Source: FDA, National Drug Code (US) Revision Year: 2018
Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors and relative selectivity over the MT3 receptor.
The activity of ramelteon at the MT1 and MT2receptors 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 pharmacologically active and has approximately one tenth and one fifth the binding affinity of the parent molecule for the human MT1 and MT2 receptors, respectively. However, M-II circulates at higher concentrations than the parent producing 20- to 100-fold greater mean systemic exposure when compared to ramelteon. 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 (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.
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 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.
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 postdose.
Repeated once daily dosing with ROZEREM does not result in significant accumulation owing to the short elimination half-life of ramelteon (on average, approximately one to 2.6 hours).
The half-life of M-II is two to five 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 AUC0-inf for a single 16 mg dose of ROZEREM 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 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 [see Dosage and Administration (2.1)].
In a group of 24 elderly subjects aged 63 to 79 years administered a single ROZEREM 16 mg dose, the mean Cmax and AUC0-inf values were 11.6 ng/mL (SD, 13.8) and 18.7 ng∙hr/mL (SD, 19.4), respectively. The elimination half-life was 2.6 hours (SD, 1.1). Compared with younger adults, the total exposure (AUC0-inf) and Cmax of ramelteon were 97 and 86% higher, respectively, in elderly subjects. The AUC0-inf and Cmax of M-II were increased by 30 and 13%, respectively, in elderly subjects.
There are no clinically meaningful gender-related differences in the pharmacokinetics of ROZEREM or its metabolites.
Exposure to ROZEREM was increased almost four-fold in subjects with mild hepatic impairment after seven days of dosing with 16 mg/day; exposure was further increased (more than ten-fold) in subjects with moderate hepatic impairment. Exposure to M-II was only marginally increased in mildly and moderately impaired subjects relative to healthy matched controls. The pharmacokinetics of ROZEREM have not been evaluated in subjects with severe hepatic impairment (Child-Pugh Class C). ROZEREM should be used with caution in patients with moderate hepatic impairment [see Warnings and Precautions (5.6)].
The pharmacokinetic characteristics of ROZEREM were studied after administering a 16 mg dose to subjects with mild, moderate, or severe renal impairment based on predose creatinine clearance (53 to 95, 35 to 49, or 15 to 30 mL/min/1.73 m², respectively), and in subjects who required chronic hemodialysis. Wide intersubject variability was seen in ROZEREM exposure parameters. However, no effects on Cmax or AUC0-t of parent drug or M-II were seen in any of the treatment groups; the incidence of adverse events was similar across groups. These results are consistent with the negligible renal clearance of ramelteon, which is principally eliminated via hepatic metabolism. No adjustment of ROZEREM dosage is required in patients with renal impairment, including patients with severe renal impairment (creatinine clearance of ≤30 mL/min/1.73 m²) and patients who require chronic hemodialysis.
ROZEREM has a highly variable intersubject pharmacokinetic profile (approximately 100% coefficient of variation in Cmax 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.
When fluvoxamine 100 mg twice daily was administered for three days prior to single-dose coadministration of ROZEREM 16 mg and fluvoxamine, the AUC0-inf for ramelteon increased approximately 190-fold, and the Cmax increased approximately 70-fold, compared to ROZEREM administered alone. ROZEREM should not be used in combination with fluvoxamine. Other less strong CYP1A2 inhibitors have not been adequately studied. ROZEREM should be administered with caution to patients taking less strong CYP1A2 inhibitors [see Contraindications (4), Drug Interactions (7)].
Administration of rifampin 600 mg once daily for 11 days resulted in a mean decrease of approximately 80% (40 to 90%) in total exposure to ramelteon and metabolite M-II, (both AUC0-inf and Cmax) after a single 32 mg dose of ROZEREM. Efficacy may be reduced when ROZEREM is used in combination with strong CYP enzyme inducers such as rifampin [see Drug Interactions (7)].
The AUC0-inf and Cmax of ramelteon increased by approximately 84% and 36%, respectively, when a single 16 mg dose of ROZEREM was administered on the fourth day of ketoconazole 200 mg twice daily administration, compared to administration of ROZEREM alone. Similar increases were seen in M-II pharmacokinetic variables. ROZEREM should be administered with caution in subjects taking strong CYP3A4 inhibitors such as ketoconazole [see Drug Interactions (7)].
The total and peak systemic exposure (AUC0-inf and Cmax) of ramelteon after a single 16 mg dose of ROZEREM was increased by approximately 150% when administered with fluconazole. Similar increases were also seen in M-II exposure. ROZEREM should be administered with caution in subjects taking strong CYP2C9 inhibitors such as fluconazole [see Drug Interactions (7)].
Administration of donepezil 10 mg once daily for 26 days resulted in a mean increase of approximately 100% in overall exposure to ramelteon, (AUC0-inf) and a mean increase of approximately 87% in maximum exposure to ramelteon (Cmax) after a single 8 mg dose of ROZEREM. No change was seen in M-II exposure. Patients should be closely monitored when ROZEREM is coadministered with donepezil [see Drug Interactions (7)].
Administration of doxepin 10 mg once daily for 23 days resulted in a mean increase of approximately 66% in overall exposure to ramelteon, (AUC0-inf) and a mean increase of approximately 69% in maximum exposure to ramelteon (Cmax) after a single 8 mg dose of ROZEREM. No change was seen in M-II exposure. Patients should be closely monitored when ROZEREM is coadministered with doxepin [see Drug Interactions (7)].
Interaction studies of concomitant administration of ROZEREM with fluoxetine (CYP2D6 inhibitor), omeprazole (CYP1A2 inducer/CYP2C19 inhibitor), theophylline (CYP1A2 substrate), dextromethorphan (CYP2D6 substrate), sertraline, venlafaxine, escitalopram, gabapentin, and zolpidem did not produce clinically meaningful changes in either peak or total exposures to ramelteon or the M-II metabolite.
Administration of ramelteon 8 mg once daily for 11 days resulted in an increase in median Tmax of zolpidem by approximately 20 minutes and exposure to zolpidem (both AUC0-inf and Cmax) was unchanged after a single 10 mg dose of zolpidem. Ordinarily zolpidem should not be given in a patient taking ROZEREM.
Concomitant administration of ROZEREM with omeprazole (CYP2C19 substrate), dextromethorphan (CYP2D6 substrate), midazolam (CYP3A4 substrate), theophylline (CYP1A2 substrate), digoxin (p-glycoprotein substrate), warfarin (CYP2C9 [S]/CYP1A2 [R] substrate), venlafaxine, fluvoxamine, donepezil, doxepin, sertraline, escitalopram, and gabapentin did not produce clinically meaningful changes in peak and total exposures to these drugs.
With single-dose, daytime coadministration 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 postdose 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.
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 based on body surface area (mg/m²).
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 based on mg/m².
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.
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 RHD of 8 mg/day based on mg/m². Oral administration of ramelteon (up to 600 mg/kg/day) to male rats had no effects on sperm quality or reproductive performance.
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 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 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 six 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 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 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 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 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 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 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 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 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; ROZEREM is 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 ROZEREM 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 ROZEREM 8 or 16 mg; the other two studies employed subjective measures of sleep-onset insomnia in elderly subjects receiving ROZEREM 4 or 8 mg, and in younger adult subjects receiving ROZEREM 8 or 16 mg. There was no evidence that ROZEREM caused rebound insomnia during the posttreatment period.
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 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, ROZEREM 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 ROZEREM 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 ROZEREM therapy is not clear.
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