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Ramelteon: Drug information

Ramelteon: Drug information
(For additional information see "Ramelteon: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Rozerem
Pharmacologic Category
  • Hypnotic, Miscellaneous;
  • Melatonin Receptor Agonist
Dosing: Adult
Delirium, ICU related

Delirium (prevention), ICU related (off-label use): Oral: 8 mg once daily at bedtime (Hatta 2014; Nishikimi 2018). Additional trials may be necessary to further define the role of ramelteon in the prevention of ICU delirium.

Insomnia, sleep onset

Insomnia, sleep onset:

Note: Limit long-term use (>4 weeks) to cases for which nonpharmacologic treatments are not available or not effective and benefits are felt to outweigh risks (ACP [Qaseem 2016]).

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

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

No dosage adjustment necessary.

Dosing: Hepatic Impairment: Adult

Mild impairment: There are no dosage adjustments provided in the manufacturer's labeling.

Moderate impairment: There are no dosage adjustments provided in the manufacturer's labeling; use with caution.

Severe impairment: Use is not recommended.

Dosing: Older Adult

Refer to adult dosing; use with caution.

Dosage Forms: US

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

Tablet, Oral:

Rozerem: 8 mg

Generic: 8 mg

Generic Equivalent Available: US

Yes

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021782s022lbl.pdf#page=17, must be dispensed with this medication.

Administration: Adult

Oral: Administration with or immediately after a high-fat meal is not recommended due to delayed Tmax, reduced Cmax, and increased AUC. Manufacturer labeling recommends that tablets should be swallowed whole, not broken; however, studies support crushing tablets when administering to patients with NG tubes (Jaiswal 2019; Nishikimi 2018). After taking ramelteon, patients should confine their activities to those necessary to prepare for bed.

Use: Labeled Indications

Insomnia, sleep onset: Treatment of insomnia characterized by difficulty falling asleep.

Use: Off-Label: Adult

Delirium (prevention), ICU related

Medication Safety Issues
Sound-alike/look-alike issues:

Ramelteon may be confused with Remeron

Rozerem may be confused with Razadyne, Remeron

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

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

Contraindications

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

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).

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.

Metabolism/Transport Effects

Substrate of CYP1A2 (major), CYP2C19 (minor), CYP2C9 (major), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

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

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

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: 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. Risk D: Consider therapy modification

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

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

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

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: 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. Risk D: Consider therapy modification

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: 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. Risk D: Consider therapy modification

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

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

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

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

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

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

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

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

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

DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification

Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: 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. Risk C: 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. Risk D: Consider therapy modification

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

Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination

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. Risk D: Consider therapy modification

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

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. Risk D: Consider therapy modification

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

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: 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). Risk C: Monitor therapy

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

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

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. 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. Risk D: Consider therapy modification

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

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

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

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

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. Risk D: Consider therapy modification

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

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

Oxybate Salt Products: Hypnotics (Nonbenzodiazepine) may enhance the CNS depressant effect of Oxybate Salt Products. Risk X: 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. Risk D: Consider therapy modification

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

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

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

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

Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification

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

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

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: 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. Risk D: Consider therapy modification

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

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

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: 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. Risk D: Consider therapy modification

Food Interactions

Taking with high-fat meal delays Tmax and increases AUC (~31%). Management: Do not take with a high-fat meal.

Reproductive Considerations

May cause disturbances of reproductive hormonal regulation (eg, disruption of menses or decreased libido). Evaluate prolactin and testosterone levels as appropriate.

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies.

Breastfeeding Considerations

Ramelteon and its active metabolite (M-II) are present in breast milk.

Data related to the presence of ramelteon in breast milk is available from a case report. Ramelteon 8 mg daily was initiated immediately postpartum. Breast milk was sampled once daily for the first 3 days (at random times; peak concentrations not specifically evaluated). Breast milk concentrations of ramelteon ranged from 0.2 ng/mL (9.1 hours after the maternal dose) to 2.6 ng/mL (2.2 hours after the maternal dose). Corresponding breast milk concentrations of M-II were 7.1 and 88.9 ng/mL, respectively. Authors of this study calculated the estimated exposure of ramelteon and M-II to the breastfeeding infant to be 0.24 mcg/kg/day (relative infant dose [RID] 0.24% based on a weight adjusted maternal dose of 0.12 mg/kg/day). This patient was taking zolpidem in addition to ramelteon; ramelteon was discontinued after 5 days due to lack of improvement in insomnia symptoms. Adverse events were not observed in the infant who was partially breastfed (Saito 2021). In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000).

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Monitor infants exposed to ramelteon via breast milk for somnolence and feeding problems. Alternately, lactating patients may pump and discard breast milk during treatment and for 25 hours after the last dose to decrease potential exposure to a breastfed infant.

Dietary Considerations

Do not take with high-fat meal.

Mechanism of Action

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).

Pharmacokinetics

Onset of action: 30 minutes

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

Distribution: 74 L

Protein binding: ~82%

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

Bioavailability: Absolute: 1.8%

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

Time to peak, plasma: Median: 0.5 to 1.5 hours

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

Pharmacokinetics: Additional Considerations

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

Older adult: 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.

Pricing: US

Tablets (Ramelteon Oral)

8 mg (per each): $12.19 - $14.78

Tablets (Rozerem Oral)

8 mg (per each): $15.56

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Rozerem (BB, ID, JP, PH)


For country code abbreviations (show table)
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  2. Devlin JW, Skrobik Y, Gélinas C, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018;46(9):e825‐e873. doi:10.1097/CCM.0000000000003299 [PubMed 30113379]
  3. Hatta K, Kishi Y, Wada K, et al; DELIRIA-J Group. Preventive effects of ramelteon on delirium: a randomized placebo-controlled trial. JAMA Psychiatry. 2014;71(4):397-403. doi:10.1001/jamapsychiatry.2013.3320 [PubMed 24554232]
  4. Hatta K, Kishi Y, Wada K. Ramelteon for delirium in hospitalized patients. JAMA. 2015;314(10):1071-1072. doi:10.1001/jama.2015.8522 [PubMed 26348758]
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  6. Jaiswal SJ, Vyas AD, Heisel AJ, et al. Ramelteon for prevention of postoperative delirium: a randomized controlled trial in patients undergoing elective pulmonary thromboendarterectomy. Crit Care Med. 2019;47(12):1751-1758. doi:10.1097/CCM.0000000000004004 [PubMed 31567351]
  7. Kato K, Hirai K, Nishiyama K, et al, Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology. 2005;48(2):301-310. [PubMed 15695169]
  8. Nguyen NN, Uy SS, and Song JC, Ramelteon: a novel melatonin receptor agonist for the treatment of insomnia. Formulary. 2005;40:146-155.
  9. Nishikimi M, Numaguchi A, Takahashi K, et al. Effect of administration of ramelteon, a melatonin receptor agonist, on the duration of stay in the ICU: a single-center randomized placebo-controlled trial. Crit Care Med. 2018;46(7):1099-1105. doi:10.1097/CCM.0000000000003132 [PubMed 29595562]
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  11. Rozerem (ramelteon) [prescribing information]. Lexington, MA: Takeda Pharmaceuticals America Inc; November 2021.
  12. Saito J, Tachibana Y, Sano Wada Y, et al. Presence of hypnotics in the cord blood and breast milk, with no adverse effects in the infant: a case report. Breastfeed Med. 2021. doi:10.1089/bfm.2021.0321 [PubMed 34935466]
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