2.1 Dosage in Adults

The recommended dose of ROZEREM is 8 mg taken within 30 minutes of going to bed. It is recommended that ROZEREM not be taken with or immediately after a high-fat meal.

The total ROZEREM dose should not exceed 8 mg per day.

2.2 Dosing in Patients with Hepatic Impairment

ROZEREM is not recommended in patients with severe hepatic impairment. ROZEREM should be used with caution in patients with moderate hepatic impairment [see Warnings and Precautions (5.6), Clinical Pharmacology (12.4)].

2.3 Administration with Other Medications

ROZEREM should not be used in combination with fluvoxamine. ROZEREM should be used with caution in patients taking other CYP1A2 inhibiting drugs [see Drug Interactions (7), Clinical Pharmacology (12.5)].

5.1 Severe Anaphylactic and Anaphylactoid Reactions

Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of ROZEREM. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with ROZEREM should not be rechallenged with the drug.

5.2 Need to Evaluate for Comorbid Diagnoses

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 7 to 10 days 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. Exacerbation of insomnia and emergence of cognitive and behavioral abnormalities were seen with ROZEREM during the clinical development program.

5.3 Abnormal Thinking and Behavioral Changes

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 and completed suicides) has been reported in association with the use of hypnotics.

Hallucinations, as well as behavioral changes such as bizarre behavior, agitation and mania have been reported with ROZEREM use. Amnesia, anxiety and other neuro-psychiatric symptoms may also occur unpredictably.

Complex behaviors such as "sleep-driving" (i.e., driving while not fully awake after ingestion of a hypnotic) and other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex), with amnesia for the event, have been reported in association with hypnotic use. The use of alcohol and other CNS depressants may increase the risk of such behaviors. These events can occur in hypnotic-naive as well as in hypnotic-experienced persons. Complex behaviors have been reported with the use of ROZEREM. Discontinuation of ROZEREM should be strongly considered for patients who report any complex sleep behavior.

5.4 CNS Effects

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.

Patients should be advised not to consume alcohol in combination with ROZEREM as alcohol and ROZEREM may have additive effects when used in conjunction.

5.5 Reproductive Effects

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 Clinical Trials (14.3)].

5.6 Use in Patients with Concomitant Illness

ROZEREM has not been studied in subjects with severe sleep apnea and is not recommended for use in this population [see Use in Specific Populations (8.7)].

ROZEREM should not be used by patients with severe hepatic impairment [see Clinical Pharmacology (12.4)].

5.7 Laboratory Tests

6.1 Clinical Trials Experience

7.1 Effects of Other Drugs on ROZEREM

7.2 Effect of Alcohol on ROZEREM

Alcohol by itself impairs performance and can cause sleepiness. Since the intended effect of ROZEREM is to promote sleep, patients should be cautioned not to consume alcohol when using ROZEREM [see Clinical Pharmacology (12.5)]. Use of the products in combination may have an additive effect.

7.3 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.

8.1 Pregnancy

8.2 Lactation

8.4 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 prepubescent and pubescent patients.

8.5 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.

A double-blind, randomized, placebo-controlled study in elderly subjects with insomnia (n=33) evaluated the effect of a single dose of ROZEREM on balance, mobility, and memory functions after middle of the night awakening. There is no information on the effect of multiple dosing. Night time dosing of ROZEREM 8 mg did not impair middle of the night balance, mobility, or memory functions relative to placebo. The effects on night balance in the elderly cannot be definitively known from this study.

8.6 Chronic Obstructive Pulmonary Disease

The respiratory depressant effect of ROZEREM was evaluated in a crossover design study of subjects (n=26) with mild to moderate COPD after administering a single 16 mg dose or placebo, and in a separate study (n=25), the effects of ROZEREM on respiratory parameters were evaluated after administering an 8 mg dose or placebo in a crossover design to patients with moderate to severe COPD, defined as patients who had forced expiratory volume at one second (FEV1)/forced vital capacity ratio of <70%, and a FEV1 <80% of predicted with <12% reversibility to albuterol. Treatment with a single dose of ROZEREM has no demonstrable respiratory depressant effects in subjects with mild to severe COPD, as measured by arterial O2 saturation (SaO2). There is no available information on the respiratory effects of multiple doses of ROZEREM in patients with COPD. The respiratory depressant effects in patients with COPD cannot be definitively known from this study.

8.7 Sleep Apnea

The effects of ROZEREM were evaluated after administering a 16 mg dose or placebo in a crossover design to subjects (n=26) with mild to moderate obstructive sleep apnea. Treatment with ROZEREM 16 mg for one night showed no difference compared with placebo on the Apnea/Hypopnea Index (the primary outcome variable), apnea index, hypopnea index, central apnea index, mixed apnea index, and obstructive apnea index. Treatment with a single dose of ROZEREM does not exacerbate mild to moderate obstructive sleep apnea. There is no available information on the respiratory effects of multiple doses of ROZEREM in patients with sleep apnea. The effects on exacerbation in patients with mild to moderate sleep apnea cannot be definitively known from this study.

ROZEREM has not been studied in subjects with severe obstructive sleep apnea; use of ROZEREM is not recommended in such patients.

8.8 Hepatic Impairment

Exposure to ROZEREM was increased by four-fold in subjects with mild hepatic impairment and by more than ten-fold in subjects with moderate hepatic impairment. ROZEREM should be used with caution in patients with moderate hepatic impairment [see Clinical Pharmacology (12.4)]. ROZEREM is not recommended in patients with severe hepatic impairment.

8.9 Renal Impairment

No effects on Cmax and AUC0-t of parent drug or M-II were seen. No adjustment of ROZEREM dosage is required in patients with renal impairment [see Clinical Pharmacology (12.4)].

Human Data

A laboratory abuse potential study was performed with ROZEREM [see Clinical Studies (14.2)].

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.

Poison Control Center

As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. Contact a poison control center for current information on the management of overdosage.

12.1 Mechanism of Action

Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors and relative selectivity over the MT3 receptor.

The activity of ramelteon at the MT1 and MT2 receptors is believed to contribute to its sleep-promoting properties, as these receptors, acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle.

Ramelteon has no appreciable affinity for the GABA receptor complex or for receptors that bind neuropeptides, cytokines, serotonin, dopamine, noradrenaline, acetylcholine, and opiates. Ramelteon also does not interfere with the activity of a number of selected enzymes in a standard panel.

The major metabolite of ramelteon, M-II, is pharmacologically active and has approximately one tenth and one fifth the binding affinity of the parent molecule for the human MT1 and MT2 receptors, respectively. However, M-II circulates at higher concentrations than the parent producing 20- to 100-fold greater mean systemic exposure when compared to ramelteon. Similar to ramelteon, M-II does not interfere with the activity of a number of endogenous enzymes.

All other known metabolites of ramelteon are inactive.

12.3 Pharmacokinetics

The pharmacokinetic profile of ROZEREM has been evaluated in healthy subjects as well as in subjects with hepatic or renal impairment. When administered orally to humans in doses ranging from 4 to 64 mg, ramelteon undergoes rapid, high first-pass metabolism, and exhibits linear pharmacokinetics. Maximal serum concentration (Cmax) and area under the concentration-time curve (AUC) data show substantial intersubject variability, consistent with the high first-pass effect; the coefficient of variation for these values is approximately 100%. Several metabolites have been identified in human serum and urine.

12.4 Pharmacokinetics in Special Populations

Age

In a group of 24 elderly subjects aged 63 to 79 years administered a single ROZEREM 16 mg dose, the mean Cmax and AUC0-inf values were 11.6 ng/mL (SD, 13.8) and 18.7 ng∙hr/mL (SD, 19.4), respectively. The elimination half-life was 2.6 hours (SD, 1.1). Compared with younger adults, the total exposure (AUC0-inf) and Cmax of ramelteon were 97 and 86% higher, respectively, in elderly subjects. The AUC0-inf and Cmax of M-II were increased by 30 and 13%, respectively, in elderly subjects.

Gender

There are no clinically meaningful gender-related differences in the pharmacokinetics of ROZEREM or its metabolites.

Hepatic Impairment

Exposure to ROZEREM was increased almost four-fold in subjects with mild hepatic impairment after seven days of dosing with 16 mg/day; exposure was further increased (more than ten-fold) in subjects with moderate hepatic impairment. Exposure to M-II was only marginally increased in mildly and moderately impaired subjects relative to healthy matched controls. The pharmacokinetics of ROZEREM have not been evaluated in subjects with severe hepatic impairment (Child-Pugh Class C). ROZEREM should be used with caution in patients with moderate hepatic impairment [see Warnings and Precautions (5.6)].

Renal Impairment

The pharmacokinetic characteristics of ROZEREM were studied after administering a 16 mg dose to subjects with mild, moderate, or severe renal impairment based on predose creatinine clearance (53 to 95, 35 to 49, or 15 to 30 mL/min/1.73 m2, respectively), and in subjects who required chronic hemodialysis. Wide intersubject variability was seen in ROZEREM exposure parameters. However, no effects on Cmax or AUC0-t of parent drug or M-II were seen in any of the treatment groups; the incidence of adverse events was similar across groups. These results are consistent with the negligible renal clearance of ramelteon, which is principally eliminated via hepatic metabolism. No adjustment of ROZEREM dosage is required in patients with renal impairment, including patients with severe renal impairment (creatinine clearance of ≤30 mL/min/1.73 m2) and patients who require chronic hemodialysis.

12.5 Drug-Drug Interactions

ROZEREM has a highly variable intersubject pharmacokinetic profile (approximately 100% coefficient of variation in Cmax 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Controlled Clinical Trials

14.2 Studies Pertinent to Safety Concerns for Sleep-Promoting Drugs

14.3 Studies to Evaluate Effects on Endocrine Function

Two controlled studies evaluated the effects of ROZEREM on endocrine function.

In the first trial, ROZEREM 16 mg once daily or placebo was administered to 99 healthy volunteer subjects for four weeks. This study evaluated the thyroid axis, adrenal axis and reproductive axis. No clinically significant endocrinopathies were demonstrated in this study. However, the study was limited in its ability to detect such abnormalities due to its limited duration.

In the second trial, ROZEREM 16 mg once daily or placebo was administered to 122 subjects with chronic insomnia for six months. This study evaluated the thyroid axis, adrenal axis and reproductive axis. There were no significant abnormalities seen in either the thyroid or the adrenal axes. Abnormalities were, however, noted within the reproductive axis. Overall, the mean serum prolactin level change from baseline was 4.9 mcg/L (34% increase) for women in the ROZEREM group compared with -0.6 mcg/L (4% decrease) for women in the placebo group (p=0.003). No differences between active- and placebo-treated groups occurred among men. Thirty two percent of all patients who were treated with ramelteon in this study (women and men) had prolactin levels that increased from normal baseline levels compared to 19% of patients who were treated with placebo. Subject-reported menstrual patterns were similar between the two treatment groups.

In a 12 month, open-label study in adult and elderly patients, there were two patients who were noted to have abnormal morning cortisol levels, and subsequent abnormal ACTH stimulation tests. A 29 year old female patient was diagnosed with a prolactinoma. The relationship of these events to ROZEREM therapy is not clear.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep container tightly closed and protected from moisture and humidity.

Severe Anaphylactic and Anaphylactoid Reactions

Inform patients that severe anaphylactic and anaphylactoid reactions have occurred with ramelteon. Describe the relevant signs/symptoms and advise seeking immediate medical attention if any such things occur.

Sleep-Driving and other Complex Behaviors

There have been reports of people getting out of bed after taking a sleep medication and driving their cars while not fully awake, often with no memory of the event. If a patient experiences such an episode, it should be reported to his or her doctor immediately, since "sleep-driving" can be dangerous. This behavior is more likely to occur when sleep medications are taken with alcohol or other central nervous system depressants. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sleep medication. As with sleep-driving, patients usually do not remember these events.

Endocrine Effects

Patients should consult their healthcare providers if they experience one of the following: cessation of menses or galactorrhea in females, decreased libido, or problems with fertility. Describe the relevant signs/symptoms and advise seeking medical attention if any such things occur.

Administration Instructions

• 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 that they should not take ROZEREM with or immediately after a high-fat meal.
• Do not break the tablet; it should be swallowed whole.

Lactation

Advise mothers using ROZEREM to monitor neonates for signs of somnolence and feeding problems. A lactating woman may consider pumping and discarding breast milk during treatment and for 25 hours after ROZEREM administration to minimize drug exposure to a breastfed infant [see Use in Specific Populations (8.2)].