Ramelteon
Ramelteon Prescribing Information
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)
Three randomized, double-blind trials in subjects with chronic insomnia employing polysomnography (PSG) were provided as objective support of ramelteon tablet’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 ramelteon tablet (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.
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.
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.
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 tablet 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 tablet 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 tablet did not have next-morning residual effects that were different from placebo at Week 5.
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.
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 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 posttreatment period.
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.
- Adult dose: 8 mg taken within 30 minutes of going to bed.
2.1 Dosage in AdultsThe recommended dose of ramelteon tablet 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 tablet dose should not exceed 8 mg per day.
- Should not be taken with or immediately after a high-fat meal.
2.1 Dosage in AdultsThe recommended dose of ramelteon tablet 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 tablet dose should not exceed 8 mg per day.
- Total daily dose should not exceed 8 mg.
2.1 Dosage in AdultsThe recommended dose of ramelteon tablet 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 tablet dose should not exceed 8 mg per day.
Ramelteon tablet is available in an 8 mg strength tablet for oral administration.
Ramelteon tablets, 8 mg are yellow colored, circular, biconvex, film-coated tablets, debossed with "RM" on one face and plain on other face with an approximate diameter of 7.00 mm.
- Pediatric use: Safety and effectiveness not established.
8.4 Pediatric UseSafety 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.
- Geriatric use: No overall differences in safety and efficacy between elderly and younger adult subjects.
8.5 Geriatric UseA total of 654 subjects in double-blind, placebo-controlled, efficacy trials who received ramelteon tablets 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 ramelteon tablets 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 ramelteon tablets 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.
- Hepatic impairment: Is not recommended in patients with severe impairment; use with caution in moderate impairment.
8.8 Hepatic ImpairmentExposure to ramelteon tablets were increased by four-fold in subjects with mild hepatic impairment and by more than ten-fold in subjects with moderate hepatic impairment. Ramelteon tablets should be used with caution in patients with moderate hepatic impairment
[see Clinical Pharmacology (12.4)].Ramelteon tablets are not recommended in patients with severe hepatic impairment.
Patients who develop angioedema after treatment with ramelteon tablets should not be rechallenged with the drug.
Patients should not take ramelteon tablet in conjunction with fluvoxamine
- Rifampin (strong CYP enzyme inducer): Decreases exposure to and effects of ramelteon. (7.1)
- Ketoconazole (strong CYP3A4 inhibitor): Increases AUC for ramelteon; administer with caution. (7.1)
- Fluconazole (strong CYP2C9 inhibitor): Increases systemic exposure of ramelteon; administer with caution. (7.1)
- Donepezil: Increases systemic exposure of ramelteon; patients should be closely monitored when ramelteon is coadministered with donepezil. (7.1)
- Doxepin: Increases systemic exposure of ramelteon; patients should be closely monitored when ramelteon is coadministered with doxepin. (7.1)
- Alcohol: Causes additive psychomotor impairment; should not be used in combination. (7.2)
AUC0 to inffor ramelteon increased approximately 190-fold, and the Cmaxincreased 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
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
The AUC0 to infand Cmaxof 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
The AUC0 to infand Cmaxof 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
The AUC0 to infand Cmaxof ramelteon increased by approximately 100% and 87%, respectively upon coadministration of donepezil with ramelteon tablets. Patients should be closely monitored when ramelteon tablet is coadministered with donepezil
The AUC0 to infand Cmaxof ramelteon increased by approximately 66% and 69%, respectively, upon coadministration of doxepin with ramelteon tablets. Patients should be closely monitored when ramelteon tablets were coadministered with doxepin
Alcohol by itself impairs performance and can cause sleepiness. Since the intended effect of ramelteon tablets are to promote sleep, patients should be cautioned not to consume alcohol when using ramelteon tablets
Ramelteon tablets are not known to interfere with commonly used clinical laboratory tests. In addition,
- Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis have been reported. Do not rechallenge if such reactions occur. ()
5.1 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 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: Reevaluate if insomnia persists after 7 to 10 days of treatment. ()
5.2 Need to Evaluate for Comorbid 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 ramelteon tablets during the clinical development program. - Abnormal thinking, behavioral changes, complex behaviors: May include “sleep-driving” and hallucinations. Immediately evaluate any new onset behavioral changes. ()
5.3 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 ramelteon tablets 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 ramelteon tablets. Discontinuation of ramelteon tablets should be strongly considered for patients who report any complex sleep behavior.
- Depression: Worsening of depression or suicidal thinking may occur. ()
5.3 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 ramelteon tablets 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 ramelteon tablets. Discontinuation of ramelteon tablets should be strongly considered for patients who report any complex sleep behavior.
- CNS effects: Potential impairment of activities requiring complete mental alertness such as operating machinery or driving a motor vehicle, after ingesting the drug. ()
5.4 CNS EffectsPatients 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: Include decreased testosterone and increased prolactin levels. Effect on reproductive axis in developing humans is unknown. ()
5.5 Reproductive EffectsRamelteon tablets have 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
[see Clinical Trials (14.3)]. - Patients with severe sleep apnea: Ramelteon tablet is not recommended for use in this population. ()
5.6 Use in Patients with Concomitant IllnessRamelteon tablet 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)].Ramelteon tablets should not be used by patients with severe hepatic impairment
[see Clinical Pharmacology (12.4)].