Ramelteon Uses, Dosage, Side Effects and more

Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2receptors, and lower selectivity for the MT3 receptor. Melatonin production is concurrent with nocturnal sleep, meaning that an increase in melatonin levels is related to the onset of self-reported sleepiness and an increase in sleep propensity. MT1 receptors are believed to be responsible for regulation of sleepiness and facilitation of sleep onset, and MT2 receptors are believed to mediate phase-shifting effects of melatonin on the circadian rhythm. While MT1 and MT2 receptors are associated with the sleep-wake cycle, MT3 has a completely different profile, and therefore is not likely to be involved in the sleep-wake cycle. Remelteon has no appreciable affinity for the gamma-aminobutyric acid (GABA) receptor complex or receptors that bind neuropeptides, cytokines, serotonin, dopamine, norepinephrine, acetylcholine, or opiates.

Ramelteon is the first selective melatonin agonist. It works by mimicking melatonin (MT), a naturally occuring hormone that is produced during the sleep period and thought to be responsible for the regulation of circadian rhythm underlying the normal sleep-wake cycle. Ramelteon has a high affinity for the MT1 and MT2 receptors. The MT1 and MT2 receptors are located in the brain's suprachiasmatic nuclei (SCN),which is known as the body's "master clock" because it regulates the 24-hour sleep-wake cycle. Ramelteon has an active metabolite that is less potent but circulates in higher concentrations than the parent compound. The metabolite also has weak affinity for the 5HT2b receptor.

Trade Name	Ramelteon
Availability	Prescription only
Generic	Ramelteon
Ramelteon Other Names	Ramelteon
Related Drugs	amitriptyline, lorazepam, melatonin, zolpidem, diphenhydramine, Ativan
Weight	8mg
Type	Oral tablet
Formula	C16H21NO2
Weight	Average: 259.3434 Monoisotopic: 259.157228921
Protein binding	~82% (in human serum)
Groups	Approved, Investigational
Therapeutic Class	Miscellaneous sedatives & hypnotics
Manufacturer
Available Country	United States
Last Updated:	January 7, 2025 at 1:49 am

Uses

Ramelteoni s used for the treatment of insomnia characterized by difficulty with sleep onset

Ramelteon is also used to associated treatment for these conditions: Insomnia

How Ramelteon works

Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT₁ and MT₂ receptors, and lower selectivity for the MT₃ receptor. Melatonin production is concurrent with nocturnal sleep, meaning that an increase in melatonin levels is related to the onset of self-reported sleepiness and an increase in sleep propensity. MT₁ receptors are believed to be responsible for regulation of sleepiness and facilitation of sleep onset, and MT₂ receptors are believed to mediate phase-shifting effects of melatonin on the circadian rhythm. While MT₁ and MT₂ receptors are associated with the sleep-wake cycle, MT₃ has a completely different profile, and therefore is not likely to be involved in the sleep-wake cycle. Remelteon has no appreciable affinity for the gamma-aminobutyric acid (GABA) receptor complex or receptors that bind neuropeptides, cytokines, serotonin, dopamine, norepinephrine, acetylcholine, or opiates.

Dosage

Adult dose: 8 mg taken within 30 minutes of going to bed. Should not be taken with or immediately after a high-fat meal. The total daily dose should not exceed 8 mg.

Side Effects

Most common adverse reactions (≥3% and more common than with placebo) are: somnolence, dizziness, fatigue, nausea, and exacerbated insomnia

Precaution

Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis have been reported. Do not rechallenge if such reactions occur.

Need to evaluate for co-morbid diagnoses: Reevaluate if insomnia persists after 7 to 10 days of treatment.

Abnormal thinking, behavioral changes, complex behaviors: May include "sleep-driving" and hallucinations. Immediately evaluate any new onset behavioral changes.

Depression: Worsening of depression or suicidal thinking may occur.

CNS effects: Potential impairment of activities requiring complete mental alertness such as operating machinery or driving a motor vehicle, after ingesting the drug.

Reproductive effects: Include decreased testosterone and increased prolactin levels. Effect on the reproductive axis in developing humans is unknown

Patients with severe sleep apnea: Rozerem is not recommended for use in this population

Interaction

Rifampin (strong CYP enzyme inducer): Decreases exposure to and effects of ramelteon.

Ketoconazole (strong CYP3A4 inhibitor): Increases AUC for ramelteon; administer with caution.

Fluconazole (strong CYP2C9 inhibitor): Increases systemic exposure of ramelteon; administer with caution. Donepezil increases systemic exposure of ramelteon; patients should be closely monitored when ramelteon is co administered with donepezil. Doxepin increases systemic exposure of ramelteon; patients should be closely monitored when ramelteon is co administered with doxepin.

Alcohol: Causes additive psychomotor impairment; should not be used in combination

Food Interaction

• Avoid alcohol.
• Do not take with or immediately after a high-fat meal.

[Moderate] GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of ramelteon.

Use in combination may result in additive central nervous system depression and
ADJUST DOSING INTERVAL: Administration of ramelteon with or immediately after a high-fat

In study subjects, administration of a 16 mg dose of ramelteon with a high-fat meal decreased the peak plasma drug concentration (Cmax) by 22% and delayed the median time to reach peak plasma drug concentration (Tmax) by approximately 45 minutes compared to administration in a fasted state.

MANAGEMENT: Patients receiving ramelteon should be advised to avoid the consumption of alcohol.

For faster sleep onset, ramelteon should not be administered with or immediately after a high-fat

Drug Interaction

Moderate: aripiprazole, zolpidem, lorazepam, suvorexant, diphenhydramine, duloxetine, venlafaxine, lamotrigine, pregabalin, quetiapine, alprazolam, sertraline, cetirizineUnknown: amphetamine / dextroamphetamine, omega-3 polyunsaturated fatty acids, metoprolol, metoprolol, polyethylene glycol 3350, cyanocobalamin, cholecalciferol

Disease Interaction

Major: depression, severe renal impairment, sleep apneaModerate: glaucoma, liver disease

Volume of Distribution

• 73.6 L

Elimination Route

Rapid, total absorption is at least 84%.

Half Life

~1-2.6 hours

Elimination Route

Following oral administration of radiolabeled ramelteon, 84% of total radioactivity was excreted in urine and approximately 4% in feces, resulting in a mean recovery of 88%. Less than 0.1% of the dose was excreted in urine and feces as the parent compound.

Pregnancy & Breastfeeding use

Pregnancy: Based on animal data may cause fetal harm. Do not use unless the potential benefit justifies the potential risk.

Nursing mothers: Use with caution.

Contraindication

• History of angioedema while taking Ramelteon.
• Fluvoxamine (strong CYP1A2 inhibitor): Increases AUC for ramelteon and should not be used in combination

Special Warning

Pediatric use: Safety and effectiveness not established.

Geriatric use: No overall differences in safety and efficacy between elderly and younger adult subjects.

Hepatic impairment: Is not recommended in patients with severe impairment; use with caution in moderate impairment.

Storage Condition

Store at 25°C; excursions permitted to 15° to 30°C. Keep container tightly closed and protected from moisture and humidity.

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