CLINICAL PHARMACOLOGY
Pharmacodynamics and Mechanism of Action
ROZEREM (ramelteon) is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors and selectivity over the MT3 receptor. Ramelteon demonstrates full agonist activity in vitro in cells expressing human MT1 or MT2 receptors, and high selectivity for human MT1 and MT2 receptors compared to the MT3 receptor.
The activity of ramelteon at the MT1 and MT2 receptors 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 active and has approximately one tenth and one fifth the binding affinity of the parent molecule for the human MT1 and MT2 receptors, respectively, and is 17 – 25-fold less potent than ramelteon in in vitro functional assays. Although the potency of M-II at MT1 and MT2 receptors is lower than the parent drug, M-II circulates at higher concentrations than the parent producing 20 – 100-fold greater mean systemic exposure when compared to ramelteon. M-II has weak affinity for the serotonin 5-HT2B receptor, but no appreciable affinity for other receptors or enzymes. 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.
Pharmacokinetics
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.
Absorption
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.
Distribution
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
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.
Elimination
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 post-dose.
Repeated once daily dosing with ROZEREM does not result in significant accumulation owing to the short elimination half-life of ramelteon (on average, approximately 1- 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 Food
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).
Special Populations
Age: 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.
Gender: There are no clinically meaningful gender-related differences in the pharmacokinetics of ROZEREM or its metabolites.
Hepatic Impairment: Exposure to ROZEREM was increased almost 4-fold in subjects with mild hepatic impairment after 7 days of dosing with 16 mg/day; exposure was further increased (more than 10-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).
Renal Impairment: The pharmacokinetic characteristics of ROZEREM were studied after administering a 16 mg dose to subjects with mild, moderate, or severe renal impairment based on pre-dose 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.
Chronic Obstructive Pulmonary Disease: The effects of ROZEREM were evaluated after administering a 16 mg dose or placebo in a crossover design to subjects with mild to moderate chronic obstructive pulmonary disease. Treatment with ROZEREM 16 mg for one night showed no difference compared with placebo on mean arterial oxygen saturation during sleep for the entire night, for each stage of sleep, or for each hour of sleep, and no significant difference in the Apnea/Hypopnea Index. While ROZEREM did not show a respiratory depressant effect in this study of patients with chronic obstructive pulmonary disease, the effect of ROZEREM in patients with severe COPD (e.g., those with elevated pCO2 levels or those needing nocturnal oxygen therapy) has not been studied.
Sleep Apnea: The effects of ROZEREM were evaluated after administering a 16 mg dose or placebo in a crossover design to subjects with mild to moderate obstructive sleep apnea. Treatment with ROZEREM 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. Mean SaO2 during the REM stage of sleep was statistically significantly higher for ROZEREM than for placebo. No differences from placebo were detected in all other secondary outcome variables. These results indicate that ROZEREM does not exacerbate mild to moderate obstructive sleep apnea. ROZEREM has not been studied in subjects with severe obstructive sleep apnea; use of ROZEREM is not recommended in such patients.
Results of drug-drug interaction trials are discussed under PRECAUTIONS.
CLINICAL TRIALS
Controlled Trials Supporting Efficacy
Chronic Insomnia
ROZEREM was studied in two randomized, double-blind trials in subjects with chronic insomnia employing polysomnography (PSG).
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 mg 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. Both doses of ROZEREM reduced the average latency to persistent sleep at each of the time points when compared to placebo.
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 mg 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 compared to placebo.
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 mg or 8 mg or placebo for 35 nights. Both doses of ROZEREM reduced patient-reported sleep latency compared to placebo. A similarly designed study performed in younger adults (aged 18-64 years) using 8 mg and 16 mg of ramelteon did not replicate this finding of reduced patient-reported sleep latency compared to placebo.
Transient Insomnia
In a randomized, double-blind, parallel-group trial using a first-night-effect model, healthy adults received placebo or ROZEREM 8 mg or 16 mg before spending one night in a sleep laboratory and being evaluated with PSG. The 8 mg dose demonstrated a decrease in mean latency to persistent sleep as compared to placebo.
Studies Pertinent to Safety Concerns for Sleep-Promoting Agents
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 ROZEREM (16, 80, or 160 mg), triazolam (0.25, 0.50, or 0.75 mg) or placebo. All subjects received each of the 7 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.
Residual Pharmacological Effects 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 2 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). Neither ROZEREM dose had next-morning residual effects that were different from placebo at Week 5.
Rebound Insomnia/Withdrawal
Potential rebound insomnia and withdrawal effects were assessed in three long-term insomnia studies in which subjects received ROZEREM for 35 days. These studies included a total of 2082 subjects, of whom 829 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. 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 studies, subjects receiving ROZEREM 4 mg, 8 mg, or 16 mg daily reported BWSQ scores similar to those of subjects receiving placebo.
Rebound Insomnia: Rebound insomnia was assessed in three of the long-term studies by continuing to measure sleep latency after abrupt treatment discontinuation. One of these studies employed PSG in younger adult subjects receiving ROZEREM 8 mg or 16 mg; the other two studies employed subjective measures of sleep-onset insomnia in elderly subjects receiving ROZEREM 4 mg or 8 mg, and in younger adult subjects receiving ROZEREM 8 mg or 16 mg. In each of these studies, there was no evidence that ROZEREM caused rebound insomnia at any time during the post-treatment period at any of the three doses.
Special Studies to Evaluate Effects on Endocrine Function
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 4 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 6 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 µg/L (34% increase) for women in the ROZEREM group compared with -0.6 µg/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 also diagnosed with a prolactinoma. The relationship of these events to ROZEREM therapy is not clear.
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