Ramelteon Drug Information
Generic name: RAMELTEON
Melatonin Receptor Agonist [EPC]
Uses of Ramelteon
Ramelteon Tablets are indicated for the treatment of insomnia characterized by difficulty with sleep onset. The clinical trials performed in support of efficacy were up to six months in duration. The final formal assessments of sleep latency were performed after two days of treatment during the crossover study (elderly only), at five weeks in the six week studies (adults and elderly), and at the end of the six month study (adults and elderly) . Ramelteon Tablets are indicated for the treatment of insomnia characterized by difficulty with sleep onset.
Dosage & Administration of Ramelteon
Dosage in Adults
The recommended dose of Ramelteon Tablets is 8 mg taken within 30 minutes of going to bed. It is recommended that Ramelteon Tablets not be taken with or immediately after a high-fat meal. The total Ramelteon Tablets dose should not exceed 8 mg per day.
Dosing in Patients with Hepatic Impairment Ramelteon Tablets is not recommended in
patients with severe hepatic impairment. Ramelteon Tablets should be used with caution in patients with moderate hepatic impairment .
Administration with Other Medications Ramelteon Tablets should not be used in combination
with fluvoxamine. Ramelteon Tablets should be used with caution in patients taking other CYP1A2 inhibiting drugs .
Side Effects of Ramelteon
Clinical Trials Experience Adverse Reactions Resulting in Discontinuation of Treatment
The data described in this section reflect exposure to Ramelteon Tablets in 5373 subjects, including 722 exposed for six months or longer, and 448 subjects for one year. Six percent of the 5373 individual subjects exposed to Ramelteon Tablets 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 Ramelteon Tablets were somnolence, dizziness, nausea, fatigue, headache, and insomnia; all of which occurred in 1% of the patients or less.
Ramelteon Tablets Most Commonly Observed Adverse Events Table 1 displays the incidence of adverse events reported by the 2861 patients with chronic insomnia who participated in placebo-controlled trials of Ramelteon Tablets. 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%
Warnings & Cautions for Ramelteon
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 Ramelteon Tablets. 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 Ramelteon Tablets should not be rechallenged with the drug.
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 Ramelteon Tablets 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 Ramelteon Tablets use.
Amnesia, anxiety and other neuropsychiatric 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 Ramelteon Tablets. Discontinuation of Ramelteon Tablets should be strongly considered for patients who report any complex sleep behavior.
CNS Effects Patients should avoid engaging in hazardous activities that require concentration
(such as operating a motor vehicle or heavy machinery) after taking Ramelteon Tablets. After taking Ramelteon Tablets, patients should confine their activities to those necessary to prepare for bed. Patients should be advised not to consume alcohol in combination with Ramelteon Tablets as alcohol and Ramelteon Tablets may have additive effects when used in conjunction.
Reproductive Effects Ramelteon Tablets 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 Ramelteon Tablets may have on the reproductive axis in developing humans .
Use in Patients with
Concomitant Illness Ramelteon Tablets have not been studied in subjects with severe sleep apnea and is not recommended for use in this population . Ramelteon Tablets should not be used by patients with severe hepatic impairment.
Laboratory Tests Monitoring 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 Ramelteon Tablets are 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 Interactions with Ramelteon
Effects of Other Drugs on Ramelteon Tablets Fluvoxamine (strong
CYP1A2 inhibitor) AUC 0-inf for ramelteon increased approximately 190-fold, and the C max increased approximately 70-fold upon coadministration of fluvoxamine and Ramelteon Tablets, compared to Ramelteon Tablets administered alone. Ramelteon Tablets should not be used in combination with fluvoxamine . Other less strong CYP1A2 inhibitors have not been adequately studied. Ramelteon Tablets 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 Ramelteon Tablets are used in combination with strong CYP enzyme inducers such as rifampin. Ketoconazole (strong CYP3A4 inhibitor) The AUC 0-inf and C max of ramelteon increased by approximately 84% and 36% upon coadministration of ketoconazole with Ramelteon Tablets. Ramelteon Tablets should be administered with caution in subjects taking strong CYP3A4 inhibitors such as ketoconazole.
Fluconazole (strong CYP2C9 inhibitor) The AUC 0-inf and C max of ramelteon was increased by approximately 150% when Ramelteon Tablets were coadministered with fluconazole. Ramelteon Tablets should be administered with caution in subjects taking strong CYP2C9 inhibitors such as fluconazole. Donepezil The AUC 0-inf and C max of ramelteon increased by approximately 100% and 87%, respectively upon coadministration of donepezil with Ramelteon Tablets.
Patients should be closely monitored when Ramelteon Tablets are coadministered with donepezil. Doxepin The AUC 0-inf and C max of ramelteon increased by approximately 66% and 69%, respectively, upon coadministration of doxepin with Ramelteon Tablets. Patients should be closely monitored when Ramelteon Tablets are coadministered with doxepin.
Effect of Alcohol on Ramelteon Tablets Alcohol by itself impairs performance and
can cause sleepiness. Since the intended effect of Ramelteon Tablets is to promote sleep, patients should be cautioned not to consume alcohol when using Ramelteon Tablets . Use of the products in combination may have an additive effect.
Drug/Laboratory Test Interactions Ramelteon Tablets are 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.
Pregnancy Safety for Ramelteon
Pregnancy Risk Summary Available data from post marketing reports with Ramelteon Tablets use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, ramelteon produced evidence of developmental toxicity, including teratogenic effects, in rats at doses greater than 36 times the recommended human dose (RHD) of 8 mg/day based on body surface area (mg/m 2 ) (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 - 4% and 15 - 20%, respectively. Data Animal Data 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 based on mg/m 2. 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 based on mg/m 2 ). 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 based on mg/m 2. Increased incidences of malformation and death among offspring were seen at the highest dose.
Pediatric Use of Ramelteon
Pediatric Use Safety and effectiveness of Ramelteon Tablets 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.
Contraindications for Ramelteon
Patients who develop angioedema after treatment with Ramelteon Tablets should not be rechallenged with the drug. Patients should not take Ramelteon Tablets in conjunction with fluvoxamine. History of angioedema while taking Ramelteon Tablets.
Fluvoxamine (strong CYP1A2 inhibitor): Increases AUC for ramelteon and should not be used in combination.
Overdosage Information for Ramelteon
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 Ramelteon Tablets. Therefore, the use of dialysis in the treatment of overdosage is not appropriate. 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.
Clinical Studies of Ramelteon
Controlled Clinical Trials Chronic Insomnia Three randomized, double-blind trials in subjects with
chronic insomnia employing polysomnography (PSG) were provided as objective support of Ramelteon Tablets 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 Ramelteon Tablets (8 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.
Ramelteon Tablets 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 Ramelteon Tablets (4 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 Ramelteon Tablets 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 Ramelteon Tablets 8 mg or matching placebo for six months. PSG was performed on the first two nights of Week 1 and Months 1, 3, 5, and 6. Ramelteon Tablets 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 Ramelteon Tablets (4 or 8 mg) or placebo for 35 nights. Ramelteon Tablets reduced patient-reported sleep latency compared to placebo.
A similarly designed study performed in younger adults (aged 18 to 64 years) using 8 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. Transient Insomnia In a randomized, double-blind, parallel-group trial using a first-night-effect model, healthy adults received placebo or Ramelteon Tablets before spending one night in a sleep laboratory and being evaluated with PSG. Ramelteon Tablets demonstrated a decrease in mean latency to persistent sleep as compared to placebo.
Studies Pertinent to Safety Concerns for Sleep-Promoting Drugs Results from Human Laboratory
Abuse Liability Studies 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 Ramelteon Tablets (16, 80, or 160 mg), triazolam (0.25, 0.50, or 0.75 mg) or placebo. All subjects received each of the seven 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 Ramelteon Tablets 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. Residual Pharmacological Effect in Insomnia Trials 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 two 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 Ramelteon Tablets 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 Ramelteon Tablets 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 Ramelteon Tablets 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 Ramelteon Tablets 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 Ramelteon Tablets or placebo for up to six months; three were 35 day studies, one was a six month study. These studies included a total of 2533 subjects, of whom 854 were elderly. Tyrer Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ) The BWSQ is a self-report questionnaire that solicits specific information on 20 symptoms commonly experienced during withdrawal from benzodiazepine receptor agonists; Ramelteon Tablets are not a benzodiazepine receptor agonist.
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 Ramelteon Tablets 4, 8, or 16 mg daily reported BWSQ scores similar to those of subjects receiving placebo. In the six month study, there was no evidence of withdrawal from the 8 mg dose as measured by the BWSQ. Rebound Insomnia Rebound insomnia was assessed in the 35 day studies by measuring sleep latency after abrupt treatment discontinuation.
One of these studies employed PSG in younger adult subjects receiving Ramelteon Tablets 8 or 16 mg; the other two studies employed subjective measures of sleep-onset insomnia in elderly subjects receiving Ramelteon Tablets 4 or 8 mg, and in younger adult subjects receiving Ramelteon Tablets 8 or 16 mg. There was no evidence that Ramelteon Tablets caused rebound insomnia during the post treatment period.
Studies to Evaluate Effects on Endocrine Function Two controlled studies evaluated the
effects of Ramelteon Tablets on endocrine function. In the first trial, Ramelteon Tablets 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, Ramelteon Tablets 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 Ramelteon Tablets 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 Ramelteon Tablets therapy is not clear.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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