Ramelteon (Page 3 of 6)

8.7 Sleep Apnea

The effects of Ramelteon Tablets 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 Ramelteon Tablets 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 Ramelteon Tablets does not exacerbate mild to moderate obstructive sleep apnea. There is no available information on the respiratory effects of multiple doses of Ramelteon Tablets in patients with sleep apnea. The effects on exacerbation in patients with mild to moderate sleep apnea cannot be definitively known from this study.

Ramelteon Tablets have not been studied in subjects with severe obstructive sleep apnea; use of Ramelteon Tablets is not recommended in such patients.

8.8 Hepatic Impairment

Exposure to Ramelteon Tablets was 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.

8.9 Renal Impairment

No effects on C max and AUC 0-t of parent drug or M-II were seen. No adjustment of Ramelteon Tablet dosage is required in patients with renal impairment [see Clinical Pharmacology (12.4)].

9 DRUG ABUSE AND DEPENDENCE

Ramelteon Tablets are not a controlled substance.

Discontinuation of ramelteon in animals or in humans after chronic administration did not produce withdrawal signs. Ramelteon does not appear to produce physical dependence.

Human Data

A laboratory abuse potential study was performed with Ramelteon Tablets [see Clinical Studies (14.2)].

Animal Data

Ramelteon did not produce any signals from animal behavioral studies indicating that the drug produces rewarding effects. Monkeys did not self-administer ramelteon and the drug did not induce a conditioned place preference in rats. There was no generalization between ramelteon and midazolam. Ramelteon did not affect rotorod performance, an indicator of disruption of motor function, and it did not potentiate the ability of diazepam to interfere with rotorod performance.

10 OVERDOSAGE

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.

11 DESCRIPTION

Ramelteon Tablets are an orally active hypnotic chemically designated as ( S)- N -[2-(1,6,7,8-tetrahydro-2 H -indeno-[5,4- b ]furan-8-yl)ethyl]propionamide and containing one chiral center. The compound is produced as the (S)-enantiomer, with an empirical formula of C 16 H 21 NO 2 , molecular weight of 259.34, and the following chemical structure:

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Ramelteon is freely soluble in organic solvents, such as methanol, ethanol, and dimethyl sulfoxide; soluble in 1-octanol and acetonitrile; and very slightly soluble in water and in aqueous buffers from pH 3 to pH 11.

Each Ramelteon Tablet includes the following inactive ingredients: lactose monohydrate, pregelatinized starch, hydroxypropyl cellulose, crospovidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc and iron oxide yellow.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT 1 and MT 2 receptors and relative selectivity over the MT 3 receptor.

The activity of ramelteon at the MT 1 and MT 2 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 pharmacologically active and has approximately one tenth and one fifth the binding affinity of the parent molecule for the human MT 1 and MT 2 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.

12.3 Pharmacokinetics

The pharmacokinetic profile of Ramelteon Tablets 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 (C max ) 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 postdose.

Repeated once daily dosing with Ramelteon Tablets 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.

Effect of Food

When administered with a high-fat meal, the AUC 0-inf for a single 16 mg dose of Ramelteon Tablets was 31% higher and the C max was 22% lower than when given in a fasted state. Median T max was delayed by approximately 45 minutes when Ramelteon Tablets were administered with food. Effects of food on the AUC values for M-II were similar. It is therefore recommended that Ramelteon Tablets not be taken with or immediately after a high-fat meal [see Dosage and Administration (2.1)].

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