Ramelteon

• Primary Insomnia:
• Treatment of sleep-onset insomnia characterized by difficulty falling asleep.
• Off-label Uses (Clinically Accepted):
• Management of circadian rhythm sleep disorders, such as delayed sleep phase syndrome.
• Potential adjunct for patients with insomnia related to psychiatric disorders.
• Occasionally used off-label for jet lag and shift work sleep disorder.

• Adults:
• Recommended dose is 8 mg orally once nightly, taken 30 minutes before bedtime.
• Elderly:
• No dosage adjustment necessary; generally well tolerated.
• Pediatrics:
• Safety and efficacy have not been established; use not recommended.
• Hepatic Impairment:
• Use with caution in moderate hepatic impairment; avoid in severe hepatic impairment.
• Renal Impairment:
• No dosage adjustment necessary.
• Administration:
• Oral tablet; should be taken on an empty stomach for optimal absorption.
• Duration:
• Short-term use recommended; safety beyond 10 weeks has not been established.

Ramelteon is a selective agonist of melatonin MT1 and MT2 receptors in the suprachiasmatic nucleus of the brain, which regulates circadian rhythms. By activating these receptors, ramelteon mimics the action of endogenous melatonin, facilitating the initiation of sleep without the sedative, anxiolytic, or muscle-relaxant properties seen with benzodiazepines or other hypnotics. This receptor specificity promotes sleep onset with minimal risk of dependence or rebound insomnia.

• Absorption: Rapidly absorbed with peak plasma concentrations reached in approximately 0.75 hours.
• Bioavailability: Low oral bioavailability (~1.8%) due to extensive first-pass metabolism.
• Distribution: Highly protein-bound (~82%).
• Metabolism: Extensively metabolized in the liver primarily via CYP1A2, CYP2C, and CYP3A4 isoenzymes to active and inactive metabolites.
• Elimination: Mainly excreted in urine as metabolites; elimination half-life is about 1 to 2.6 hours.
• Onset of Action: Typically within 30 minutes of administration.

• Pregnancy:
• FDA Category C: Animal studies have shown some adverse effects at high doses; human data are insufficient. Use only if benefits justify potential risks.
• Lactation:
• Unknown whether ramelteon is excreted in human milk; caution advised when administered to breastfeeding mothers.

• Hypnotic agent
• Melatonin receptor agonist

• Known hypersensitivity to ramelteon or any excipients.
• Concurrent use with fluvoxamine (strong CYP1A2 inhibitor) due to increased ramelteon levels.
• Severe hepatic impairment.

• Use caution in patients with depression or history of suicidal ideation.
• Monitor for next-day impairment, especially in activities requiring alertness.
• Potential for hormonal effects: rare reports of decreased testosterone and increased prolactin levels.
• Avoid use in severe hepatic impairment.
• Not recommended for pediatric use.
• Avoid alcohol and other CNS depressants during treatment.
• Monitor for allergic reactions.

Common:

• Somnolence
• Fatigue
• Dizziness
• Nausea
• Headache

Rare/Serious:

• Worsening depression or suicidal ideation
• Allergic reactions (rash, angioedema)
• Hormonal changes (decreased libido, galactorrhea)

• Fluvoxamine: Strong CYP1A2 inhibitor, greatly increases ramelteon plasma levels; co-administration contraindicated.
• CYP3A4 inhibitors (ketoconazole, clarithromycin): May increase ramelteon levels; monitor for enhanced effects.
• CYP1A2 inducers (smoking, rifampin): May reduce efficacy by decreasing plasma concentrations.
• Alcohol and other CNS depressants may enhance sedative effects.

• Recent clinical guidelines recommend ramelteon as a non-controlled hypnotic option with a low abuse potential for sleep-onset insomnia.
• No new FDA warnings; current use guidelines emphasize caution in hepatic impairment and avoidance with strong CYP1A2 inhibitors.
• Recognized as safe for short-term use; long-term safety data remain limited.

• Store at 20°C to 25°C (68°F to 77°F).
• Protect from moisture and light.
• Keep tablets in original packaging until use.
• No refrigeration required.