Introduction
Ramelteon is a selective melatonin receptor agonist approved by the FDA for the treatment of insomnia characterized by difficulty with sleep onset. Unlike traditional sedative-hypnotics, ramelteon does not act on GABA receptors and is not classified as a controlled substance, making it a unique option in the insomnia treatment landscape.
Mechanism of Action
Ramelteon exerts its therapeutic effects through selective agonism of melatonin MT₁ and MT₂ receptors in the suprachiasmatic nucleus of the hypothalamus. This action mimics the effects of endogenous melatonin, helping to regulate the body's circadian rhythm and sleep-wake cycle. The drug has no appreciable affinity for GABAergic, dopaminergic, adrenergic, or serotonergic receptors.
Indications
- FDA-approved for the treatment of insomnia characterized by difficulty with sleep onset
- Not indicated for sleep maintenance insomnia
Dosage and Administration
Standard adult dosage: 8 mg taken within 30 minutes of bedtime Administration: Oral tablet; should not be taken with or immediately after a high-fat meal Special populations:- Hepatic impairment: Contraindicated in severe hepatic impairment
- Renal impairment: No dosage adjustment necessary
- Geriatric patients: No dosage adjustment necessary
- Pediatric patients: Safety and effectiveness not established
Pharmacokinetics
Absorption: Rapidly absorbed with median Tmax of 0.75 hours; high-fat meal decreases AUC by 22% and Cmax by 44% Distribution: Approximately 82% bound to plasma proteins; volume of distribution is 0.9 L/kg Metabolism: Extensive hepatic metabolism primarily via CYP1A2 with minor contributions from CYP2C and CYP3A4 Elimination: Primarily excreted in urine (84%) as metabolites; less than 0.1% excreted unchanged; terminal half-life of 1-2.6 hoursContraindications
- Hypersensitivity to ramelteon or any component of the formulation
- Severe hepatic impairment
- Concomitant use with fluvoxamine
- History of angioedema with previous ramelteon use
Warnings and Precautions
- Need to evaluate for comorbid diagnoses: Should not be used until underlying causes of insomnia are evaluated
- Depression: Worsening depression or suicidal ideation may occur; monitor patients appropriately
- CNS effects: May impair cognitive and motor performance; caution patients about driving or operating machinery
- Reproductive effects: May affect reproductive hormones; monitor if long-term use is anticipated
- Severe anaphylactic reactions: Angioedema has been reported
Drug Interactions
Major interactions:- Fluvoxamine: Increases ramelteon exposure 70-fold; contraindicated
- Other CYP1A2 inhibitors (ciprofloxacin, levofloxacin): May increase ramelteon concentrations
- CYP inducers (rifampin): May decrease ramelteon efficacy
- Alcohol: Additive CNS depression
- No clinically significant interactions with warfarin, digoxin, omeprazole, theophylline, or oral contraceptives
Adverse Effects
Common (≥2% and more frequent than placebo):- Somnolence (3%)
- Fatigue (3%)
- Dizziness (5%)
- Nausea (3%)
- Exacerbated insomnia (3%)
- Headache (4%)
- Anaphylaxis and angioedema
- Complex sleep behaviors
- Hormonal effects (decreased testosterone, increased prolactin)
- Worsening depression or suicidal ideation
Monitoring Parameters
- Sleep latency and quality assessment
- Mental status and mood changes
- Cognitive and motor function, especially when initiating therapy
- Reproductive hormone levels with long-term use (if clinically indicated)
- Liver function tests in patients with hepatic impairment
Patient Education
- Take within 30 minutes of bedtime
- Do not take with or immediately after a high-fat meal
- Avoid alcohol while taking ramelteon
- Do not engage in activities requiring mental alertness after taking medication
- Report any signs of allergic reactions (swelling, difficulty breathing)
- Inform healthcare provider of all medications being taken
- Not recommended for use during pregnancy or breastfeeding
- Do not exceed prescribed dosage
- Report any changes in mood or suicidal thoughts
References
1. US Food and Drug Administration. (2005). Rozerem (ramelteon) prescribing information. 2. Neubauer DN. (2008). The evolution and development of ramelteon. Expert Opinion on Drug Metabolism & Toxicology, 4(7), 861-871. 3. Kuriyama A, Honda M, Hayashino Y. (2014). Ramelteon for the treatment of insomnia in adults: a systematic review and meta-analysis. Sleep Medicine, 15(4), 385-392. 4. Michelson D, Snyder E, Paradis E, et al. (2014). Safety and efficacy of ramelteon in patients with chronic insomnia: a 1-year study. Sleep, 37(4), 675-683. 5. Liu J, Wang LN. (2018). Ramelteon in the treatment of chronic insomnia: systematic review and meta-analysis. International Journal of Clinical Practice, 72(6), e13087. 6. Lexicomp Online. (2023). Ramelteon monograph. Wolters Kluwer Clinical Drug Information.