Ramelteon

Pronunciation: ra-MEL-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.

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Pharmacokinetics

Absorption

Rapidly absorbed; T max is 0.75 h after fasted oral administration. Total absorption is 84%; absolute bioavailability is 1.8% because of extensive first-pass metabolism. AUC increased 31%, C max decreased 22%, and T max delayed 45 min following administration with high-fat meal.

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 half-life is 1 to 2.6 h. The half-life 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

Renal Function Impairment

No effects on C max or AUC 0-t of parent drug or M-II were seen in any of the treatment groups.

Hepatic Function Impairment

4-fold increase in exposure in patients with mild hepatic impairment. More than 10-fold increase in exposure in patients with moderate hepatic impairment. The pharmacokinetics of ramelteon have not been evaluated in patients with severe hepatic impairment.

Elderly

AUC is 97% higher and C max is 86% higher than in younger adults. AUC and C max of M-II metabolite increased 30% and 13%, respectively.

Gender

There are no clinically meaningful gender-related differences in the pharmacokinetics of ramelteon or its metabolites.

Indications and Usage

Treatment of insomnia characterized by sleep-onset difficulty.

Contraindications

Patients who develop angioedema after treatment with ramelteon; concomitant use with fluvoxamine.

Dosage and Administration

Adults

PO 8 mg within 30 min of going to bed (max, 8 mg/day).

General Advice

  • Do not administer with or immediately after a high-fat meal.
  • After taking ramelteon, patients should confine their activities to those necessary to prepare for bed.

Storage/Stability

Store at 59° to 86°F. Protect from moisture and humidity.

Drug Interactions

Alcohol, other CNS depressants

May have additive pharmacologic effects. Avoid concurrent use.

Strong CYP enzyme inducers (eg, rifampin)

Ramelteon plasma concentrations may be reduced, decreasing the pharmacologic effects. Closely monitor the clinical response of the patient when a strong CYP enzyme inducer is started or stopped and adjust the ramelteon dose as needed.

Strong CYP1A2 inhibitors (eg, fluvoxamine)

Ramelteon plasma concentrations may be elevated, increasing the pharmacologic and adverse effects. Avoid coadministration of fluvoxamine and ramelteon. Use ramelteon with caution in patients taking less strong CYP1A2 inhibitors.

Strong CYP2C9 inhibitors (eg, fluconazole)

Ramelteon plasma concentrations may be elevated, increasing the pharmacologic and adverse effects. Coadminister with caution. Monitor the clinical response of the patient and adjust the ramelteon dose as needed.

Strong CYP3A4 inhibitors (eg, ketoconazole)

Ramelteon plasma concentrations may be elevated, increasing the pharmacologic and adverse effects. Coadminister with caution. Monitor the clinical response of the patient and adjust the ramelteon dose as needed.

Adverse Reactions

CNS

Dizziness (4%); exacerbated insomnia, fatigue, somnolence (3%).

GI

Nausea (3%).

Precautions

Monitor

Consider 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.

Hypersensitivity

Rare cases of angioedema involving the tongue, glottis, or larynx have been reported. Airway obstruction may occur and be fatal. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Do not rechallenge patients who develop angioedema after treatment with ramelteon.

Hepatic Function

Use with caution in patients with moderate hepatic impairment; do not use in patients with severe hepatic impairment.

Hazardous Tasks

Patients should avoid engaging in hazardous activities requiring concentration after taking ramelteon.

CNS effects

Hallucinations, bizarre behavior, agitation, and mania have been reported; amnesia, anxiety, and other neuropsychiatric symptoms may also occur. Complex behaviors, such as “sleep driving,” preparing and eating food, making phone calls, and having sex with amnesia for the event, have been reported with hypnotic use.

COPD

Use with caution in patients with 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 7 to 10 days, 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 information reported.

Patient Information

  • Advise patient to read the Medication Guide before starting therapy and with each refill.
  • Inform patients that severe anaphylactic and anaphylactoid reactions have occurred.
  • Advise patient to take within 30 min of going to bed and to confine activities to those necessary to prepare for bed.
  • 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 while taking this medication.
  • Tell patients not to break the tablet, but to swallow it whole.
  • 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: decreased libido, menstrual changes, problems with infertility, unexplained production of breast milk.
  • Advise patient to avoid engaging in hazardous activities (eg, driving) after taking ramelteon.
  • Caution patient that there have been reports of people getting out of bed after taking a sleep medication and driving their cars while not fully awake, often with no memory of the event. Other complex behaviors (eg, preparing and eating food, making phone calls, having sex) have also been reported in patients who are not fully awake after taking a sleep medicine. Advise patient to report such episodes to their heath care provider.

Copyright © 2009 Wolters Kluwer Health.

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