Rozerem Information
Rozerem () Indications And Usage
Rozerem () is indicated for the treatment of insomnia characterized by difficulty with sleep onset.
Rozerem () Dosage And Administration
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.
Rozerem () Dosage Forms And Strengths
Rozerem () is available in an 8 mg strength tablet for oral administration.
Rozerem () 8 mg tablets are round, pale orange-yellow, film-coated, with “TAK” and “RAM-8” printed on one side.
Rozerem () Contraindications
Patients who develop angioedema after treatment with Rozerem () should not be rechallenged with the drug.
Patients should not take Rozerem () in conjunction with fluvoxamine (Luvox) .
Rozerem () Warnings And Precautions
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.
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.
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.
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
Rozerem () has not been studied in subjects with severe sleep apnea and is not recommended for use in this population .
Rozerem () should not be used by patients with severe hepatic impairment .
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.
Rozerem () is not known to interfere with commonly used clinical laboratory tests. In addition, 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 .
Rozerem () Adverse Reactions
The following serious adverse reactions are discussed in greater detail in other sections:
Rozerem () Use In Specific Populations
In animal studies, ramelteon produced evidence of developmental toxicity, including teratogenic effects, in rats at doses much greater than the recommended human dose (RHD) of 8 mg/day. There are no adequate and well-controlled studies in pregnant women. Rozerem () should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Oral administration of ramelteon (10, 40, 150 or 600 mg/kg/day) to pregnant rats during the period of organogenesis was associated with increased incidences of fetal structural abnormalities (malformations and variations) at doses greater than 40 mg/kg/day. The no-effect dose is approximately 50 times the RHD on a body surface area (mg/m) basis. Treatment of pregnant rabbits during the period of organogenesis produced no evidence of embryo-fetal toxicity at oral doses of up to 300 mg/kg/day (or up to 720 times the RHD on a mg/m basis).
When rats were orally administered ramelteon (30, 100, or 300 mg/kg/day) throughout gestation and lactation, growth retardation, developmental delay, and behavioral changes were observed in the offspring at doses greater than 30 mg/kg/day. The no-effect dose is 36 times the RHD on a mg/m basis. Increased incidences of malformation and death among offspring were seen at the highest dose.
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.
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.
Rozerem () Drug Abuse And Dependence
Rozerem () is not a controlled substance.
Discontinuation of ramelteon in animals or in humans after chronic administration did not produce withdrawal signs. Ramelteon does not appear to produce physical dependence.
Rozerem () Overdosage
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.
Rozerem () Description
Rozerem () (ramelteon) is an orally active hypnotic chemically designated as ()--[2-(1,6,7,8-tetrahydro-2-indeno-[5,4-]furan-8-yl)ethyl]propionamide and containing one chiral center. The compound is produced as the ()-enantiomer, with an empirical formula of CHNO, molecular weight of 259.34, and the following chemical structure:
Ramelteon is freely soluble in organic solvents, such as methanol, ethanol, and dimethyl sulfoxide; soluble in 1-octanol and acetonitrile; and very slightly soluble in water and in aqueous buffers from pH 3 to pH 11.
Each Rozerem () tablet includes the following inactive ingredients: lactose monohydrate, starch, hydroxypropyl cellulose, magnesium stearate, hypromellose, copovidone, titanium dioxide, yellow ferric oxide, polyethylene glycol 8000, and ink containing shellac and synthetic iron oxide black.
Rozerem () Clinical Pharmacology
Rozerem () (ramelteon) is a melatonin receptor agonist with both high affinity for melatonin MT and MTreceptors and selectivity over the MT receptor. Ramelteon demonstrates full agonist activity in cells expressing human MT or MT receptors.
The activity of ramelteon at the MT and MTreceptors 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 active and has approximately one tenth and one fifth the binding affinity of the parent molecule for the human MT and MT receptors, respectively, and is 17- to 25-fold less potent than ramelteon in functional assays. Although the potency of M-II at MT and MT receptors is lower than the parent drug, M-II circulates at higher concentrations than the parent producing 20- to 100-fold greater mean systemic exposure when compared to ramelteon. M-II has weak affinity for the serotonin 5-HT receptor, but no appreciable affinity for other receptors or enzymes. 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.
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 (C) 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.
Ramelteon is absorbed rapidly, with median peak concentrations occurring at approximately 0.75 hour (range, 0.5 to 1.5 hours) after fasted oral administration. Although the total absorption of ramelteon is at least 84%, the absolute oral bioavailability is only 1.8% due to extensive first-pass metabolism.
In vitro
Ramelteon has a mean volume of distribution after intravenous administration of 73.6 L, suggesting substantial tissue distribution.
Metabolism of ramelteon consists primarily of oxidation to hydroxyl and carbonyl derivatives, with secondary metabolism producing glucuronide conjugates. CYP1A2 is the major isozyme involved in the hepatic metabolism of ramelteon; the CYP2C subfamily and CYP3A4 isozymes are also involved to a minor degree.
The rank order of the principal metabolites by prevalence in human serum is M-II, M-IV, M-I, and M-III. These metabolites are formed rapidly and exhibit a monophasic decline and rapid elimination. The overall mean systemic exposure of M-II is approximately 20- to 100-fold higher than parent drug.
Following oral administration of radiolabeled ramelteon, 84% of total radioactivity was excreted in urine and approximately 4% in feces, resulting in a mean recovery of 88%. Less than 0.1% of the dose was excreted in urine and feces as the parent compound. Elimination was essentially complete by 96 hours post-dose.
Repeated once daily dosing with Rozerem () does not result in significant accumulation owing to the short elimination half-life of ramelteon (on average, approximately 1- 2.6 hours).
The half-life of M-II is 2 to 5 hours and independent of dose. Serum concentrations of the parent drug and its metabolites in humans are at or below the lower limits of quantitation within 24 hours.
When administered with a high-fat meal, the AUC for a single 16 mg dose of Rozerem () was 31% higher and the C was 22% lower than when given in a fasted state. Median T was delayed by approximately 45 minutes when Rozerem () was administered with food. Effects of food on the AUC values for M-II were similar. It is therefore recommended that Rozerem () not be taken with or immediately after a high-fat meal .
Rozerem () has a highly variable intersubject pharmacokinetic profile (approximately 100% coefficient of variation in C 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.
Rifampin (strong CYP enzyme inducer):
Ketoconazole (strong CYP3A4 inhibitor):
Fluconazole (strong CYP2C9 inhibitor):
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.
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.
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 () .
Rozerem () Clinical Studies
Three randomized, double-blind trials in subjects with chronic insomnia employing polysomnography (PSG) were provided as objective support of Rozerem () ’s effectiveness in sleep initiation.
One study enrolled younger adults (aged 18 to 64 years, inclusive) with chronic insomnia and employed a parallel design in which the subjects received a single, nightly dose of Rozerem () (8 mg or 16 mg) or matching placebo for 35 days. PSG was performed on the first two nights in each of Weeks 1, 3, and 5 of treatment. Rozerem () reduced the average latency to persistent sleep at each of the time points when compared to placebo. The 16 mg dose conferred no additional benefit for sleep initiation.
The second study employing PSG was a three-period crossover trial performed in subjects aged 65 years and older with a history of chronic insomnia. Subjects received Rozerem () (4 mg or 8 mg) or placebo and underwent PSG assessment in a sleep laboratory for two consecutive nights in each of the three study periods. Both doses of Rozerem () reduced latency to persistent sleep when compared to placebo.
The third study evaluated long term efficacy and safety in adults with chronic insomnia. Subjects received a single, nightly dose of Rozerem () 8 mg or matching placebo for 6 months. PSG was performed on the first two nights of Week 1 and Months 1, 3, 5, and 6. Rozerem () reduced sleep latency at each time point when compared to placebo. In this study, when the PSG results from nights 1 and 2 of Month 7 were compared to the results from nights 22 and 23 of Month 6, there was a statistically significant increase in LPS of 33% (9.5 minutes) in the ramelteon group. There was no increase in LPS in the placebo group when the same time periods were compared.
A randomized, double-blind, parallel group study was conducted in outpatients aged 65 years and older with chronic insomnia and employed subjective measures of efficacy (sleep diaries). Subjects received Rozerem () (4 mg or 8 mg) or placebo for 35 nights. Rozerem () reduced patient-reported sleep latency compared to placebo. A similarly designed study performed in younger adults (aged 18-64 years) using 8 mg and 16 mg of ramelteon did not replicate this finding of reduced patient-reported sleep latency compared to placebo.
While the 16 mg dose was evaluated as a potential treatment for adults, it was shown to confer no additional benefit for sleep initiation and was associated with higher incidences of fatigue, headache and next-day somnolence.
In a randomized, double-blind, parallel-group trial using a first-night-effect model, healthy adults received placebo or Rozerem () before spending one night in a sleep laboratory and being evaluated with PSG. Rozerem () demonstrated a decrease in mean latency to persistent sleep as compared to placebo.
A human laboratory abuse potential study was performed in 14 subjects with a history of sedative/hypnotic or anxiolytic drug abuse. Subjects received single oral doses of Rozerem () (16, 80, or 160 mg), triazolam (0.25, 0.50, or 0.75 mg) or placebo. All subjects received each of the 7 treatments separated by a wash-out period and underwent multiple standard tests of abuse potential. No differences in subjective responses indicative of abuse potential were found between Rozerem () and placebo at doses up to 20 times the recommended therapeutic dose. The positive control drug, triazolam, consistently showed a dose-response effect on these subjective measures, as demonstrated by the differences from placebo in peak effect and overall 24-hour effect.
In order to evaluate potential next-day residual effects, the following scales were used: a Memory Recall Test, a Word List Memory Test, a Visual Analog Mood and Feeling Scale, the Digit-Symbol Substitution Test, and a post-sleep questionnaire to assess alertness and ability to concentrate. There was no evidence of next-day residual effect seen after 2 nights of ramelteon use during the crossover studies.
In a 35-night, double-blind, placebo-controlled, parallel-group study in adults with chronic insomnia, measures of residual effects were performed at three time points. Overall, the magnitudes of any observed differences were small. At Week 1, patients who received 8 mg of Rozerem () had a mean VAS score (46 mm on a 100 mm scale) indicating more fatigue in comparison to patients who received placebo (42 mm). At Week 3, patients who received 8 mg of Rozerem () had a lower mean score for immediate recall (7.5 out of 16 words) compared to patients who received placebo (8.2 words); and the patients treated with Rozerem () had a mean VAS score indicating more sluggishness (27 mm on a 100 mm VAS) in comparison to the placebo-treated patients (22 mm). Patients who received Rozerem () did not have next-morning residual effects that were different from placebo at Week 5.
Rebound Insomnia/Withdrawal
Potential rebound insomnia and withdrawal effects were assessed in four studies in which subjects received Rozerem () or placebo for up to 6 months; 3 were 35-day studies, one was a 6 month study. These studies included a total of 2533 subjects, of whom 854 were elderly.
Tyrer Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ):
In two of the three 35-day insomnia studies, the questionnaire was administered one week after completion of treatment; in the third study, the questionnaire was administered on Days 1 and 2 after completion. In all three of the 35-day studies, subjects receiving Rozerem () 4 mg, 8 mg, or 16 mg daily reported BWSQ scores similar to those of subjects receiving placebo.
In the 6 month study, there was no evidence of withdrawal from the 8 mg dose as measured by the BWSQ.
Rebound Insomnia:
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 4 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 6 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 μg/L (34% increase) for women in the Rozerem () group compared with −0.6 μg/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.
Rozerem () How Supplied/storage And Handling
Rozerem () is available as round, pale orange-yellow, film-coated, 8 mg tablets, with “TAK” and “RAM-8” printed on one side, in the following quantities:
NDC 21695-183-30 Bottles of 30
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.
Rozerem () Patient Counseling Information
Prescribers or other healthcare professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with hypnotics, should counsel them in their appropriate use and should instruct them to read the accompanying Medication Guide .
See attached leaflet.
Manufactured by
Manufactured in
Distributed by
Repackaged by:
Rebel Distributors Corp
Thousand Oaks, CA 91320
Rozerem () is a registered trademark of Takeda Pharmaceutical Company Limited and used under license by Takeda Pharmaceuticals America, Inc.
©2005, 2008 Takeda Pharmaceuticals America, Inc.
05-1143 Revised: 10/2008
Rozerem ()
Rozerem ()
