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:
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.
No dosage adjustment necessary.
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.
Refer to adult dosing; use with caution.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Rozerem: 8 mg
Generic: 8 mg
Yes
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.
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.
Insomnia, sleep onset: Treatment of insomnia characterized by difficulty falling asleep.
Delirium (prevention), ICU related
Ramelteon may be confused with Remeron
Rozerem may be confused with Razadyne, Remeron
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
History of angioedema with previous ramelteon therapy (do not rechallenge); concurrent use with fluvoxamine
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.
Substrate of CYP1A2 (major), CYP2C19 (minor), CYP2C9 (major), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
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
Taking with high-fat meal delays Tmax and increases AUC (~31%). Management: Do not take with a high-fat meal.
May cause disturbances of reproductive hormonal regulation (eg, disruption of menses or decreased libido). Evaluate prolactin and testosterone levels as appropriate.
Adverse events were observed in some animal reproduction studies.
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.
Do not take with high-fat meal.
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).
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%)
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.
Tablets (Ramelteon Oral)
8 mg (per each): $12.19 - $14.78
Tablets (Rozerem Oral)
8 mg (per each): $15.56
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