5 WARNINGS AND PRECAUTIONS

5.1 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.

5.2 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.

5.3 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 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.

5.4 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.

5.5 Reproductive Effects

Ramelteon 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)].

5.6 Use in Patients with Concomitant Illness

Ramelteon tablets have not been studied in subjects with severe sleep apnea and are 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)].

5.7 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.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections:

• Severe anaphylactic and anaphylactoid reactions [see Warnings and Precautions (5.1)]

• Abnormal thinking, behavior changes, and complex behaviors [see Warnings and Precautions (5.3)]

• CNS effects [see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience

Adverse Reactions Resulting in Discontinuation of Treatment

The data described in this section reflect exposure to ramelteon tablets in 5,373 subjects, including 722 exposed for six months or longer and 448 subjects for one year.

Six percent of the 5,373 individual subjects exposed to Ramelteon tablets in clinical studies discontinued treatment owing to an adverse event, compared with 2% of the 2,279 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 2,861 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=1,456)	Ramelteon 8 mg (n=1,405)
Somnolence	2%	3%
Fatigue	2%	3%
Dizziness	3%	4%
Nausea	2%	3%
Insomnia exacerbated	2%	3%

7 DRUG INTERACTIONS

7.1 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, compared to ramelteon administered alone. Ramelteon tablets should not be used in combination with fluvoxamine [see Contraindications (4),Clinical Pharmacology (12.5)]. 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 [see Clinical Pharmacology (12.5)].

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. Ramelteon

tablets should be administered with caution in subjects taking strong CYP3A4 inhibitors such as ketoconazole [see Clinical Pharmacology (12.5)].

Fluconazole (strong CYP2C9 inhibitor):

The AUC 0-inf and C max of ramelteon was increased by approximately 150% when ramelteon was coadministered with fluconazole. Ramelteon tablets should be administered with caution in subjects taking strong CYP2C9 inhibitors such as fluconazole [see Clinical Pharmacology (12.5)].

Donepezil:

The AUC 0-inf and C max of ramelteon increased by approximately 100% and 87%, respectively upon coadministration of donepezil with ramelteon. Patients should be closely monitored when ramelteon tablets are coadministered with donepezil [see Clinical Pharmacology (12.5)].

Doxepin:

The AUC 0-inf and C max of ramelteon increased by approximately 66% and 69%, respectively, upon coadministration of doxepin with ramelteon. Patients should be closely monitored when ramelteon tablets are coadministered with doxepin [see Clinical Pharmacology (12.5)].

7.2 Effect of Alcohol on Ramelteon Tablets

Alcohol by itself impairs performance and can cause sleepiness. Since the intended effect of ramelteon is to promote sleep, patients should be cautioned not to consume alcohol when using ramelteon tablets [see Clinical Pharmacology (12.5)]. Use of the products in combination may have an additive effect.

7.3 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available data from post marketing reported with ramelteon 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) (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 to 4% and 15 to 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 on a based on mg/m 2. Increased incidences of malformation and death among offspring were seen at the highest dose.

8.2 Lactation

Risk Summary

There are no data regarding the presence of ramelteon or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Ramelteon and/or its metabolites are present in rat milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the mechanism of action of ramelteon, there is a potential risk for somnolence in a breastfed infant ( see Clinical Considerations) . The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for ramelteon tablets and any potential adverse effects on the breastfed infant from ramelteon tablets or from the underlying maternal condition.

Clinical Considerations

Infants exposed to ramelteon tablets through breastmilk should be monitored for somnolence and feeding problems. A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment and for 25 hours (approximately 5 elimination half-lives) after ramelteon tablets administration in order to minimize drug exposure to a breastfed infant.

8.4 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.

8.5 Geriatric Use

A 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.

8.6 Chronic Obstructive Pulmonary Disease

The respiratory depressant effect of ramelteon was evaluated in a crossover design study of subjects (n=26) with mild to moderate COPD after administering a single 16 mg dose or placebo, and in a separate study (n=25), the effects of ramelteon on respiratory parameters were evaluated after administering an 8 mg dose or placebo in a crossover design to patients with moderate to severe COPD, defined as patients who had forced expiratory volume at one second (FEV 1 )/forced vital capacity ratio of <70%, and a FEV 1 <80% of predicted with <12% reversibility to albuterol. Treatment with a single dose of ramelteon tablets has no demonstrable respiratory depressant effects in subjects with mild to severe COPD, as measured by arterial O 2 saturation (SaO 2). There is no available information on the respiratory effects of multiple doses of ramelteon tablets in patients with COPD. The respiratory depressant effects in patients with COPD cannot be definitively known from this study.

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 are not recommended in such patients.

8.8 Hepatic Impairment

Exposure 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.

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 dosage is required in patients with renal impairment [see Clinical Pharmacology (12.4)].

9 DRUG ABUSE AND DEPENDENCE

Ramelteon tablet is 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.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ramelteon is a melatonin receptor agonist with both high affinity for melatoninMT****1 andMT****2 receptors and relative selectivity over theMT****3receptor.

The activity of ramelteon at theMT****1andMT****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 humanMT****1 and** MT****2** receptors, respectively. However,M-IIcirculates 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 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,** andM-III. These metabolites are formed rapidly and exhibit a monophasic decline and rapid elimination. The overall mean systemic exposure ofM-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 ofM-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 forM-IIwere 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)].

12.4 Pharmacokinetics in Special Populations

Age

In a group of 24 elderly subjects aged 63 to 79 years administered a single ramelteon 16 mg dose, the mean C max and AUC 0-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 (AUC 0-inf) and C max of ramelteon were 97 and 86% higher, respectively, in elderly subjects. The AUC 0-inf and C max ofM-II were increased by 30 and 13%, respectively, in elderly subjects.

Gender

There are no clinically meaningful gender-related differences in the pharmacokinetics of ramelteon or its metabolites.

Hepatic Impairment

Exposure to ramelteon 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 toM-II was only marginally increased in mildly and moderately impaired subjects relative to healthy matched controls. The pharmacokinetics of ramelteon tablets have not been evaluated in subjects with severe hepatic impairment (Child-Pugh Class C). Ramelteon tablets should be used with caution in patients with moderate hepatic impairment [see Warnings and Precautions (5.6)].

Renal Impairment

The pharmacokinetic characteristics of ramelteon 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 m 2, respectively), and in subjects who required chronic hemodialysis. Wide intersubject variability was seen in ramelteon, exposure parameters. However, no effects on C max or AUC 0-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 ramelteon dosage is required in patients with renal impairment, including patients with severe renal impairment (creatinine clearance of ≤30 mL/min/1.73 m 2) and patients who require chronic hemodialysis.

12.5 Drug-Drug Interactions

Ramelteon 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 ramelteon; the CYP2C subfamily and CYP3A4 isozymes are also involved to a minor degree.

Effects of Other Drugs on Ramelteon Tablets Metabolism

Fluvoxamine (strong CYP1A2 inhibitor)

When fluvoxamine 100 mg twice daily was administered for three days prior to single-dose coadministration of ramelteon 16 mg and fluvoxamine, the AUC 0-inf for ramelteon increased approximately 190-fold, and the Cmax increased approximately 70-fold, compared to ramelteon administered alone. Ramelteon should not be used in combination with fluvoxamine. Other less strong CYP1A2 inhibitors have not been adequately studied. Ramelteon should be administered with caution to patients taking less strong CYP1A2 inhibitors [see Contraindications ( 4), Drug Interactions ( 7)].

Rifampin (strong CYP enzyme inducer)

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 metaboliteM-II, (both AUC 0-inf and C max) after a single 32 mg dose of ramelteon. Efficacy may be reduced when ramelteon is used in combination with strong CYP enzyme inducers such as rifampin [see Drug Interactions ( 7)].

Ketoconazole (strong CYP3A4 inhibitor)

The AUC 0-inf and Cmax of ramelteon increased by approximately 84% and 36%, respectively, when a single 16 mg dose of ramelteon was administered on the fourth day of ketoconazole 200 mg twice daily administration, compared to administration of ramelteon alone. Similar increases were seen inM-II pharmacokinetic variables. Ramelteon should be administered with caution in subjects taking strong CYP3A4 inhibitors such as ketoconazole [see Drug Interactions( 7)].

Fluconazole (strong CYP2C9 inhibitor)

The total and peak systemic exposure (AUC 0-inf and C max) of ramelteon after a single 16 mg dose of ramelteon was increased by approximately 150% when administered with fluconazole. Similar increases were also seen in**M-II **exposure. Ramelteon should be administered with caution in subjects taking strong CYP2C9 inhibitors such as fluconazole [see Drug Interactions ( 7)].

Donepezil

Administration of donepezil 10 mg once daily for 26 days resulted in a mean increase of approximately 100% in overall exposure to ramelteon, (AUC 0-inf) and a mean increase of approximately 87% in maximum exposure to ramelteon (C max) after a single 8 mg dose of ramelteon. No change was seen inM-II exposure. Patients should be closely monitored when ramelteon is coadministered with donepezil [see Drug Interactions ( 7)].

Doxepin

Administration of doxepin 10 mg once daily for 23 days resulted in a mean increase of approximately 66% in overall exposure to ramelteon, (AUC 0-inf) and a mean increase of approximately 69% in maximum exposure to ramelteon (C max) after a single 8 mg dose of ramelteon. No change was seen inM-II exposure. Patients should be closely monitored whenramelteon is coadministered with doxepin [see Drug Interactions ( 7)].

Interaction studies of concomitant administration of ramelteon 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.

Effects of Ramelteon Tablets on Metabolism of Other Drugs

Zolpidem

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 AUC 0-inf and C max) was unchanged after a single 10 mg dose of zolpidem. Ordinarily zolpidem should not be given in a patient taking ramelteon tablets.

Concomitant administration of ramelteon tablets 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.

Effect of Alcohol on Ramelteon Tablets

With single-dose, daytime coadministration of ramelteon 32 mg and alcohol (0.6 g/kg), there were no clinically meaningful
or statistically significant effects on peak or total exposure to ramelteon. 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 ramelteon is to promote
sleep, patients should be cautioned not to consume alcohol when using ramelteon tablets.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

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/m 2).

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/m 2.

Mutagenesis

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.

Impairment of Fertility

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/m 2). Oral administration of ramelteon (up to 600 mg/kg/day) to male rats had no effects on sperm quality or reproductive performance.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Severe Anaphylactic and Anaphylactoid Reactions

Inform patients that severe anaphylactic and anaphylactoid reactions have occurred with ramelteon.Describe the relevant signs/symptoms and advise seeking immediate medical attention if any such things occur.

Sleep-Driving and other Complex Behaviors

There have been reports of people getting out of bed after taking a sleep medication and driving their cars while not fully awake, often with no memory of the event. If a patient experiences such an episode, it should be reported to his or her doctor immediately, since "sleep-driving" can be dangerous. This behavior is more likely to occur when sleep medications are taken with alcohol or other central nervous system depressants. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sleep medication. As with sleep-driving, patients usually do not remember these events.

Endocrine Effects

Patients should consult their healthcare providers if they experience one of the following: cessation of menses or galactorrhea in females, decreased libido, or problems with fertility. Describe the relevant signs/symptoms and advise seeking medical attention if any such things occur.

Administration Instructions

• Patients should be advised to take ramelteon tablets within 30 minutes prior to going to bed and should confine their activities to those necessary to prepare for bed.

• Patients should be advised that they should not take Ramelteon tablets with or immediately after a high-fat meal.

• Do not break the tablet; it should be swallowed whole.

Lactation

Advise mothers using ramelteon tablets to monitor neonates for signs of somnolence and feeding problems. A lactating woman may consider pumping and discarding breast milk during treatment and for 25 hours after ramelteon tablets administration to minimize drug exposure to a breastfed infant [see Use in Specific Populations (8.2)].

Print Medication Guide available at: https://granulespharma.com/product/ramelteon-tab/

Manufactured by:
Granules Pharmaceuticals Inc.
Chantilly, VA 20151

Rev. 05/2023