AHFS Class:

• Melatonin Receptor Agonists 28:24.48

Generic Name(s):

• Ramelteon

Ramelteon, a melatonin receptor agonist, is a hypnotic agent.1,2

Insomnia

Ramelteon is used in the management of insomnia characterized by difficulty with sleep onset.1

Efficacy of ramelteon in the management of transient insomnia was established in a randomized, double-blind, parallel-group study in healthy adults 18-64 years of age.1,2 In this study, an 8-mg (but not a 16-mg) dose of ramelteon was superior to placebo in decreasing mean sleep latency, as determined by polysomnography (PSG).1,2

Efficacy of ramelteon in the management of chronic insomnia was established in 3 randomized, double-blind studies of up to 35 days' duration in patients with chronic insomnia persisting for at least 3 months.1,2,3,4,5 In the first study, patients 18-64 years of age were randomized to receive 8 or 16 mg of ramelteon or placebo at bedtime for 35 nights.1,2,3 PSG was performed during the first 2 nights of weeks 1, 3, and 5.1,2,3 At each of these time points, both the 8- and 16-mg doses of ramelteon were superior to placebo in decreasing mean sleep latency.1,2,3 In the second study (3-period crossover study), geriatric patients (65 years of age and older) were randomized to receive 4 or 8 mg of ramelteon or placebo for 2 consecutive nights, followed by a 5- to 12-day washout period between each treatment.1,2,4 Both the 4- and 8-mg doses of ramelteon were superior to placebo in decreasing mean sleep latency (as determined by PSG) in geriatric patients.1,2,4 The third study evaluated efficacy of ramelteon in geriatric patients by employing subjective efficacy measures (i.e., sleep diaries).1,5 In this study, treatment with 4 or 8 mg of ramelteon at bedtime for 35 consecutive nights was superior to placebo in decreasing subjective mean sleep latency.1,2,5 A similarly designed study in younger adults receiving 8- and 16-mg doses of the drug did not replicate these results.1

Administration

Ramelteon is administered orally within 30 minutes of bedtime.1,2 The drug should not be administered with or immediately after a high-fat meal because of a potentially decreased rate of absorption.1,2 (See Description.)

Dosage

The recommended adult dosage of ramelteon for the management of insomnia is 8 mg within 30 minutes of bedtime.1,2

Special Populations

No specific dosage recommendations for patients with hepatic impairment at this time.1 Ramelteon should be used with caution in patients with moderate hepatic impairment; the drug should not be used in those with severe hepatic impairment.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

No dosage adjustment is necessary in patients with mild, moderate, or severe (i.e., creatinine clearance of 30 mL/minute or less) renal impairment or in those requiring chronic hemodialysis.1

Contraindications

Hypersensitivity to ramelteon or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Adequate Patient Evaluation

Because sleep disturbances may be the principal manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after careful evaluation of the patient.1 Failure of insomnia to remit after a reasonable treatment period may indicate the presence of an underlying psychiatric and/or medical condition requiring evaluation.1 Exacerbation of insomnia and/or emergence of new cognitive or behavioral abnormalities, which have been reported with ramelteon, also may indicate the presence of an underlying psychiatric or physical disorder that requires further patient evaluation.1 (See Psychiatric Effects under Warnings/Precautions: Major Toxicities, in Cautions.)

Complex Sleep-related Behaviors

There is a potential risk of complex sleep-related behaviors such as sleep-driving (i.e., driving while not fully awake after ingesting a sedative-hypnotic drug, with no memory of the event), making phone calls, or preparing and eating food while asleep.6

Sensitivity Reactions

There is a potential risk of anaphylaxis and angioedema in patients receiving ramelteon; such reactions may occur as early as with the first dose of the drug.6

Major Toxicities

Psychiatric Effects

Cognitive and behavioral changes have been reported with hypnotic agents, including ramelteon.1 In primarily depressed patients, exacerbation of depression and suicidal ideation have been reported following use of hypnotics.1 As with other sedative-hypnotics, emergence of new psychiatric abnormalities during ramelteon therapy requires evaluation.1

Endocrine Effects

Increased prolactin concentrations have been reported in patients with chronic insomnia receiving ramelteon therapy (16 mg once daily for 6 months).1 Effects of intermittent or long-term ramelteon therapy on the human reproductive axis is not known.1

Abnormal morning cortisol concentrations (resulting in abnormal corticotropin [ACTH] stimulation test results) were reported in 2 patients and prolactinoma was reported in 1 patient receiving long-term (up to 12 months) ramelteon therapy; a causal relationship to the drug has not been established.1

If unexplained amenorrhea, galactorrhea, decreased libido, or fertility problems occur, consider evaluating prolactin or testosterone concentrations.1

Abuse Potential and Dependence

No evidence of abuse potential was detected following administration of relatively high ramelteon doses (up to 20 times the recommended hypnotic dose) in patients with a history of drug (e.g., sedative-hypnotic, anxiolytic) abuse or dependence.1,2

Ramelteon does not appear to produce physical dependence.1

Withdrawal Effects

Studies employing subjective measures (e.g., questionnaires) did not reveal evidence of a withdrawal syndrome (including rebound insomnia) following discontinuance of long-term ramelteon therapy (4, 8, or 16 mg daily for up to 35 days).1,2

Residual Effects

In a 35-night randomized study evaluating next-day residual effects of ramelteon, adult patients receiving 8 mg of the drug every night experienced reduced immediate/delayed memory recall and increased sluggishness, fatigue, and irritation at weeks 1 and 3 of treatment compared with those receiving placebo.1,2 However, next-day residual effects were not substantially different between ramelteon- and placebo-treated patients at week 5.1,2 A similar study in geriatric patients receiving 4 or 8 mg of ramelteon every night did not produce any substantial differences in measures of residual effects.1,2

General Precautions

Long-term Safety

Long-term safety of ramelteon was evaluated in a multicenter, open-label study of up to 1 year's duration in patients with chronic insomnia.2 In this study, treatment with 8 or 16 mg of ramelteon daily in geriatric patients or younger adults, respectively, for up to 1 year resulted in no clinically meaningful changes in laboratory parameters, endocrine tests, vital signs, ECG recordings, or intensity of menstrual bleeding over time.2 Furthermore, rebound insomnia, as determined by subjective sleep latency, was not observed following 1 year of therapy.2

Concomitant Diseases

Ramelteon did not demonstrate a respiratory depressant effect in patients with mild to moderate chronic obstructive pulmonary disease (COPD).1 The effect of ramelteon in patients with severe COPD (e.g., those with elevated pCO₂, those requiring nocturnal oxygen therapy) has not been studied, and use in these patients is not recommended.1

In studies in patients with mild to moderate obstructive sleep apnea, ramelteon did not produce differences in measures of apnea indices.1 However, the effect of ramelteon on severe obstructive sleep apnea has not been studied, and use in these patients is not recommended.1

Specific Populations

Pregnancy

Category C. (See Users Guide.)1 Ramelteon has no established use in labor or delivery.1

Lactation

Distributed into milk in rats; not known whether ramelteon is distributed into human milk.1 Use in nursing women is not recommended.1

Pediatric Use

Safety and efficacy of ramelteon have not been established in pediatric patients.1

Geriatric Use

Increased exposure to ramelteon has been reported in geriatric patients.1 However, no substantial differences in safety and efficacy relative to younger adults have been observed.1

Hepatic Impairment

Following administration of 16 mg of ramelteon daily for 7 days, exposure to the drug was increased by approximately fourfold in patients with mild hepatic impairment and more than tenfold in those with moderate hepatic impairment.1 The pharmacokinetics of ramelteon have not been evaluated in patients with severe hepatic impairment (Child-Pugh class C).1

Use with caution in patients with moderate hepatic impairment; avoid use in those with severe hepatic impairment.1

Renal Impairment

The pharmacokinetics of ramelteon were not altered in patients with renal impairment or in those requiring chronic hemodialysis.1 No dosage adjustment is necessary in such patients.1

Common Adverse Effects

Adverse effects reported in 2% or more of patients receiving ramelteon during clinical trials include headache, somnolence, fatigue, dizziness, nausea, exacerbation of insomnia, upper respiratory tract infection, diarrhea, myalgia, depression, dysgeusia, and arthralgia.1

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of the cytochrome P-450 (CYP) 1A2 isoenzyme: Pharmacokinetic interaction observed during concomitant use with fluvoxamine (substantially increased ramelteon concentrations).1 Avoid concomitant use with fluvoxamine; caution if used concomitantly with less potent CYP1A2 inhibitors.1

Inhibitors of CYP3A4 isoenzyme: Pharmacokinetic interaction observed during concomitant use with ketoconazole (increased concentrations of ramelteon and active metabolite).1 Caution if used concomitantly with ketoconazole or other potent inhibitors of CYP3A4.1

Inhibitors of CYP2C9 isoenzyme: Pharmacokinetic interaction observed during concomitant use with fluconazole (increased concentrations of ramelteon and active metabolite).1 Caution if used concomitantly with fluconazole or other potent inhibitors of CYP2C9.1

Inhibitors of CYP2D6 isoenzyme: Pharmacokinetic interaction with fluoxetine unlikely.1

Inducers of CYP isoenzymes: Pharmacokinetic interaction observed during concomitant use with rifampin (decreased concentrations of ramelteon and active metabolite).1 Possibly reduced ramelteon efficacy when used concomitantly with potent CYP inducers such as rifampin.1,2

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP isoenzymes 1A2 (e.g., theophylline), 2C9 (e.g., warfarin), 2C19 (e.g., omeprazole), 2D6 (e.g., dextromethorphan), or 3A4 (e.g., midazolam): Pharmacokinetic interaction unlikely.1

Alcohol

Potential pharmacologic interaction (additive sedative effects).1 Avoid concomitant use with alcohol.1

Digoxin

Pharmacokinetic interaction unlikely.1

Warfarin

Pharmacokinetic interaction unlikely.1

Laboratory Test Interferences

In vitro data indicate that ramelteon does not elicit false-positive results for benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines in 2 standard urine drug screening methods.1

Description

Ramelteon, a melatonin receptor agonist, is a hypnotic agent.1,2 The drug exhibits high affinity for melatonin MT₁ and MT₂ receptors.1,2 The agonist activity of ramelteon at these receptors is thought to contribute to the drug's sleep-inducing properties, as stimulation of these receptors by endogenous melatonin is thought to be responsible for the regulation of circadian rhythm underlying the normal sleep-wake cycle.1 Ramelteon demonstrates lower selectivity for melatonin MT₃ receptors than for MT₁ and MT₂ receptors; the drug has no appreciable affinity for the gamma-aminobutyric acid (GABA) receptor complex or for receptors that bind neuropeptides, cytokines, serotonin, dopamine, norepinephrine, acetylcholine, or opiates.1

Ramelteon is rapidly absorbed and undergoes extensive first-pass metabolism.1 Following oral administration in the fasting state, peak ramelteon concentrations occur at approximately 0.75 hours (range: 0.5-1.5 hours).1 Although total absorption of ramelteon is at least 84%, the absolute bioavailability is only 1.8% due to extensive first-pass metabolism.1 Administration with a high-fat meal delays GI absorption, reduces peak plasma concentration, and increases the area under the plasma-concentration time curve (AUC) of ramelteon.1 Ramelteon is extensively distributed to tissues; the drug is approximately 82% bound to human serum proteins (mainly [70%] albumin).1

Ramelteon is metabolized by the cytochrome P-450 (CYP) microsomal enzyme system, principally by CYP1A2 and, to a lesser extent, by the CYP2C subfamily and by CYP3A4 to active (M-II) and inactive metabolites.1 The elimination half-life of ramelteon or M-II is 1-2.6 or 2-5 hours, respectively.1 Following oral administration of radiolabeled ramelteon, approximately 84% of the radioactivity is eliminated in urine and 4% is eliminated in feces, principally as metabolites.1

Advice to Patients

Necessity of taking ramelteon within 30 minutes of bedtime and of limiting activities to only those necessary to prepare for bed.1 Avoid taking with or immediately after a high-fat meal.1

Necessity of avoiding driving, operating machinery, or performing hazardous tasks after taking ramelteon.1 Importance of avoiding alcohol during therapy.1

Importance of consulting a clinician if worsening insomnia or emergence of new behavioral manifestations occurs.1

Importance of consulting a clinician if cessation of menses or galactorrhea (in women), decreased libido, or problems with fertility occur.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Takeda Pharmaceuticals America, Inc. Rozerem^® (ramelteon) tablets prescribing information. Lincolnshire, IL; 2005 Aug.

2. Takeda Pharmaceuticals America, Inc., Lincolnshire, IL: Personal communication.

3. Zammit G, Roth T, Erman M et al. Double-blind, placebo-controlled polysomnography and outpatient trial to evaluate the efficacy and safety of ramelteon in adult patients with chronic insomnia. Sleep . 2005; 28(Suppl):A228-9. [PubMed 16477959]

4. Roth T, Seiden D, Weigand S et al. Phase III study to determine the efficacy of ramelteon in elderly patients with chronic insomnia. Proceedings of New Clinical Drug Evaluation Unit. June 6-9, 2005, Boca Raton, Fla. Poster abstract.

5. Roth T, Seiden D, Zee P et al. Phase III outpatient trial of ramelteon for the treatment of chronic insomnia in elderly patients. J Am Geriatr Soc . 2005; 53(Suppl):S25.

6. Food and Drug Administration. Rozerem^® (ramelteon) tablets. [March 14, 2007: Takeda] MedWatch drug labeling changes. Rockville, MD; April 2007. From FDA websites ([Web]) and ([Web]).