Is Ramelteon Safe?
Yes, ramelteon is safe and well-tolerated for treating insomnia, with no evidence of significant adverse events compared to placebo, no abuse potential, and no withdrawal symptoms or rebound insomnia. 1, 2
Safety Profile
Adverse Events
- Clinical trials demonstrate no statistically significant difference from placebo for adverse events 1
- The most common side effects are mild: headache (7%), dizziness (5%), somnolence (5%), fatigue (4%), and nausea (3%) 3
- The American Academy of Sleep Medicine concluded that benefits outweigh potential harms despite marginal efficacy 1
Abuse and Dependence Potential
- Ramelteon showed no differences in subjective responses indicative of abuse potential compared to placebo at doses up to 20 times the recommended therapeutic dose (160 mg) 2
- It is not classified as a DEA-controlled substance, making it particularly suitable for patients with a history of substance use disorders 1, 4
- No evidence of withdrawal symptoms, rebound insomnia, or tolerance development 5, 6
Next-Day Effects
- No impairment of next-day cognitive or motor performance 5, 7
- No residual pharmacological effects on memory, alertness, or concentration 2
Important Safety Warnings
Rare but Serious Reactions
- Rare cases of severe anaphylactic reactions including angioedema involving the tongue, glottis, or larynx have been reported 2
- Patients who develop angioedema should not be rechallenged with ramelteon 2
Complex Sleep Behaviors
- Complex behaviors such as "sleep-driving" and other activities with amnesia have been reported with ramelteon use 2
- Strongly consider discontinuation if patients report any complex sleep behavior 2
- Alcohol and other CNS depressants increase the risk of these behaviors 2
Hormonal Effects
- Ramelteon has been associated with decreased testosterone levels and increased prolactin levels 2
- For patients with unexplained amenorrhea, galactorrhea, decreased libido, or fertility problems, assess prolactin and testosterone levels 2
Contraindications and Precautions
Populations to Avoid
- Do not use in patients with severe hepatic impairment 2
- Not recommended for patients with severe sleep apnea (not studied in this population) 2
Psychiatric Considerations
- Worsening of depression, including suicidal ideation, has been reported with hypnotics in depressed patients 2
- Hallucinations, bizarre behavior, agitation, mania, amnesia, and anxiety may occur unpredictably 2
- Failure of insomnia to remit after 7-10 days warrants evaluation for underlying psychiatric or medical disorders 2
Clinical Context
Duration of Use
- FDA approval contains no limitation on duration of prescription 4
- Clinical trials supporting efficacy were up to 6 months in duration 2
- Long-term studies (6 months and 1 year) demonstrated continued efficacy and tolerability 6, 7