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Ramelteon

Pronunciation

(ra MEL tee on)

Index Terms

  • TAK-375

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Slideshow: Need To Catch Some Shut-Eye? Tips on Getting the Sleep You Need

Tablet, Oral:

Rozerem: 8 mg

Brand Names: U.S.

  • Rozerem

Pharmacologic Category

  • Hypnotic, Miscellaneous
  • Melatonin Receptor Agonist

Pharmacology

Potent, selective agonist of melatonin receptors MT1 and MT2 (with little affinity for MT3) within the suprachiasmic nucleus of the hypothalamus, an area responsible for determination of circadian rhythms and synchronization of the sleep-wake cycle. Agonism of MT1 is thought to preferentially induce sleepiness, while MT2 receptor activation preferentially influences regulation of circadian rhythms. Ramelteon is eightfold more selective for MT1 than MT2 and exhibits nearly sixfold higher affinity for MT1 than melatonin, presumably allowing for enhanced effects on sleep induction.

Absorption

Rapid; high-fat meal delays Tmax and increases AUC (~31%)

Distribution

74 L

Metabolism

Extensive first-pass effect; oxidative metabolism primarily through CYP1A2 and to a lesser extent through CYP2C and CYP3A4; forms active metabolite (M-II)

Excretion

Primarily as metabolites: Urine (84%); feces (4%)

Onset of Action

30 minutes

Time to Peak

Median: 0.5-1.5 hours

Half-Life Elimination

Ramelteon: 1-2.6 hours; M-II: 2-5 hours

Protein Binding

~82%

Special Populations: Renal Function Impairment

No effects on Cmax or AUC0-t of parent drug or M-II were seen in any of the treatment groups.

Special Populations: 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.

Special Populations: Elderly

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

Special Populations: Gender

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

Use: Labeled Indications

Treatment of insomnia characterized by difficulty with sleep onset

Contraindications

History of angioedema with previous ramelteon therapy (do not rechallenge); concurrent use with fluvoxamine

Dosage

Oral: Adults: One 8 mg tablet within 30 minutes of bedtime

Dosage adjustment in renal impairment: No dosage adjustment necessary.

Dosage adjustment in hepatic impairment:

Mild-to-moderate impairment: No dosage adjustment necessary. Use with caution.

Severe impairment: Use is not recommended.

Administration

Do not administer with a high-fat meal. Swallow tablet whole; do not break.

Dietary Considerations

Do not take with high-fat meal.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from moisture.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Monitor therapy

CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Monitor therapy

CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Consider therapy modification

CYP2C9 Inhibitors (Strong): May increase the serum concentration of Ramelteon. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Ramelteon. Monitor therapy

Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Fluconazole: May increase the serum concentration of Ramelteon. Monitor therapy

FluvoxaMINE: May increase the serum concentration of Ramelteon. Avoid combination

Hydrocodone: CNS Depressants may enhance the CNS depressant effect of Hydrocodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

Metyrosine: CNS Depressants may enhance the sedative effect of Metyrosine. Monitor therapy

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Peginterferon Alfa-2b: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Rifamycin Derivatives: May increase the metabolism of Ramelteon. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Sodium Oxybate: Hypnotics (Nonbenzodiazepine) may enhance the CNS depressant effect of Sodium Oxybate. Avoid combination

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Vemurafenib: May increase the serum concentration of CYP1A2 Substrates. Management: Consider alternatives to such combinations whenever possible, particularly if the CYP1A2 substrate has a relatively narrow therapeutic index. Consider therapy modification

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Adverse Reactions

1% to 10%:

Central nervous system: Dizziness (4% to 5%), somnolence (3% to 5%), fatigue (3% to 4%), insomnia worsened (3%), depression (2%)

Endocrine & metabolic: Serum cortisol decreased (1%)

Gastrointestinal: Nausea (3%), taste perversion (2%)

Neuromuscular & skeletal: Myalgia (2%), arthralgia (2%)

Respiratory: Upper respiratory infection (3%)

Miscellaneous: Influenza (1%)

Postmarketing and/or case reports: Anaphylaxis, angioedema, complex sleep-related behavior (sleep-driving, cooking or eating food, making phone calls), prolactin levels increased, testosterone levels decreased

Warnings/Precautions

Concerns related to adverse effects:

• Abnormal thinking/behavioral changes: Hypnotics/sedatives have been associated with abnormal thinking and behavior changes including decreased inhibition, aggression, bizarre behavior, agitation, hallucinations, and depersonalization. These changes may occur unpredictably and may indicate previously unrecognized psychiatric disorders; evaluate appropriately.

• CNS depression: May cause CNS depression impairing physical and mental capabilities; patients must be cautioned about performing tasks, which require mental alertness (operating machinery or driving).

• Hypersensitivity reactions: Postmarketing studies have indicated that the use of hypnotic/sedative agents (including ramelteon) for sleep has been associated with hypersensitivity reactions including anaphylaxis as well as angioedema. Do not rechallenge patients who have developed angioedema with ramelteon therapy.

• Reproductive hormonal regulation disturbances: May cause disturbances of reproductive hormonal regulation (eg, disruption of menses or decreased libido).

• Sleep-related activities: An increased risk for hazardous sleep-related activities such as sleep-driving; cooking and eating food, and making phone calls while asleep have also been noted.

Disease-related concerns:

• Depression: Use with caution in patients with depression; worsening of depression, including suicidal ideation has been reported with the use of hypnotics.

• Hepatic impairment: Use with caution in patients with hepatic impairment; use not recommended with severe impairment.

• Respiratory disease: Use with caution in patients with respiratory compromise, COPD or sleep apnea.

Concurrent drug therapy issues:

• CNS depressants/psychoactive medications: Use with caution in patients receiving other CNS depressants or psychoactive medication; effects with other sedative drugs or ethanol may be potentiated.

• CYP1A2 inhibitors: Use with caution when administered concomitantly with strong CYP1A2 inhibitors.

Other warnings/precautions:

• Appropriate use: Symptomatic treatment of insomnia should be initiated only after careful evaluation of potential causes of sleep disturbance. Failure of sleep disturbance to resolve after a reasonable period of treatment may indicate psychiatric and/or medical illness.

• Rapid onset: Because of the rapid onset of action, administer immediately prior to bedtime or after the patient has gone to bed and is having difficulty falling asleep.

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal studies have demonstrated teratogenic effects. May cause disturbances of reproductive hormonal regulation (eg, disruption of menses or decreased libido). There are no adequate and well-controlled studies in pregnant women.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, dizziness, or asthenia. Have patient report immediately to prescriber signs of depression (ie, suicidal ideation, anxiety, emotional instability, illogical thinking), behavioral changes, hallucinations, memory impairment, amenorrhea, nipple discharge, decreased libido, or infertility (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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