for a brief summary of prescribing information for rozerem...

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.

For a brief summary of prescribing information for R

Reviewer:

Disclosure:

Michelle Kasperowicz, RPhPharmacistShop 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 InsomniaThe prevalence and characteristics of insomnia, how it is diagnosed, and its impact on patients .............................................1

Treatment of InsomniaA brief overview of available treatments for patients with insomnia .............................................................................1

The Pharmacist’s Guide to Assessing Patients With InsomniaWhen to assess patients for insomnia and the types of questions to ask .................................................................................3

What Pharmacists Should Know About ROZEREM® (ramelteon)The effi cacy and safety of ROZEREM* .........................................................4

Supporting Appropriate Use of ROZEREMImportant information for educating patients about the appropriate use of ROZEREM, in a practical, straightforward, question-and-answer format ...............................................6

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

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

Here’s what you’ll fi nd in this therapeutic review . . .

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

Insomnia is defi ned as unsatisfactory sleep that impacts daytime functioning in a patient who has the opportunity to sleep.1 , 2

It may be characterized as diffi culty falling asleep (i.e., long sleep-onset latency), diffi culty staying asleep (i.e., nocturnal awak-ening), 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 insomnia2 (lasting 30 days or longer)4 ; another 25% to 35% experience occasional insomnia.5, 6

Causes of InsomniaThere 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, fi nancial 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 conditions1 (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 identifi ed, 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

Diagnosing InsomniaThe 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 specifi c 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

TREATMENT OF INSOMNIA

UNDERSTANDING INSOMNIA

A number of strategies are used in the treatment of insomnia, including both nonpharmacologic and phar-macologic 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’ understand-ing 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

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 prod-ucts containing diphenhydramine, 7,8 are used by almost 25% of patients with insomnia; however, there are several drawbacks associated with these products. Their effi cacy is weak, and they may reduce sleep quality and can cause residual daytime drowsiness1 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 1. Medications That May Cause Insomnia1

■ 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)

(ramelteon)(ramelteon)(ramelteon)

Table 2. Good Sleep Hygiene Measures2,34

Establish a regular sleep schedule

· Avoid daytime naps· Go to bed and get up at the same time every day, including weekends (whenever possible)· Establish a relaxing bedtime routine

Create a relaxing sleep environment

· 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

Practice stimulus control— train your body to associate the bed with sleep

· 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 stimulants close to bedtime

· 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 gen-eral, 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 medi-cations 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 sleep4 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, non-benzodiazepines, and melatonin receptor agonists.11

Benzodiazepines, such as flurazepam, temazepam, and triazolam, improve sleep onset and reduce noctur-

nal awakening, increasing total sleep time, by binding to GABA receptors in the brain.1 Residual daytime sleepi-ness11 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, zolpi-dem, or zolpidem CR,1 are more selective in their affini-ties for different subtypes of GABA receptors.11 They have fewer adverse effects than benzodiazepines but can cause memory impairment,1 rebound insomnia, with-drawal 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 con-sulted 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 el-derly, 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 cogni-tive dysfunction, falls, depression, potential early institutionalization, decreased quality of life, and increased mortality.9

Treatment of insomnia in the elderly generally follows the same rec-ommendations 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 in-somnia 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 agents11 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.

Rozerem® (ramelteon)

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?”

3

WHAT PHARMACISTS SHOULD KNOWABOUT ROZEREM®

(ramelteon)

4 TODAY IN PHARMACY DRUG THERAPY

ROZEREM is a melatonin receptor agonist that was approved by the U.S. Food and Drug Administra-

tion (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-the-night 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 suprachias-matic 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

MT2.19 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 mela-tonin 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 MT1 and

MT2 receptors in the brain. The activity

at these receptors in the SCN is believed to promote sleep.14,21

EfficacyThe efficacy of ROZEREM in

decreasing the mean latency to persis-tent sleep (LPS) has been demonstrated in clinical trials using dosages ranging

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 in-somnia, for up to five weeks of treatment in adults (Table 3).14,24,25,26 No evidence of rebound insomnia (worsening of in-somnia after stopping use of a sleep aid) or withdrawal effects were seen in any of these clinical studies.14

Special PopulationsAdditional 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-

Table 3. Clinical Studies Demonstrating the Efficacy of ROZEREM

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

Patient Population and Study Intervention

Objective Results

375 healthy adults 35–60 years of age in a novel sleep environment

Single dose of ROZEREM 16 mg, 64 mg, or placebo

To evaluate the efficacy of ROZEREM for the treatment of transient insomnia in healthy adults

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 post-sleep questionnaire.22

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

To evaluate the efficacy, safety, and dose response of ROZEREM in patients with chronic primary insomnia

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 question-naire. Several assessments revealed no next-day residual effects at any dose.23

405 adults with chronic insomnia

Five weeks’ treatment with ROZEREM 8 mg, 16 mg, or placebo

To evaluate safety and efficacy of ROZEREM in subjects with chronic primary insomnia

Both dosages of ROZEREM significantly reduced objective LPS throughout the five weeks of treatment. Objective TST was in-creased for both dosages at week 1, and continued to be signifi-cantly 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 subjec-tive 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

829 older adults with chronic insomnia, ≥65 years of age

Five weeks’ treatment with ROZEREM 4 mg, 8 mg, or placebo

To assess the safety and efficacy of ROZEREM for chronic insomnia treat-ment in older adults

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

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)

To assess the efficacy and safety of ROZEREM for insomnia treatment in older adults (crossover)

Both dosages of ROZEREM significantly reduced LPS and im-proved 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

Rozerem® (ramelteon) 5

nificant effect on any measure of arterial oxygen percent saturation (SaO

2). The

mean percent SaO2 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 pa-tients with severe COPD29; however, the FDA has not yet evaluated these studies and ROZEREM is not currently recom-mended for this patient population.14

A similar study was conducted to assess the safety of ROZEREM in pa-tients 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 sig-nificant 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 rec-ommended for this patient population.14

Safety and PrecautionsROZEREM is well tolerated, with

rates of adverse events reported in clini-cal trials similar to those seen with pla-cebo. 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 func-tion. 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 adrenocorti-cotropic hormone, cortisol, estradiol, follicle-stimulating hormone, luteiniz-ing 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

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, galactor-rhea, 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

Potential for AbuseAvailable 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 recep-tors associated with abuse and impair-

ment (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 last-ing up to 5 weeks. Likewise, no signs of memory or psychomotor impairment have been noted.12

Dosage and AdministrationThe 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 metabo-lized 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 al-ter the pharmacokinetics of ROZEREM, but may have an additive effect on measures of alcohol performance. Be-cause of these additive effects, patients should be cautioned not to consume alcohol when using ROZEREM.14

Table 4. Treatment-Emergent Adverse Events in Phase 1–3 Clinical Trials of ROZEREM14

Adverse Event

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

TODAY IN PHARMACY DRUG THERAPY6

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 drug-drug 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 signifi-cantly reduce latency to persistent sleep. Therefore, it is likely to benefit patients whose insomnia is charac-terized by long sleep-onset latency (i.e., patients who have trouble falling asleep). Efficacy has been dem-onstrated 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 bed-time. Patients should be instructed to avoid consum-ing 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 inhibi-tor, 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 COPD29; however, the FDA has not yet evaluated these studies and ROZEREM is not currently recommended for this patient population.

Q. How does ROZEREM work?

A. ROZEREM targets the MT1 and MT

2 receptors14

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 MT2 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

Questions your patients may have about ROZEREM

Online Resources

Books for Patients

RESOURCESThis 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 Medicinehttp://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 Associationhttp://www.americaninsomniaassociation.orgThe 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.

National Center on Sleep Disorders Researchhttp://www.nhlbi.nih.gov/about/ncsdr/index.htmThe 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 Foundationhttp://www.sleepfoundation.orgThe 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 sleep-related issues, and outreach to health care providers.

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 tech-niques; and enhance peace of mind.

Rozerem® (ramelteon) 7

Books for Health Care Providers

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

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.

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, cre-ating 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.

TODAY IN PHARMACY DRUG THERAPY8

REFERENCES11. Ramakrishnan K and Scheid D. Treatment op-

tions for insomnia. American Family Physician 2007;76:517-526, 527-528.

12. Hamblin J. Insomnia: an ignored health problem. Prim Care Clin Office Pract 2007:34:659-674.

13. Walsh J. Clinical and socioeconomic correlates of insomnia. J Clin Psych 2004;65(suppl 8):13-19.

14. NIH State-of-the Science Conference Statement on Manifestations and Management of Chronic Insomnia in Adults. NIH Consens Sci State-ments. 2005. Jun 13-15;22(2)1-30.

15. Ford D, Kamerow D. Epidemiologic study of sleep disturbances and psychiatric disor-ders: an opportunity for prevention? JAMA 1989;262:1479-1484.

16. Roth T. New developments for treating sleep disorders. J Clin Psych 2001;62(suppl 10):3-4.

17. Food and Drug Administration. Department of Health and Human Services. Diphenhydramine; marketing status as a nighttime sleep-aid drug product for over-the-counter human use; notice of enforcement policy. Federal Register Docket No. 75N-0244. April 23, 1982;47:79:17740-17741.

18. Food and Drug Administration. Department of Health and Human Services. Nighttime sleep-aid drug products for over-the-counter human use; final monograph. Federal Register Docket No. 75N-0244. February 14, 1989;54:29:6814-6827.

19. Harrington J and Lee-Chiong T. Sleep and older patients. Clin Chest Med 2007:28:673–684.

10. Johnson E and Roehrs T. Epidemiology of alcohol and medication as aids to sleep in early adulthood. Sleep 1998:21:178-186.

11. Tariq S and Pulisetty S. Pharmacotherapy for insomnia. Clin Geriatr Med 2008:24:93-105.

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 for the treatment of insomnia. Sleep Medicine Reviews 2000;4:551-581.

14. ROZEREM Prescribing Information.15. Wang-Weigand S, Zammit G, Peng X. Placebo-

controlled, double-blind trial examining the effects of ramelteon vs placebo with zolpidem as a reference on balance in older adults after middle-of-the-night awakening. Abstract. Ameri-can Psychiatric Association 2007 Annual Meet-ing; San Diego, CA.

16. Nutt D and Malizia A. New insights into the role of GABA

A— benzodiazepine receptor in

psychiatric disorder. British Journal of Psychiatry 2001;179:390-396.

17. Vela-Bueno A and Olavarrieta-Bernardino S. Melatonin, sleep and sleep disorders. Sleep Med Clin 2007:2:303-312.

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.

20. Liu C, Weaver D, Jin X, et al. Molecular dis-section 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. Neuro-chemical properties of ramelteon (TAK-375), a selective MT

1/MT

2 receptor agonist. Neurophar-

macology 2005;48:301–10.22. Roth T, Stubbs C, Walsh J. Ramelteon (TAK-375),

a selective MT1/MT

2-receptor agonist, reduces

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 al. Evaluation of the efficacy and safety of ramelteon in subjects with chronic insomnia. J Clin Sleep Med 2007;3:495–504.

26. Zammit G, Schwartz H, Roth T. Effect of ramelteon, a selective MT

1/MT

2 receptor,

agonist in a first-night-effect model of transient insomnia. Abstract. Annual Meeting of Associated Professional Sleep Societies 2006.

27. Kryger M, Wang-Weigand S, Zhang J, et al. Effect of ramelteon, a selective MT

1/MT

2-receptor ago-

nist, on respiration during sleep in mild to mod-erate COPD. Sleep Breath 2007;s11325-007-0156-4.

28. Sainati S, Tsymbalov S, Demissie S. Phase II 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 [pub-lished online ahead of print June 27, 2008].

30. Kryger M, Wang-Weigand S, Roth T. Safety of ramelteon in individuals with mild to mod-erate 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. Available at: http://www.sleepfoundation.org/site/c.huIXKjM0IxF/b.2422637/k.5B7E/Ask_the_Sleep_Expert_Sleep_Hygiene.htm. Accessed June 6, 2008.

34. National Sleep Foundation. Healthy Sleep Tips. Available at: http://www.sleepfoundation.org/site/c.huIXKjM0IxF/b.2419247/k.BCB0/Healthy_Sleep_Tips.htm. Accessed June 6, 2008.

Brief Summary of Prescribing Information

ROZEREM™

(ramelteon) TabletsINDICATIONS AND USAGEROZEREM is indicated for the treatment of insomnia characterized by difficulty with sleep onset.

CONTRAINDICATIONSROZEREM is contraindicated in patients with a hypersensitivity to ramelteonor any components of the ROZEREM formulation.

WARNINGSSince sleep disturbances may be the presenting manifestation of a physicaland/or psychiatric disorder, symptomatic treatment of insomnia should beinitiated only after a careful evaluation of the patient. The failure of insomnia toremit after a reasonable period of treatment may indicate the presence of aprimary psychiatric and/or medical illness that should be evaluated. Worseningof insomnia, or the emergence of new cognitive or behavioral abnormalities,may be the result of an unrecognized underlying psychiatric or physicaldisorder and requires further evaluation of the patient. As with other hypnotics,exacerbation of insomnia and emergence of cognitive and behavioral abnor-malities 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 (seePRECAUTIONS: Drug Interactions).

A variety of cognitive and behavior changes have been reported to occurin association with the use of hypnotics. In primarily depressed patients,worsening of depression, including suicidal ideation, has been reported inassociation 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 thosenecessary to prepare for bed.

PRECAUTIONSGeneralROZEREM has not been studied in subjects with severe sleep apnea orsevere COPD and is not recommended for use in those populations.

Patients should be advised to exercise caution if they consume alcohol incombination with ROZEREM.

Use in Adolescents and ChildrenROZEREM has been associated with an effect on reproductive hormones inadults, e.g., decreased testosterone levels and increased prolactin levels. It isnot known what effect chronic or even chronic intermittent use of ROZEREMmay have on the reproductive axis in developing humans (see Pediatric Use).

Information for PatientsPatients should be advised to take ROZEREM within 30 minutes prior to goingto bed and should confine their activities to those necessary to prepare for bed.Patients should be advised to avoid engaging in hazardous activities (suchas operating a motor vehicle or heavy machinery) after taking ROZEREM.Patients should be advised that they should not take ROZEREM with orimmediately after a high-fat meal.Patients should be advised to consult their health care provider if theyexperience worsening of insomnia or any new behavioral signs or symptoms of concern.Patients should consult their health care provider if they experience one ofthe following: cessation of menses or galactorrhea in females, decreasedlibido, or problems with fertility.

Laboratory TestsNo standard monitoring is required.

For patients presenting with unexplained amenorrhea, galactorrhea,decreased libido, or problems with fertility, assessment of prolactin levelsand testosterone levels should be considered as appropriate.

Drug InteractionsROZEREM has a highly variable intersubject pharmacokinetic profile (approxi-mately 100% coefficient of variation in Cmax and AUC). As noted above,CYP1A2 is the major isozyme involved in the metabolism of ROZEREM; theCYP2C subfamily and CYP3A4 isozymes are also involved to a minor degree.

Effects of Other Drugs on ROZEREM MetabolismFluvoxamine (strong CYP1A2 inhibitor): When fluvoxamine 100 mg twicedaily was administered for 3 days prior to single-dose co-administration ofROZEREM 16 mg and fluvoxamine, the AUC0-inf for ramelteon increasedapproximately 190-fold, and the Cmax increased approximately 70-fold,compared to ROZEREM administered alone. ROZEREM should not be usedin combination with fluvoxamine (see WARNINGS). Other less potent CYP1A2inhibitors have not been adequately studied. ROZEREM should be admin-istered with caution to patients taking less strong CYP1A2 inhibitors.

Rifampin (strong CYP enzyme inducer): Administration of rifampin 600 mgonce daily for 11 days resulted in a mean decrease of approximately 80%(40% to 90%) in total exposure to ramelteon and metabolite M-II, (bothAUC0-inf and Cmax) after a single 32 mg dose of ROZEREM. Efficacy may bereduced when ROZEREM is used in combination with strong CYP enzymeinducers such as rifampin.

Ketoconazole (strong CYP3A4 inhibitor): The AUC0-inf and Cmax of ramelteonincreased by approximately 84% and 36%, respectively, when a single16 mg dose of ROZEREM was administered on the fourth day of ketoconazole200 mg twice daily administration, compared to administration of ROZEREMalone. Similar increases were seen in M-II pharmacokinetic variables.ROZEREM should be administered with caution in subjects taking strongCYP3A4 inhibitors such as ketoconazole.

Fluconazole (strong CYP2C9 inhibitor): The total and peak systemic exposure(AUC0-inf and Cmax) of ramelteon after a single 16 mg dose of ROZEREM wasincreased by approximately 150% when administered with fluconazole.Similar increases were also seen in M-II exposure. ROZEREM should beadministered with caution in subjects taking strong CYP2C9 inhibitors suchas 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 totalexposures to ramelteon or the M-II metabolite.

Effects of ROZEREM on Metabolism of Other DrugsConcomitant administration of ROZEREM with omeprazole (CYP2C19 substrate), dextromethorphan (CYP2D6 substrate), midazolam (CYP3A4substrate), theophylline (CYP1A2 substrate), digoxin (p-glycoprotein substrate),and warfarin (CYP2C9 [S]/CYP1A2 [R] substrate) did not produce clinicallymeaningful changes in peak and total exposures to these drugs.

Effect of Alcohol on RozeremAlcohol: With single-dose, daytime co-administration of ROZEREM 32mg andalcohol (0.6 g/kg), there were no clinically meaningful or statistically significanteffects on peak or total exposure to ROZEREM. However, an additive effect wasseen on some measures of psychomotor performance (i.e., the Digit SymbolSubstitution Test, the Psychomotor Vigilance Task Test, and a Visual AnalogScale of Sedation) at some post-dose time points. No additive effect was seenon the Delayed Word Recognition Test. Because alcohol by itself impairsperformance, and the intended effect of ROZEREM is to promote sleep,patients should be cautioned not to consume alcohol when using ROZEREM.

Drug/Laboratory Test InteractionsROZEREM is not known to interfere with commonly used clinical laboratorytests. 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 screeningmethods in vitro.

Carcinogenesis, Mutagenesis, and Impairment of FertilityCarcinogenesisIn a two-year carcinogenicity study, B6C3F1 mice were administeredramelteon 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 hepatictumors at dose levels ≥ 100 mg/kg/day including hepatic adenoma, hepaticcarcinoma, and hepatoblastoma. Female mice developed a dose-relatedincrease in the incidence of hepatic adenomas at dose levels ≥ 300 mg/kg/dayand hepatic carcinoma at the 1000 mg/kg/day dose level. The no-effect levelfor hepatic tumors in male mice was 30 mg/kg/day (103-times and 3-timesthe therapeutic exposure to ramelteon and the active metabolite M-II,respectively, at the maximum recommended human dose [MRHD] based onan area under the concentration-time curve [AUC] comparison). The no-effectlevel for hepatic tumors in female mice was 100 mg/kg/day (827-times and12-times the therapeutic exposure to ramelteon and M-II, respectively, atthe 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-relatedincrease in the incidence of hepatic adenoma and benign Leydig cell tumorsof the testis at dose levels ≥ 250 mg/kg/day and hepatic carcinoma at the1000 mg/kg/day dose level. Female rats exhibited a dose-related increase inthe incidence of hepatic adenoma at dose levels ≥ 60 mg/kg/day andhepatic carcinoma at the 1000 mg/kg/day dose level. The no-effect level forhepatic tumors and benign Leydig cell tumors in male rats was60 mg/kg/day (1,429-times and 12-times the therapeutic exposure toramelteon and M-II, respectively, at the MRHD based on AUC).The no-effectlevel for hepatic tumors in female rats was 15 mg/kg/day (472-times and16-times the therapeutic exposure to ramelteon and M-II, respectively, atthe MRHD based on AUC).

The development of hepatic tumors in rodents following chronic treatmentwith non-genotoxic compounds may be secondary to microsomal enzymeinduction, a mechanism for tumor generation not thought to occur in humans.Leydig cell tumor development following treatment with non-genotoxiccompounds in rodents has been linked to reductions in circulating testosterone levels with compensatory increases in luteinizing hormonerelease, which is a known proliferative stimulus to Leydig cells in the rattestis. Rat Leydig cells are more sensitive to the stimulatory effects ofluteinizing hormone than human Leydig cells. In mechanistic studies conducted in the rat, daily ramelteon administration at 250 and1000 mg/kg/day for 4 weeks was associated with a reduction in plasmatestosterone levels. In the same study, luteinizing hormone levels wereelevated over a 24-hour period after the last ramelteon treatment; however,the durability of this luteinizing hormone finding and its support for theproposed mechanistic explanation was not clearly established.

Although the rodent tumors observed following ramelteon treatmentoccurred at plasma levels of ramelteon and M-II in excess of mean clinicalplasma concentrations at the MRHD, the relevance of both rodent hepatictumors and benign rat Leydig cell tumors to humans is not known.

MutagenesisRamelteon was not genotoxic in the following: in vitro bacterial reversemutation (Ames) assay; in vitro mammalian cell gene mutation assayusing the mouse lymphoma TK+/- cell line; in vivo/in vitro unscheduledDNA synthesis assay in rat hepatocytes; and in in vivo micronucleusassays conducted in mouse and rat. Ramelteon was positive in thechromosomal aberration assay in Chinese hamster lung cells in thepresence of S9 metabolic activation.

Separate studies indicated that the concentration of the M-II metaboliteformed by the rat liver S9 fraction used in the in vitro genetic toxicologystudies described above, exceeded the concentration of ramelteon; therefore, the genotoxic potential of the M-II metabolite was alsoassessed in these studies.

Impairment of FertilityRamelteon was administered to male and female Sprague-Dawley rats in aninitial 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 wereobserved with a ramelteon dose up to 600 mg/kg/day (786-times higherthan the MRHD on a mg/m2 basis). Irregular estrus cycles, reduction in thenumber of implants, and reduction in the number of live embryos werenoted with dosing females at ≥ 60 mg/kg/day (79-times higher than theMRHD on a mg/m2 basis). A reduction in the number of corpora luteaoccurred at the 600 mg/kg/day dose level. Administration of ramelteon up to600 mg/kg/day to male rats for 7 weeks had no effect on sperm quality andwhen the treated male rats were mated with untreated female rats there wasno effect on implants or embryos. In a repeat of this study using oral adminis-tration 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, butno effects were seen on implantation or embryo viability. The no-effect dosefor fertility endpoints was 20 mg/kg/day in females (26-times the MRHDon a mg/m2 basis) and 600 mg/kg/day in males (786-times higher thanthe MRHD on a mg/m2 basis) when considering all studies.

Pregnancy: Pregnancy Category CRamelteon has been shown to be a developmental teratogen in the ratwhen given in doses 197 times higher than the maximum recommendedhuman dose [MRHD] on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Ramelteon should be used duringpregnancy only if the potential benefit justifies the potential risk to the fetus.

The effects of ramelteon on embryo-fetal development were assessed inboth the rat and rabbit. Pregnant rats were administered ramelteon by oralgavage 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 ofmaternal toxicity and fetal teratogenicity was observed at doses greaterthan or equal to 150 mg/kg/day. Maternal toxicity was chiefly characterizedby decreased body weight and, at 600 mg/kg/day, ataxia and decreasedspontaneous movement. At maternally toxic doses (150 mg/kg/day orgreater), the fetuses demonstrated visceral malformations consisting ofdiaphragmatic hernia and minor anatomical variations of the skeleton(irregularly shaped scapula). At 600 mg/kg/day, reductions in fetal bodyweights and malformations including cysts on the external genitalia wereadditionally observed. The no-effect level for teratogenicity in this study was40 mg/kg/day (1,892-times and 45-times higher than the therapeuticexposure to ramelteon and the active metabolite M-II, respectively, at theMRHD based on an area under the concentration-time curve [AUC] comparison). Pregnant rabbits were administered ramelteon by oral gavageat doses of 0,12, 60, or 300 mg/kg/day during gestation days 6-18, whichis the period of organogenesis in this species. Although maternal toxicitywas apparent with a ramelteon dose of 300 mg/kg/day, no evidence offetal effects or teratogenicity was associated with any dose level. The no-effect level for teratogenicity was, therefore, 300 mg/kg/day (11,862-timesand 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 gavageat doses of 0, 30,100, or 300 mg/kg/day from day 6 of gestation throughparturition to postnatal (lactation) day 21, at which time offspring wereweaned. Maternal toxicity was noted at doses of 100 mg/kg/day orgreater and consisted of reduced body weight gain and increased adrenalgland weight. Reduced body weight during the post-weaning period wasalso noticed in the offspring of the groups given 100 mg/kg/day andhigher. Offspring in the 300 mg/kg/day group demonstrated physical anddevelopmental delays including delayed eruption of the lower incisors, adelayed acquisition of the righting reflex, and an alteration of emotionalresponse. These delays are often observed in the presence of reducedoffspring body weight but may still be indicative of developmental delay.An apparent decrease in the viability of offspring in the 300 mg/kg/daygroup was likely due to altered maternal behavior and function observedat this dose level. Offspring of the 300 mg/kg/day group also showed evidence of diaphragmatic hernia, a finding observed in the embryo-fetaldevelopment study previously described. There were no effects on thereproductive capacity of offspring and the resulting progeny were not different from those of vehicle-treated offspring. The no-effect level forpre- and post-natal development in this study was 30 mg/kg/day (39-timeshigher than the MRHD on a mg/m2 basis).

Labor and DeliveryThe potential effects of ROZEREM on the duration of labor and/or delivery,for either the mother or the fetus, have not been studied. ROZEREM hasno established use in labor and delivery.

Nursing MothersRamelteon is secreted into the milk of lactating rats. It is not knownwhether this drug is excreted in human milk. No clinical studies in nursingmothers have been performed. The use of ROZEREM in nursing mothersis not recommended.

Pediatric UseSafety and effectiveness of ROZEREM in pediatric patients have not beenestablished. Further study is needed prior to determining that this productmay be used safely in pre-pubescent and pubescent patients.

Geriatric UseA total of 654 subjects in double-blind, placebo-controlled, efficacy trialswho received ROZEREM were at least 65 years of age; of these, 199 were75 years of age or older. No overall differences in safety or efficacy wereobserved between elderly and younger adult subjects.

ADVERSE REACTIONSOverviewThe 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 TreatmentSix percent of the 3594 individual subjects exposed to ROZEREM in clinicalstudies discontinued treatment owing to an adverse event, compared with2% of the 1370 subjects receiving placebo. The most frequent adverseevents leading to discontinuation in subjects receiving ROZEREM weresomnolence (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 trialsThe 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 tractinfection 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 bedirectly compared to rates in clinical trials of other drugs, and may notreflect the rates observed in practice. The adverse reaction information fromclinical trials does, however, provide a basis for identifying the adverseevents that appear to be related to drug use and for approximating rates.

DRUG ABUSE AND DEPENDENCEROZEREM is not a controlled substance.

Human Data: See the CLINICAL TRIALS section, Studies Pertinent toSafety Concerns for Sleep-Promoting Agents, in the CompletePrescribing Information.

Animal Data: Ramelteon did not produce any signals from animal behavioralstudies indicating that the drug produces rewarding effects. Monkeys didnot self-administer ramelteon and the drug did not induce a conditionedplace preference in rats. There was no generalization between ramelteonand midazolam. Ramelteon did not affect rotorod performance, an indicatorof disruption of motor function, and it did not potentiate the ability ofdiazepam to interfere with rotorod performance.

Discontinuation of ramelteon in animals or in humans after chronicadministration did not produce withdrawal signs. Ramelteon does notappear to produce physical dependence.

OVERDOSAGESigns and SymptomsNo cases of ROZEREM overdose have been reported during clinical development.

ROZEREM was administered in single doses up to 160 mg in an abuseliability trial. No safety or tolerability concerns were seen.

Recommended TreatmentGeneral symptomatic and supportive measures should be used, along withimmediate gastric lavage where appropriate. Intravenous fluids should beadministered as needed. As in all cases of drug overdose, respiration, pulse,blood pressure, and other appropriate vital signs should be monitored, andgeneral 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 CenterAs with the management of all overdosage, the possibility of multiple drugingestion should be considered. The physician may contact a poison controlcenter 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 ParkwayDeerfield, IL 60015

ROZEREM™ is a trademark of Takeda Pharmaceutical Company Limitedand used under license by Takeda Pharmaceuticals America, Inc.

©2005, Takeda Pharmaceuticals America, Inc.

05-1124 Revised: Apr., 2006

L-RAM-00029

Rozerem deliversefficacy and safety,

night after night†

• Rozerem significantly reduced objective time to fall asleep from the first night and demonstratedsustained efficacy through 5 weeks3,5

• Rozerem is the only prescription insomniamedication that works with the body’s sleep-wake cycle to promote sleep and has not beenassociated with sedation1,6-10

• Clinical studies have shown no evidence ofpotential abuse, dependence, or withdrawal*

• A single 8-mg dose can be used safely in a varietyof patients, including older adults, patients withmild-to-moderate COPD, and patients for whomsubstance abuse may be a concern1

ZERONONSCHEDULED ROZEREM—

EVIDENCE OF ABUSE, DEPENDENCE,

OR WITHDRAWAL IN CLINICAL STUDIES*

*Rozerem is not a controlled substance. A clinical abuse liability study showedno differences indicative of abuse potential between Rozerem and placebo atdoses up to 20 times the recommended dose (N=14). Three 35-day insomniastudies showed no evidence of rebound insomnia or withdrawal symptomswith 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 lackingabuse 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 subjectswith 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 patient-reported 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 MT1/MT2 receptor agonist. Neuropharmacology.2005;48:301-310. 7. Sieghart W, Sperk G. Subunit composition, distribution andfunction of GABAA receptor subtypes. Curr Top Med Chem. 2002;2:795-816.8. Rudolph U, Crestani F, Benke D, et al. Benzodiazepine actions mediated byspecific γ-aminobutyric acidA receptor subtypes. Nature. 1999;401:796-800. 9. Rowlett JK, Platt DM, Lelas S, Atack JR, Dawson GR. Different GABAA

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. GABAA1a receptors:involvement in sleep regulation and potential of selective agonists in thetreatment 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 characterizedby difficulty with sleep onset. Rozerem can be prescribed for long-term use.

Important Safety InformationRozerem should not be used in patients with hypersensitivity toany components of the formulation, severe hepatic impairment,or in combination with fluvoxamine. Failure of insomnia to remitafter a reasonable period of time should be medically evaluated,as this may be the result of an unrecognized underlying medicaldisorder. Hypnotics should be administered with caution topatients exhibiting signs and symptoms of depression. Rozeremhas not been studied in patients with severe sleep apnea, severeCOPD, or in children or adolescents. The effects in thesepopulations are unknown. Avoid taking Rozerem with alcohol.Rozerem has been associated with decreased testosterone levelsand increased prolactin levels. Health professionals should bemindful of any unexplained symptoms which could includecessation of menses or galactorrhea in females, decreased libidoor problems with fertility that are possibly associated with suchchanges in these hormone levels. Rozerem should not be takenwith or immediately after a high-fat meal. Rozerem should betaken within 30 minutes before going to bed and activitiesconfined to preparing for bed. The most common adverse eventsseen with Rozerem that had at least a 2% incidence differencefrom 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.