Important Safety Information — Ramelteon

Indications

Ramelteon is a melatonin receptor agonist indicated for the treatment of insomnia characterized by difficulty with sleep onset. It works by selectively targeting melatonin MT1 and MT2 receptors in the suprachiasmatic nucleus, which regulates the circadian rhythm. Unlike many sleep medications, ramelteon is not a controlled substance and has not shown evidence of abuse or dependence potential.

Contraindications

• Fluvoxamine: Do not use ramelteon in combination with fluvoxamine (a strong CYP1A2 inhibitor). When co-administered, ramelteon exposure (AUC) increased approximately 190-fold and Cmax increased approximately 70-fold.
• Known hypersensitivity to ramelteon or any component of the formulation
• History of angioedema with previous ramelteon use

Warnings and Precautions

• Complex sleep behaviors: Behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake have been reported with sleep-promoting medications. Discontinue immediately if complex sleep behaviors occur.
• CNS depressant effects: Ramelteon may impair mental alertness and motor coordination. Do not engage in hazardous activities (driving, operating machinery) after taking ramelteon.
• Behavioral changes: Patients may experience behavioral changes, hallucinations, amnesia, anxiety, or other neuropsychiatric symptoms. Evaluate promptly if these occur.
• Sleep apnea: Use with caution in patients with severe sleep apnea. Not recommended for patients with severe obstructive sleep apnea.
• COPD: Use with caution in patients with severe chronic obstructive pulmonary disease.
• Depression: Use with caution in patients with depression. Worsening of depression and suicidal thinking have been reported with the use of sleep aids.
• Hepatic impairment: Use with caution in patients with moderate hepatic impairment. Not recommended in patients with severe hepatic impairment.
• Hormonal effects: Ramelteon has been associated with decreased testosterone levels and increased prolactin levels. If unexplained amenorrhea, galactorrhea, decreased libido, or fertility problems develop, consider checking prolactin and testosterone levels.
• Sufficient sleep time: Do not take ramelteon unless you can get 7 to 8 hours of sleep before being active again.

Common Side Effects

• Somnolence (drowsiness)
• Dizziness
• Fatigue
• Nausea
• Headache
• Worsening insomnia
• Upper respiratory tract infection
• Diarrhea
• Myalgia (muscle pain)
• Arthralgia (joint pain)

Serious Side Effects

Seek medical attention immediately if you experience any of the following:

• Complex sleep behaviors (sleep-walking, sleep-driving, making phone calls, preparing food while not fully awake)
• Severe allergic reaction: difficulty breathing, swelling of the tongue or throat, nausea and vomiting
• Angioedema (swelling of the face, lips, tongue, or throat)
• Hallucinations or confusion
• Worsening depression or suicidal thoughts
• Abnormal behavioral changes

Drug Interactions

• Fluvoxamine (contraindicated): Do not use together. Dramatically increases ramelteon exposure.
• Other CYP1A2 inhibitors (e.g., ciprofloxacin, zileuton): Use with caution, as they may increase ramelteon levels.
• Strong CYP enzyme inducers (e.g., rifampin): May decrease ramelteon effectiveness by approximately 80%.
• Alcohol: Do not drink alcohol with ramelteon. Alcohol can enhance the sedative effects.
• Other CNS depressants: Use with caution when combined with other sleep aids, sedatives, antihistamines, opioids, or anti-anxiety medications, as additive sedation may occur.
• Ketoconazole and fluconazole: CYP3A4 and CYP2C9 inhibitors, respectively, may increase ramelteon levels.

Use in Specific Populations

• Pregnancy: There are no adequate and well-controlled studies in pregnant women. Use only if clearly needed.
• Lactation: It is not known whether ramelteon is secreted in human breast milk. Use with caution in nursing women.
• Pediatric use: Safety and effectiveness in pediatric patients have not been established. Ramelteon has been associated with an increase in testosterone and a decrease in cortisol levels in one pediatric study.
• Geriatric use: No overall difference in safety or efficacy observed in elderly patients.
• Hepatic impairment: Use with caution in moderate impairment. Not recommended for severe impairment.