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 (ramelteon). 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 drug ingestion should be considered. Contact a poison control center for current information on the management of overdosage.
Patients who develop angioedema after treatment with ROZEREM (ramelteon) should not be rechallenged with the drug.
Patients should not take ROZEREM (ramelteon) in conjunction with fluvoxamine (Luvox).
The following serious adverse reactions are discussed in greater detail in other sections:
The data described in this section reflect exposure to ROZEREM (ramelteon) in 5373 subjects, including 722 exposed for 6 months or longer, and 448 subjects for one year.
Six percent of the 5373 individual subjects exposed to ROZEREM (ramelteon) in clinical studies discontinued treatment owing to an adverse event, compared with 2% of the 2279 subjects receiving placebo. The most frequent adverse events leading to discontinuation in subjects receiving ROZEREM (ramelteon) were somnolence, dizziness, nausea, fatigue, headache, and insomnia; all of which occurred in 1% of the patients or less.
ROZEREM (ramelteon) Most Commonly Observed Adverse EventsTable 1 displays the incidence of adverse events reported by the 2861 patients with chronic insomnia who participated in placebo-controlled trials of ROZEREM (ramelteon).
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of other drugs, and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
Table 1: Incidence (% of subjects) of Treatment-Emergent
Adverse Events
| MedDRA Preferred Term | Placebo (n=1456) |
Ramelteon 8 mg (n=1405) |
| Somnolence | 2% | 3% |
| Fatigue | 2% | 3% |
| Dizziness | 3% | 4% |
| Nausea | 2% | 3% |
| Insomnia exacerbated | 2% | 3% |
ROZEREM (ramelteon) is indicated for the treatment of insomnia characterized by difficulty with sleep onset.
The clinical trials performed in support of efficacy were up to 6 months in duration. The final formal assessments of sleep latency were performed after 2 days of treatment during the crossover study (elderly only), at 5 weeks in the 6-week studies (adults and elderly), and at the end of the 6-month study (adults and elderly).
The pharmacokinetic profile of ROZEREM (ramelteon) 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.
AbsorptionRamelteon 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.
DistributionIn vitro protein binding of ramelteon is approximately 82% in human serum, independent of concentration. Binding to albumin accounts for most of that binding, since 70% of the drug is bound in human serum albumin. Ramelteon is not distributed selectively to red blood cells.
Ramelteon has a mean volume of distribution after intravenous administration of 73.6 L, suggesting substantial tissue distribution.
MetabolismMetabolism 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.
EliminationFollowing 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 (ramelteon) does not result in significant accumulation owing to the short elimination half-life of ramelteon (on average, approximately 1 to 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.
Effect of FoodWhen administered with a high-fat meal, the AUC0-inf for a single 16 mg dose of ROZEREM (ramelteon) was 31% higher and the Cmax was 22% lower than when given in a fasted state. Median Tmax was delayed by approximately 45 minutes when ROZEREM (ramelteon) was administered with food. Effects of food on the AUC values for M-II were similar. It is therefore recommended that ROZEREM (ramelteon) not be taken with or immediately after a high-fat meal.
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 (ramelteon) 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/m²) 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/m² 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/m² basis. Increased incidences of malformation and death among offspring were seen at the highest dose.
ROZEREM (ramelteon) is available in an 8 mg strength tablet for oral administration.
ROZEREM (ramelteon) 8 mg tablets are round, pale orange-yellow, film-coated, with “TAK” and “RAM-8” printed on one side.
Storage And HandlingROZEREM (ramelteon) 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 64764-805-30 Bottles of 30
NDC 64764-805-10 Bottles of 100
NDC 64764-805-50 Bottles of 500
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). Keep container tightly closed and protected from moisture and humidity.
Distributed by: Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015. Revised: 11/10
Included as part of the PRECAUTIONS section.
PRECAUTIONS Severe Anaphylactic and Anaphylactoid ReactionsRare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of ROZEREM (ramelteon). 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 (ramelteon) should not be rechallenged with the drug.
Need to Evaluate for Co-morbid DiagnosesSince 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 (ramelteon) during the clinical development program.
Abnormal Thinking and Behavioral ChangesA 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 (ramelteon) 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 (ramelteon). Discontinuation of ROZEREM (ramelteon) should be strongly considered for patients who report any complex sleep behavior.
CNS EffectsPatients should avoid engaging in hazardous activities that require concentration (such as operating a motor vehicle or heavy machinery) after taking ROZEREM (ramelteon).
After taking ROZEREM (ramelteon) , patients should confine their activities to those necessary to prepare for bed.
Patients should be advised not to consume alcohol in combination with ROZEREM (ramelteon) as alcohol and ROZEREM (ramelteon) may have additive effects when used in conjunction.
Reproductive Effects Use in Adolescents and ChildrenROZEREM (ramelteon) 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 (ramelteon) may have on the reproductive axis in developing humans.
Use in Patients with Concomitant IllnessROZEREM (ramelteon) has not been studies in subjects with sleep apnea and is not recommended for use in this population.
ROZEREM (ramelteon) should not be used by patients with severe hepatic impairment.
Laboratory Tests MonitoringNo 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.
Interference with Laboratory TestsROZEREM (ramelteon) 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 .
Patient Counseling InformationPrescribers 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.
Severe Anaphylactic and Anaphylactoid ReactionsInform 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 BehaviorsThere 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 EffectsPatients should consult their health care 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 InstructionsSee Medication Guide.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility CarcinogenesisRamelteon was administered to mice and rats at oral doses of 0, 30, 100, 300, or 1000 mg/kg/day (mice) and 0, 15, 60, 250, or 1000 mg/kg/day (rats). Mice and rats were dosed for two years, except at the high dose (94 weeks for male and female mice and female rats). In mice, dose-related increases in the incidence of hepatic tumors (adenomas, carcinomas, hepatoblastomas) were observed in males and females. The no-effect dose for hepatic tumors in mice (30 mg/kg/day) is approximately 20 times the recommended human dose (RHD) of 8 mg/day on a body surface area (mg/m²) basis.
In rats, the incidence of hepatic adenoma and benign Leydig cell tumors of the testis was increased in males at doses ≥ 250 mg/kg/day. In females, the incidence of hepatic adenoma was increased at doses ≥ 60 mg/kg/day. The incidence of hepatic carcinoma was increased in males and female rats at 1000 mg/kg/day. The no-effect dose for tumors in rats (15 mg/kg/day) is approximately 20 times the RHD on a mg/m² basis.
MutagenesisRamelteon was not genotoxic in the in vitro bacterial reverse mutation (Ames) assay, the in vitro mouse lymphoma TK+/-assay, and in in vivo oral micronucleus assays in mouse and rat. Ramelteon was clastogenic in the in vitro chromosomal aberration assay in Chinese hamster lung cells.
Separate studies indicated that the concentration of the M-II metabolite formed in the presence of metabolic activation exceeded the concentration of ramelteon; therefore, the genotoxic potential of the M-II metabolite was also assessed in the in vitro studies.
Impairment of FertilityWhen ramelteon (doses of 6 to 600 mg/kg/day) was administered orally to male and female rats prior to and during mating and early gestation, alterations in estrus cyclicity and decreased numbers of corpora lutea, implantations, and live embryos were observed at doses greater than 20 mg/kg/day. The no-effect dose is approximately 24 times the recommended human dose of 8 mg/day on a body surface area (mg/m²) basis. Oral administration of ramelteon (up to 600 mg/kg/day) to male rats had no effects on sperm quality or reproductive performance.
Use In Specific Populations Pregnancy Pregnancy Category CIn 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 (ramelteon) 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/m²) 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/m² 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/m² basis. Increased incidences of malformation and death among offspring were seen at the highest dose.
Labor and deliveryThe potential effects of ROZEREM (ramelteon) on the duration of labor and/or delivery, for either the mother or the fetus, have not been studied. ROZEREM (ramelteon) has no established use in labor and delivery.
Nursing MothersIt is not known whether ramelteon is secreted into human milk; however ramelteon is secreted into the milk of lactating rats. Because many drugs are excreted into human milk, caution should be exercised when administered to a nursing woman.
Pediatric UseSafety and effectiveness of ROZEREM (ramelteon) in pediatric patients have not been established. Further study is needed prior to determining that this product may be used safely in pre-pubescent and pubescent patients.
Geriatric UseA total of 654 subjects in double-blind, placebo-controlled, efficacy trials who received ROZEREM (ramelteon) 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 (ramelteon) 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 (ramelteon) 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.
Chronic Obstructive Pulmonary DiseaseThe respiratory depressant effect of ROZEREM (ramelteon) 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 (ramelteon) 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 (ramelteon) 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 (ramelteon) in patients with COPD. The respiratory depressant effects in patients with COPD cannot be definitively known from this study.
Sleep ApneaThe effects of ROZEREM (ramelteon) 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 (ramelteon) 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 (ramelteon) does not exacerbate mild to moderate obstructive sleep apnea. There is no available information on the respiratory effects of multiple doses of ROZEREM (ramelteon) 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 (ramelteon) has not been studied in subjects with severe obstructive sleep apnea; use of ROZEREM (ramelteon) is not recommended in such patients.
Hepatic ImpairmentExposure to ROZEREM (ramelteon) was increased by 4-fold in subjects with mild hepatic impairment and by more than 10-fold in subjects with moderate hepatic impairment. ROZEREM (ramelteon) should be used with caution in patients with moderate hepatic impairment. ROZEREM (ramelteon) is not recommended in patients with severe hepatic impairment.
Renal ImpairmentNo effects on Cmax and AUC0-t of parent drug or M-II were seen. No adjustment of ROZEREM (ramelteon) dosage is required in patients with renal impairment.
The recommended dose of ROZEREM (ramelteon) is 8 mg taken within 30 minutes of going to bed. It is recommended that ROZEREM (ramelteon) not be taken with or immediately after a high-fat meal.
The total ROZEREM (ramelteon) dose should not exceed 8 mg per day.
Dosing in Patients with Hepatic ImpairmentROZEREM (ramelteon) is not recommended in patients with severe hepatic impairment. ROZEREM (ramelteon) should be used with caution in patients with moderate hepatic impairment.
Administration with Other MedicationsROZEREM (ramelteon) should not be used in combination with fluvoxamine. ROZEREM (ramelteon) should be used with caution in patients taking other CYP1A2 inhibiting drugs.
The following serious adverse reactions are discussed in greater detail in other sections:
The data described in this section reflect exposure to ROZEREM (ramelteon) in 5373 subjects, including 722 exposed for 6 months or longer, and 448 subjects for one year.
Six percent of the 5373 individual subjects exposed to ROZEREM (ramelteon) in clinical studies discontinued treatment owing to an adverse event, compared with 2% of the 2279 subjects receiving placebo. The most frequent adverse events leading to discontinuation in subjects receiving ROZEREM (ramelteon) were somnolence, dizziness, nausea, fatigue, headache, and insomnia; all of which occurred in 1% of the patients or less.
ROZEREM (ramelteon) Most Commonly Observed Adverse EventsTable 1 displays the incidence of adverse events reported by the 2861 patients with chronic insomnia who participated in placebo-controlled trials of ROZEREM (ramelteon).
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of other drugs, and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
Table 1: Incidence (% of subjects) of Treatment-Emergent
Adverse Events
| MedDRA Preferred Term | Placebo (n=1456) |
Ramelteon 8 mg (n=1405) |
| Somnolence | 2% | 3% |
| Fatigue | 2% | 3% |
| Dizziness | 3% | 4% |
| Nausea | 2% | 3% |
| Insomnia exacerbated | 2% | 3% |
AUC0-inf for ramelteon increased approximately 190-fold, and the Cmax increased approximately 70-fold upon coadministration of fluvoxamine and ROZEREM (ramelteon) , compared to ROZEREM (ramelteon) administered alone. ROZEREM (ramelteon) should not be used in combination with fluvoxamine. Other less strong CYP1A2 inhibitors have not been adequately studied. ROZEREM (ramelteon) should be administered with caution to patients taking less strong CYP1A2 inhibitors.
Rifampin (strong CYP enzyme inducer)Administration of multiple doses of rifampin resulted in a mean decrease of approximately 80% in total exposure to ramelteon and metabolite M-II. Efficacy may be reduced when ROZEREM (ramelteon) is used in combination with strong CYP enzyme inducers such as rifampin.
Ketoconazole (strong CYP3A4 inhibitor)The AUC0-inf and Cmax of ramelteon increased by approximately 84% and 36% upon coadministration of ketoconazole with ROZEREM (ramelteon). ROZEREM (ramelteon) should be administered with caution in subjects taking strong CYP3A4 inhibitors such as ketoconazole .
Fluconazole (strong CYP2C9 inhibitor)The AUC0-inf and Cmax of ramelteon was increased by approximately 150% when ROZEREM (ramelteon) was coadministered with fluconazole. ROZEREM (ramelteon) should be administered with caution in subjects taking strong CYP2C9 inhibitors such as fluconazole .
DonepezilThe AUC0-inf and Cmax of ramelteon increased by approximately 100% and 87%, respectively upon coadministration of donepezil with ROZEREM (ramelteon). Patients should be closely monitored when ROZEREM (ramelteon) is coadministered with donepezil.
DoxepinThe AUC0-inf and Cmax of ramelteon increased by approximately 66% and 69%, respectively, upon coadministration of doxepin donepezil with ROZEREM (ramelteon). Patients should be closely monitored when ROZEREM (ramelteon) is coadministered with doxepin.
Effect of Alcohol on ROZEREM (ramelteon)Alcohol by itself impairs performance and can cause sleepiness. Since the intended effect of ROZEREM (ramelteon) is to promote sleep, patients should be cautioned not to consume alcohol when using ROZEREM. Use of the products in combination may have an additive effect.
Drug/Laboratory Test InteractionsROZEREM (ramelteon) 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 .
Drug Abuse And DependenceROZEREM (ramelteon) 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.
Human DataA laboratory abuse potential study was performed with ROZEREM.
Animal DataRamelteon 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.
