Ramelteon

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Ramelteon
Clinical data
Trade namesRozerem, others
Other namesTAK-375
AHFS/Drugs.comMonograph
MedlinePlusa605038
License data
Dependence
liability		Low[1]
Routes of
administration		By mouth
ATC code
Legal status
Legal status
CYP2C and CYP3A4 minor)[3]
MetabolitesM-II (active metabolite)[3]
Elimination half-lifeRamelteon: 1–2.6 hours[3]
M-II: 2–5 hours[3][4]
ExcretionKidney: 84%[3]
Feces: 4%[3]
Identifiers
  • (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]
    furan-8-yl)ethyl]propionamide
JSmol)
  • CCC(=O)NCC[C@@H]1CCc2ccc3c(c21)CCO3
  • InChI=1S/C16H21NO2/c1-2-15(18)17-9-7-12-4-3-11-5-6-14-13(16(11)12)8-10-19-14/h5-6,12H,2-4,7-10H2,1H3,(H,17,18)/t12-/m1/s1 checkY
  • Key:YLXDSYKOBKBWJQ-GFCCVEGCSA-N checkY
  (verify)

Ramelteon, sold under the brand name Rozerem among others, is a

melatonin agonist medication which is used in the treatment of insomnia.[3][5] It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset.[3] It reduces the time taken to fall asleep, but the degree of clinical benefit is small.[6] The medication is approved for long-term use.[3] Ramelteon is taken by mouth.[3]

Z-drug and does not interact with GABA receptors, instead having a distinct mechanism of action.[3][8]

Ramelteon was first described in 2002

potential for misuse.[3]

Medical uses

Insomnia

Ramelteon is approved for the treatment of

SMDTooltip standardized mean difference –0.074, 95% CITooltip confidence interval –0.13 to –0.02) and sleep efficiency.[6] The clinical improvement in insomnia with ramelteon is small and of questionable benefit.[6][8]

Ramelteon is approved in the United States but was not approved in the European Union owing to concerns that it lacked effectiveness.[8] The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) noted that ramelteon had only been found to improve sleep onset and not other sleep outcomes, only one of three clinical trials actually found that it improved sleep onset, and that the improvement in sleep onset was too small to be clinically meaningful.[8] The CHMP also noted that the long-term effectiveness of ramelteon had not been demonstrated.[8]

The

melatonin.[13]

Circadian rhythm sleep disorders

quality and their findings in terms of effectiveness have been mixed.[14] Ramelteon is approved only for treatment of insomnia and is not approved for treatment of circadian rhythm sleep disorders.[14][16] It was previously under development for treatment of circadian rhythm sleep disorders, but development for these indications was discontinued.[16]

Other uses

Delirium

A systematic review, published in 2014, concluded "ramelteon was found to be beneficial in preventing delirium in medically ill individuals when compared to placebo."

hospitalized patients whereas suvorexant alone was ineffective.[18]

Bipolar disorder

Ramelteon has received attention in

melatonin for mania.[19]

Available forms

Ramelteon is available in the form of 8 mg

film-coated tablets.[3]

Contraindications

Ramelteon is not recommended for use in people with severe sleep apnea.[3]

Adverse effects

suicidal thinking in patients with pre-existing depression may occur with ramelteon.[3] Ramelteon has been found to slightly increase prolactin levels in women (+34% vs. –4% with placebo) but not in men and to decrease free testosterone levels (by 3–6% in younger men and by 13–18% in older men).[3][20][21]

Ramelteon has not been shown to produce

Z-drugs is not present in ramelteon.[3]

Increased incidence of

testicular tumors have been observed with ramelteon in rodents but only at doses equivalent to at least 20 times greater than the recommended dose in humans.[3]

Overdose

Ramelteon has been assessed at doses of up to 64 mg in clinical studies.[3]

Interactions

Ramelteon has been evaluated for potential drug interactions with the following medications and showed no significant effects: omeprazole, theophylline, dextromethorphan, and midazolam, digoxin and warfarin. There were no clinically meaningful effects when ramelteon was coadministered with any of these drugs.[medical citation needed]

A drug interaction study showed that there were no clinically meaningful effects or an increase in adverse events when ramelteon and the SSRI

Prozac (fluoxetine) were coadministered. When coadministered with ramelteon, fluvoxamine (strong CYP1A2 inhibitor) increased AUC approximately 190-fold, and the Cmax increased approximately 70-fold, compared to ramelteon administered alone. Ramelteon and fluvoxamine should not be coadministered.[3]

Ramelteon has significant

drug–drug interaction with the following drugs: amiodarone, ciprofloxacin, fluvoxamine, ticlopidine
.

Ramelteon should be administered with caution in patients taking other CYP1A2 inhibitors, strong CYP3A4 inhibitors such as ketoconazole, and strong CYP2C9 inhibitors such as fluconazole.[3]

Efficacy may be reduced when ramelteon is used in combination with potent

rifampin, since ramelteon concentrations may be decreased.[medical citation needed
]

Pharmacology

Pharmacodynamics

Ramelteon is a

5-HT1A receptor (Ki = 5.6 μM).[24]

The major

5-HT2B receptor, but no appreciable affinity for other receptors or enzymes. Similar to ramelteon, M-II does not interfere with the activity of a number of endogenous enzymes.[medical citation needed
]

Ramelteon has no appreciable affinity for the

noradrenaline, acetylcholine, and opioids. Ramelteon also does not interfere with the activity of a number of selected enzymes in a standard panel.[medical citation needed
]

Mechanism of action

The activity of ramelteon at the MT1 and MT2 receptors in the suprachiasmatic nucleus of the hypothalamus 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

sleep–wake cycle
.

Pharmacokinetics

Absorption

The total

area-under-the-curve levels of ramelteon which is consistent with high first-pass metabolism.[3]

Distribution

The

tissue distribution.[3] The plasma protein binding of ramelteon is 82% independently of concentration.[3] Ramelteon is primarily bound to albumin (70%).[3] The medication is not selectively distributed to red blood cells.[3]

Metabolism

Ramelteon is

CYP2C enzymes and CYP3A4 are involved to a minor extent.[3] The metabolites of ramelteon include M-I, M-II, M-III, and M-IV.[3] Exposure to M-II is approximately 20- to 100-fold higher than to ramelteon.[3]

Elimination

Ramelteon is excreted 84% in urine and 4% in feces.[3] Less than 0.1% of drug is excreted as unchanged ramelteon.[3] Elimination of ramelteon is essentially complete by 96 hours following a single dose.[3]

The

melatonin, which has a half-life in the range of 20 to 45 minutes.[7] Levels of ramelteon and its metabolites at or below the limit of detectability within 24 hours following a dose.[3]

Special populations

Peak levels of ramelteon and overall exposure are about 86% and 97% higher, respectively, in elderly adults compared to younger adults.

elimination half-life of ramelteon is 2.6 hours in elderly adults.[3]

History

Ramelteon was first described in the medical literature in 2002.[9] It was approved for use in the United States in July 2005.[10]

Society and culture

Ramelteon has no

drug dependence and is not a controlled substance.[25]

Research

Ramelteon, along with other melatonin receptor agonists like

sample size do not allow ruling out their beneficial effect.[19]

References

  1. PMID 36632077
    .
  2. ^ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
  3. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw ax ay az ba bb bc "Rozerem- ramelteon tablet, film coated". DailyMed. 28 December 2018. Retrieved 13 April 2020.
  4. S2CID 38171735
    .
  5. ^
    PMID 18728808
    .
  6. ^
    PMID 24656909
    .
  7. ^
    S2CID 38857779
    .
  8. ^
    S2CID 3578916
    .
  9. ^
    PMID 12213063
    .
  10. ^ a b "Drug Approval Package: Rozerem (Ramelteon) NDA #021782". U.S. Food and Drug Administration (FDA). 20 October 2005. Retrieved 13 April 2020.
  11. S2CID 72050626
    .
  12. ^
    S2CID 33979712
    .
  13. ^
    PMID 27998379
    .
  14. ^
    PMID 27500861
    .
  15. PMID 28648359
    .
  16. ^ a b "Ramelteon - Takeda". AdisInsight. Springer Nature Switzerland AG.
  17. S2CID 34291546
    .
  18. S2CID 245076331
    .
  19. ^
    S2CID 237485915
    .
  20. S2CID 23831933
    .
  21. PMID 19284927
    .
  22. PMID 16703122
    .
  23. S2CID 12767672
    .
  24. ^
    PMID 23861638
    .
  25. S2CID 262241187
    .
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