the efficacy and safety of ramelteon in subjects 

with chronic insomnia. J Clin Sleep Med. 2007;3:495-504. 4. Roth T, Seiden D, 

Sainati S, Wang-Weigand S, Zhang J, Zee P. Effects of ramelteon on patientreported 

sleep latency in older adults with chronic insomnia. Sleep Med. 

2006;7:312-318. 5. Data on file, Takeda Pharmaceuticals North America, Inc. 

6. Kato K, Hirai K, Nishiyama K, et al. Neurochemical properties of ramelteon 

(TAK-375), a selective MT 1 /MT 2 receptor agonist. Neuropharmacology. 

2005;48:301-310. 7. Sieghart W, Sperk G. Subunit composition, distribution and 

function of GABA A receptor subtypes. Curr Top Med Chem. 2002;2:795-816. 

8. Rudolph U, Crestani F, Benke D, et al. Benzodiazepine actions mediated by 

specific γ-aminobutyric acid A receptor subtypes. Nature. 1999;401:796-800. 

9. Rowlett JK, Platt DM, Lelas S, Atack JR, Dawson GR. Different GABA A 

receptor subtypes mediate the anxiolytic, abuse-related, and motor effects 

of benzodiazepine-like drugs in primates. Proc Natl Acad Sci U S A. 

2005;102(suppl 3):915-920. 10. Landolt HP, Gillin JC. GABA A1a receptors: 

involvement in sleep regulation and potential of selective agonists in the 

treatment of insomnia. CNS Drugs. 2000;13:185-199. 

For full Prescribing Information, please visit www.rozerem.com. 

Rozerem is indicated for the treatment of insomnia characterized 

by difficulty with sleep onset. Rozerem can be prescribed for longterm 

use. 

Important Safety Information 

Rozerem should not be used in patients with hypersensitivity to 

any components of the formulation, severe hepatic impairment, 

or in combination with fluvoxamine. Failure of insomnia to remit 

after a reasonable period of time should be medically evaluated, 

as this may be the result of an unrecognized underlying medical 

disorder. Hypnotics should be administered with caution to 

patients exhibiting signs and symptoms of depression. Rozerem 

has not been studied in patients with severe sleep apnea, severe 

COPD, or in children or adolescents. The effects in these 

populations are unknown. Avoid taking Rozerem with alcohol. 

Rozerem has been associated with decreased testosterone levels 

and increased prolactin levels. Health professionals should be 

mindful of any unexplained symptoms which could include 

cessation of menses or galactorrhea in females, decreased libido 

or problems with fertility that are possibly associated with such 

changes in these hormone levels. Rozerem should not be taken 

with or immediately after a high-fat meal. Rozerem should be 

taken within 30 minutes before going to bed and activities 

confined to preparing for bed. The most common adverse events 

seen with Rozerem that had at least a 2% incidence difference 

from placebo were somnolence, dizziness, and fatigue. 

Please see adjacent Brief Summary of Prescribing Information. 

Rozerem ® is a registered trademark of Takeda Pharmaceutical Company 

Limited and used under license by Takeda Pharmaceuticals North America, Inc. 

©2008 Takeda Pharmaceuticals North America 7/08 Printed in U.S.A.

Rozerem Insert pdf/2008 - American Pharmacists Association

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