Ramelteon

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

Ramelteon 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

Ramelteon 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

Ramelteon 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.

Innovators Monograph

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