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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 (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 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 (ramelteon) during the clinical development program.
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 (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.
Patients 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.
Use in Adolescents and Children
ROZEREM (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 [see Clinical Trials].
Use in Patients with Concomitant Illness
ROZEREM (ramelteon) has not been studies in subjects with sleep apnea and is not recommended for use in this population [see Use In Specific Populations].
ROZEREM (ramelteon) should not be used by patients with severe hepatic impairment [see CLINICAL PHARMACOLOGY].
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.
Interference with Laboratory Tests
ROZEREM (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 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 Medication Guide].
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.
Patients 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.
- Patients should be advised to take ROZEREM (ramelteon) 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 (ramelteon) with or immediately after a high-fat meal.
- Do not break the tablet; it should be swallowed whole.
See Medication Guide.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Ramelteon 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.
Ramelteon 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 Fertility
When 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 Category C
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.
Labor and delivery
The 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.
It 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.
Safety 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.
A 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 Disease
The 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.
The 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.
Exposure 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 [see CLINICAL PHARMACOLOGY]. ROZEREM (ramelteon) is not recommended in patients with severe hepatic impairment.
No 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 [see CLINICAL PHARMACOLOGY].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 12/14/2010
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