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Ramelteon

Medically reviewed by Drugs.com. Last updated on May 23, 2020.

Pronunciation

(ra MEL tee on)

Index Terms

  • TAK-375

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Rozerem: 8 mg

Generic: 8 mg

Brand Names: U.S.

  • Rozerem

Pharmacologic Category

  • Hypnotic, Miscellaneous
  • Melatonin Receptor Agonist

Pharmacology

Potent, selective agonist of melatonin receptors MT1 and MT2 (with little affinity for MT3) within the suprachiasmic nucleus of the hypothalamus, an area responsible for determination of circadian rhythms and synchronization of the sleep-wake cycle. Agonism of MT1 is thought to preferentially induce sleepiness, while MT2 receptor activation preferentially influences regulation of circadian rhythms. Ramelteon is eightfold more selective for MT1 than MT2 and exhibits nearly sixfold higher affinity for MT1 than melatonin, presumably allowing for enhanced effects on sleep induction (Hatta 2014).

Absorption

Rapid; high-fat meal delays Tmax and increases AUC (~31%)

Distribution

74 L

Metabolism

Extensive first-pass effect; oxidative metabolism primarily through CYP1A2 and to a lesser extent through CYP2C and CYP3A4; forms active metabolite (M-II)

Excretion

Primarily as metabolites: Urine (84%); feces (4%)

Onset of Action

30 minutes

Time to Peak

Median: 0.5 to 1.5 hours

Half-Life Elimination

Ramelteon: 1 to 2.6 hours; M-II: 2 to 5 hours

Protein Binding

~82%

Special Populations: Hepatic Function Impairment

Patients with mild and moderate hepatic impairment experienced a 4-fold and more than 10-fold increase in exposure, respectively.

Special Populations: Elderly

AUC is 97% higher and Cmax is 86% higher than in younger adults. AUC and Cmax of M-II metabolite increased 30% and 13%, respectively.

Use: Labeled Indications

Insomnia: Treatment of insomnia characterized by difficulty with sleep onset

Off Label Uses

Delirium (prevention), ICU related

Data regarding the efficacy of ramelteon for prevention of delirium in the ICU setting are conflicting. In some controlled trials, ramelteon was associated with decreases in occurrence rate and duration of delirium, but other studies showed no differences from placebo for these outcomes. In addition, no differences in duration of ICU stay or mortality rate were found between ramelteon and placebo [Hatta 2014], [Hatta 2015], [Jaiswal 2019], [Nishikimi 2018].

Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU cite study data regarding use of ramelteon for prevention of delirium, but no recommendations are made [Devlin 2018].

Contraindications

History of angioedema with previous ramelteon therapy (do not rechallenge); concurrent use with fluvoxamine

Dosing: Adult

Insomnia: Oral: 8 mg once daily administered within 30 minutes of bedtime. Maximum dose: 8 mg/day.

Delirium (prevention), ICU related (off-label use): 8 mg once daily at bedtime (Hatta 2014). Additional trials may be necessary to further define the role of ramelteon in the prevention of ICU delirium.

Dosing: Geriatric

Refer to adult dosing; use with caution.

Administration

Administration with or immediately after a high-fat meal is not recommended due to delayed Tmax, reduced Cmax, and increased AUC. Swallow tablet whole; do not break. After taking ramelteon, patients should confine their activities to those necessary to prepare for bed.

Dietary Considerations

Do not take with high-fat meal.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from moisture.

Drug Interactions

Abametapir: May increase the serum concentration of CYP1A2 Substrates (High risk with Inhibitors). Avoid combination

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Consider therapy modification

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Consider therapy modification

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

CYP1A2 Inhibitors (Moderate): May increase the serum concentration of Ramelteon. Monitor therapy

CYP1A2 Inhibitors (Strong): May increase the serum concentration of Ramelteon. Avoid combination

CYP2C9 Inhibitors (Moderate): May increase the serum concentration of Ramelteon. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Ramelteon. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Ramelteon. Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Consider therapy modification

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Consider therapy modification

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may increase the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Melatonin: May enhance the sedative effect of Hypnotics (Nonbenzodiazepine). Monitor therapy

Methotrimeprazine: May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Consider therapy modification

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Oxybate Salt Products: Hypnotics (Nonbenzodiazepine) may enhance the CNS depressant effect of Oxybate Salt Products. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Adverse Reactions

1% to 10%:

Central nervous system: Dizziness (4% to 5%), somnolence (3% to 5%), fatigue (3% to 4%), insomnia worsened (3%), depression (2%)

Endocrine & metabolic: Serum cortisol decreased (1%)

Gastrointestinal: Nausea (3%), taste perversion (2%)

Neuromuscular & skeletal: Myalgia (2%), arthralgia (2%)

Respiratory: Upper respiratory infection (3%)

Miscellaneous: Influenza (1%)

Postmarketing and/or case reports: Anaphylaxis, angioedema, complex sleep-related behavior (sleep-driving, cooking or eating food, making phone calls), prolactin levels increased, testosterone levels decreased

Warnings/Precautions

Concerns related to adverse effects:

• Abnormal thinking/behavioral changes: Hypnotics/sedatives have been associated with abnormal thinking and behavior changes including decreased inhibition, aggression, bizarre behavior, agitation, hallucinations, and depersonalization. These changes may occur unpredictably and may indicate previously unrecognized psychiatric disorders; evaluate appropriately.

• CNS depression: May cause CNS depression impairing physical and mental capabilities; patients must be cautioned about performing tasks, which require mental alertness (operating machinery or driving).

• Hyperprolactinemia: May increase prolactin levels.

• Hypersensitivity reactions: Hypersensitivity reactions, including angioedema, have been reported (rare). Do not rechallenge patient if such reactions occur.

• Sleep-related activities: An increased risk for hazardous sleep-related activities such as sleep-driving, cooking and eating food, having sex, and making phone calls while asleep have been noted; amnesia, anxiety, and other neuropsychiatric symptoms may also occur. The use of alcohol, other CNS depressants, and exceeding the recommended maximum dose may increase the risk of these activities. Discontinue treatment in patients who report any complex sleep behavior.

Disease-related concerns:

• Depression: Use with caution in patients with depression; worsening of depression, including suicidal ideation has been reported with the use of hypnotics.

• Hepatic impairment: Use with caution in patients with hepatic impairment; use not recommended with severe impairment.

• Respiratory disease: Use with caution in patients with respiratory compromise, COPD or sleep apnea. Use is not recommended in patients with severe sleep apnea (has not been studied).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Symptomatic treatment of insomnia should be initiated only after careful evaluation of potential causes of sleep disturbance. Failure of sleep disturbance to resolve after 7 to 10 days may indicate psychiatric and/or medical illness.

• Rapid onset: Because of the rapid onset of action, administer immediately prior to bedtime.

Reproductive Considerations

May cause disturbances of reproductive hormonal regulation (eg, disruption of menses or decreased libido).

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies.

Patient Education

What is this drug used for?

• It is used to treat sleep problems.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Fatigue

• Dizziness

• Loss of strength and energy

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Depression like thoughts of suicide, anxiety, emotional instability, or confusion.

• Confusion

• Behavioral changes

• Mood changes

• Sensing things that seem real but are not

• Nightmares

• Trouble with memory

• Nausea

• Vomiting

• Swelling in your throat

• No menstrual periods

• Nipple discharge

• Decreased sex drive

• Trouble getting pregnant

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.