Ramelteon
Pronouncation: (ram-EL-tee-on)Class: Melatonin receptor agonist
Trade Names:
Rozerem
- Tablets 8 mg
Pharmacology
Melatonin receptor agonist with high affinity for melatonin MT 1 and MT 2 receptors and selectivity over the MT 3 receptor. Activation of MT 1 and MT 2 receptors is believed to contribute to ramelteon's sleep-promoting properties.
Pharmacokinetics
Absorption
Rapidly absorbed; T max 0.75 h after fasted oral administration. Total absorption 84%; absolute bioavailability is 1.8% because of extensive first-pass metabolism.
Distribution
82% protein bound (albumin). Vd is 73.6 L.
Metabolism
Oxidized (primarily by CYP1A2; CYP2C subfamily and CYP3A4 to minor degree) to hydroxyl and carbonyl derivatives, with secondary metabolism to glucuronide conjugates. M-II metabolite is active.
Elimination
The t ½ is 1 to 2.6 h. The t ½ of M-II metabolite is 2 to 5 h. 84% excreted in urine, 4% in feces. Less than 0.1% excreted as parent compound.
Special Populations
Hepatic Function Impairment4-fold exposure in patients with mild hepatic function impairment. More than 10-fold exposure in patients with moderate hepatic function impairment.
ElderlyAUC is 97% and C max is 86% higher than in younger adults. AUC and C max of M-II metabolite increased 30% and 13%, respectively.
Food EffectsAUC increased 31%, C max reduced 22%, and T max delayed 45 min following administration with high-fat meal.
Indications and Usage
Treatment of insomnia characterized by sleep onset difficulty.
Contraindications
Standard considerations.
Dosage and Administration
AdultsPO 8 mg within 30 min of going to bed.
General Advice
- Do not administer with or immediately after a high-fat meal.
Storage/Stability
Store at controlled room temperature (59° to 86°F). Protect from moisture and humidity.
Drug Interactions
Alcohol, other CNS depressantsMay have additive pharmacologic effects. Avoid concurrent use.
Strong CYP enzyme inducers (eg, rifampin)Ramelteon plasma concentrations may be reduced, decreasing the pharmacologic effects.
Strong CYP1A2 inhibitors (eg, fluvoxamine)Ramelteon plasma concentrations may be elevated, increasing the pharmacologic and adverse effects. Avoid coadministration.
Strong CYP2C9 inhibitors (eg, fluconazole)Ramelteon plasma concentrations may be elevated, increasing the pharmacologic and adverse effects. Coadminister with caution.
Strong CYP3A4 inhibitors (eg, ketoconazole)Ramelteon plasma concentrations may be elevated, increasing the pharmacologic and adverse effects. Coadminister with caution.
Laboratory Test Interactions
None well documented.
Adverse Reactions
CNS
Headache (7%); somnolence, dizziness (5%); fatigue (4%); exacerbated insomnia (3%); depression (2%).
GI
Nausea (3%); diarrhea, dysgeusia (2%).
Lab Tests
Decreased blood cortisol (1%).
Musculoskeletal
Arthralgia, myalgia (2%).
Respiratory
Upper respiratory tract infection (3%); influenza (1%).
Precautions
MonitorConsider assessment of prolactin and testosterone levels, as appropriate, for patients presenting with unexplained amenorrhea, galactorrhea, decreased libido, or infertility. |
Pregnancy
Category C .
Lactation
Undetermined.
Children
Safety and efficacy not established.
Hepatic Function
Use with caution in patients with moderate hepatic function impairment; do not use in patients with severe hepatic function impairment.
Hazardous Tasks
Patients should avoid engaging in hazardous activities requiring concentration after taking ramelteon.
Adolescents and children
Ramelteon has been associated with an effect on reproductive hormones in adults (eg, decreased testosterone and increased prolactin levels). It is not known what effect chronic or chronic intermittent use may have on the reproductive axis in adolescents and children.
COPD
Not recommended for patients with severe COPD.
Depression
Use with caution; worsening of depression, including suicidal ideation, has been reported in depressed patients receiving hypnotics.
Physical and/or psychiatric disorders
Sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder. Initiate treatment only after careful evaluation. Failure of insomnia to remit after a reasonable period of treatment, worsening of insomnia, or emergence of new cognitive or behavioral abnormalities may indicate the presence of a primary psychiatric or medical illness that should be evaluated.
Sleep apnea
Not recommended for patients with severe sleep apnea.
Overdosage
Symptoms
No cases reported.
Patient Information
- Advise patient to read the patient information leaflet before starting therapy and with each refill.
- Review lifestyle changes that may improve sleep (eg, quiet and dark environment, avoidance of caffeine and nicotine, warm water bath, relaxation techniques).
- Advise patient to take within 30 min of going to bed and to confine activities to those necessary to prepare for bed.
- Advise patient to take on an empty stomach but to take with food if stomach upset occurs. Caution patient not to take with or immediately after a high-fat meal because medication may not work as well.
- Advise patient to avoid alcoholic beverages and other depressants while taking this medication.
- Instruct patient to contact health care provider if symptoms do not appear to be getting better, are getting worse, or if bothersome side effects (eg, daytime drowsiness, dizziness, incoordination, memory problems, changes in thinking or behavior) occur. Caution patient not to increase the dose if symptoms do not appear to be improving.
- Advise patient to notify health care provider if experiencing any of the following: menstrual changes; unexplained production of breast milk; decreased libido; problems with infertility.
- Advise patient to avoid engaging in hazardous activities (eg, driving) after taking ramelteon.
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More Ramelteon resources:
Ramelteon - Includes detailed dosage instructions.
