Ramelteon
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]
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Overview
Ramelteon is a nonbarbiturate hypnotic that is FDA approved for the treatment of insomnia characterized by difficulty with sleep onset. Common adverse reactions include somnolence, dizziness, fatigue, nausea and exacerbated insomnia.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Ramelteon is indicated for the treatment of insomnia characterized by difficulty with sleep onset.
- Dosage:
- Adult dose: 8 mg taken within 30 minutes of going to bed.
- Should not be taken with or immediately after a high-fat meal.
- Total daily dose should not exceed 8 mg.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ramelteon in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ramelteon in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy not established in pediatric patients
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ramelteon in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ramelteon in pediatric patients.
Contraindications
- Patients who develop angioedema after treatment with ROZEREM should not be rechallenged with the drug.
- Patients should not take ROZEREM in conjunction with fluvoxamine
Warnings
Severe Anaphylactic and Anaphylactoid Reactions
- Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of ROZEREM.
- Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department.
- If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal.
- Patients who develop angioedema after treatment with ROZEREM should not be rechallenged with the drug.
Need to Evaluate for Co-morbid Diagnoses
- Since sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient.
- The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia, or the emergence of new cognitive or behavioral abnormalities, may be the result of an unrecognized underlying psychiatric or physical disorder and requires further evaluation of the patient.
- Exacerbation of insomnia and emergence of cognitive and behavioral abnormalities were seen with ROZEREM during the clinical development program.
Abnormal Thinking and Behavioral Changes
- A variety of cognitive and behavior changes have been reported to occur in association with the use of hypnotics.
- In primarily depressed patients, worsening of depression (including suicidal ideation and completed suicides) has been reported in association with the use of hypnotics.
- Hallucinations, as well as behavioral changes such as bizarre behavior, agitation and mania have been reported with ROZEREM use. Amnesia, anxiety and other neuro-psychiatric symptoms may also occur unpredictably.
- Complex behaviors such as "sleep-driving" (i.e., driving while not fully awake after ingestion of a hypnotic) and other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex), with amnesia for the event, have been reported in association with hypnotic use. The use of alcohol and other CNS depressants may increase the risk of such behaviors. These events can occur in hypnotic-naive as well as in hypnotic-experienced persons. Complex behaviors have been reported with the use of ROZEREM. Discontinuation of ROZEREM should be strongly considered for patients who report any complex sleep behavior.
CNS Effects
- Patients should avoid engaging in hazardous activities that require concentration (such as operating a motor vehicle or heavy machinery) after taking ROZEREM.
- After taking ROZEREM, patients should confine their activities to those necessary to prepare for bed.
- Patients should be advised not to consume alcohol in combination with ROZEREM as alcohol and ROZEREM may have additive effects when used in conjunction.
Reproductive Effects
Use in Adolescents and Children
- Ramelteon has been associated with an effect on reproductive hormones in adults, e.g., decreased testosterone levels and increased prolactin levels.
- It is not known what effect chronic or even chronic intermittent use of ROZEREM may have on the reproductive axis in developing humans.
Use in Patients with Concomitant Illness
- Ramelteon has not been studied in subjects with severe sleep apnea and is not recommended for use in this population.
- Ramelteon should not be used by patients with severe hepatic impairment.
Laboratory Tests
Monitoring
- No standard monitoring is required.
- For patients presenting with unexplained amenorrhea, galactorrhea, decreased libido, or problems with fertility, assessment of prolactin levels and testosterone levels should be considered as appropriate.
Interference with Laboratory Tests
- Ramelteon is not known to interfere with commonly used clinical laboratory tests.
- In addition, in vitro data indicate that ramelteon does not cause false-positive results for benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines in two standard urine drug screening methods in vitro.
Adverse Reactions
Clinical Trials Experience
Adverse Reactions Resulting in Discontinuation of Treatment
- The data described in this section reflect exposure to ROZEREM in 5373 subjects, including 722 exposed for 6 months or longer, and 448 subjects for one year.
- Six percent of the 5373 individual subjects exposed to ROZEREM in clinical studies discontinued treatment owing to an adverse event, compared with 2% of the 2279 subjects receiving placebo. The most frequent adverse events leading to discontinuation in subjects receiving ROZEREM were somnolence, dizziness, nausea, fatigue, headache, and insomnia; all of which occurred in 1% of the patients or less.
Ramelteon Most Commonly Observed Adverse Events
- Table 1 displays the incidence of adverse events reported by the 2861 patients with chronic insomnia who participated in placebo-controlled trials of ROZEREM.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of other drugs, and may not reflect the rates observed in practice.
- The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
Postmarketing Experience
There is limited information regarding Ramelteon Postmarketing Experience in the drug label.
Drug Interactions
Effects of Other Drugs on ROZEREM
- Fluvoxamine (strong CYP1A2 inhibitor): AUC0-inf for ramelteon increased approximately 190-fold, and the Cmax increased approximately 70-fold upon coadministration of fluvoxamine and ROZEREM, compared to ROZEREM administered alone. ROZEREM should not be used in combination with fluvoxamine. Other less strong CYP1A2 inhibitors have not been adequately studied. ROZEREM should be administered with caution to patients taking less strong CYP1A2 inhibitors.
- Rifampin (strong CYP enzyme inducer): Administration of multiple doses of rifampin resulted in a mean decrease of approximately 80% in total exposure to ramelteon and metabolite M-II. Efficacy may be reduced when ROZEREM is used in combination with strong CYP enzyme inducers such as rifampin.
- Ketoconazole (strong CYP3A4 inhibitor): The AUC0-inf and Cmax of ramelteon increased by approximately 84% and 36% upon coadministration of ketoconazole with ROZEREM. ROZEREM should be administered with caution in subjects taking strong CYP3A4 inhibitors such as ketoconazole.
- Fluconazole (strong CYP2C9 inhibitor): The AUC0-inf and Cmax of ramelteon was increased by approximately 150% when ROZEREM was coadministered with fluconazole. ROZEREM should be administered with caution in subjects taking strong CYP2C9 inhibitors such as fluconazole.
- Donepezil: The AUC0-inf and Cmax of ramelteon increased by approximately 100% and 87%, respectively upon coadministration of donepezil with ROZEREM. Patients should be closely monitored when ROZEREM is coadministered with donepezil.
- Doxepin: The AUC0-inf and Cmax of ramelteon increased by approximately 66% and 69%, respectively, upon coadministration of doxepin with ROZEREM. Patients should be closely monitored when ROZEREM is coadministered with doxepin.
Drug/Laboratory Test Interactions
- Ramelteon is not known to interfere with commonly used clinical laboratory tests. In addition, in vitro data indicate that ramelteon does not cause false-positive results for benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines in two standard urine drug screening methods in vitro.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): C In animal studies, ramelteon produced evidence of developmental toxicity, including teratogenic effects, in rats at doses much greater than the recommended human dose (RHD) of 8 mg/day. There are no adequate and well-controlled studies in pregnant women. ROZEREM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Oral administration of ramelteon (10, 40, 150 or 600 mg/kg/day) to pregnant rats during the period of organogenesis was associated with increased incidences of fetal structural abnormalities (malformations and variations) at doses greater than 40 mg/kg/day. The no-effect dose is approximately 50 times the RHD on a body surface area (mg/m2) basis. Treatment of pregnant rabbits during the period of organogenesis produced no evidence of embryo-fetal toxicity at oral doses of up to 300 mg/kg/day (or up to 720 times the RHD on a mg/m2 basis.
When rats were orally administered ramelteon (30, 100, or 300 mg/kg/day) throughout gestation and lactation, growth retardation, developmental delay, and behavioral changes were observed in the offspring at doses greater than 30 mg/kg/day. The no-effect dose is 36 times the RHD on a mg/m2 basis. Increased incidences of malformation and death among offspring were seen at the highest dose.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ramelteon in women who are pregnant.
Labor and Delivery
The potential effects of ROZEREM on the duration of labor and/or delivery, for either the mother or the fetus, have not been studied. ROZEREM has no established use in labor and delivery.
Nursing Mothers
It is not known whether ramelteon is secreted into human milk; however ramelteon is secreted into the milk of lactating rats. Because many drugs are excreted into human milk, caution should be exercised when administered to a nursing woman.
Pediatric Use
Safety and effectiveness of ROZEREM in pediatric patients have not been established. Further study is needed prior to determining that this product may be used safely in pre-pubescent and pubescent patients.
Geriatic Use
A total of 654 subjects in double-blind, placebo-controlled, efficacy trials who received ROZEREM were at least 65 years of age; of these, 199 were 75 years of age or older. No overall differences in safety or efficacy were observed between elderly and younger adult subjects.
A double-blind, randomized, placebo-controlled study in elderly subjects with insomnia (n=33) evaluated the effect of a single dose of ROZEREM on balance, mobility, and memory functions after middle of the night awakening. There is no information on the effect of multiple dosing. Night time dosing of ROZEREM 8 mg did not impair middle of the night balance, mobility, or memory functions relative to placebo. The effects on night balance in the elderly cannot be definitively known from this study.
Gender
There is no FDA guidance on the use of Ramelteon with respect to specific gender populations.
Race
There is no FDA guidance on the use of Ramelteon with respect to specific racial populations.
Renal Impairment
No effects on Cmax and AUC0-t of parent drug or M-II were seen. No adjustment of ROZEREM dosage is required in patients with renal impairment.
Hepatic Impairment
Exposure to ROZEREM was increased by 4-fold in subjects with mild hepatic impairment and by more than 10-fold in subjects with moderate hepatic impairment. ROZEREM should be used with caution in patients with moderate hepatic impairment. ROZEREM is not recommended in patients with severe hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ramelteon in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Ramelteon in patients who are immunocompromised.
Sleep Apnea
The effects of ROZEREM were evaluated after administering a 16 mg dose or placebo in a crossover design to subjects (n=26) with mild to moderate obstructive sleep apnea. Treatment with ROZEREM 16 mg for one night showed no difference compared with placebo on the Apnea/Hypopnea Index (the primary outcome variable), apnea index, hypopnea index, central apnea index, mixed apnea index, and obstructive apnea index. Treatment with a single dose of ROZEREM does not exacerbate mild to moderate obstructive sleep apnea. There is no available information on the respiratory effects of multiple doses of ROZEREM in patients with sleep apnea. The effects on exacerbation in patients with mild to moderate sleep apnea cannot be definitively known from this study.
ROZEREM has not been studied in subjects with severe obstructive sleep apnea; use of ROZEREM is not recommended in such patients.
Chronic Obstructive Pulmonary Disease
The respiratory depressant effect of ROZEREM was evaluated in a crossover design study of subjects (n=26) with mild to moderate COPD after administering a single 16 mg dose or placebo, and in a separate study (n=25), the effects of ROZEREM on respiratory parameters were evaluated after administering an 8 mg dose or placebo in a crossover design to patients with moderate to severe COPD, defined as patients who had forced expiratory volume at one second (FEV1)/forced vital capacity ratio of <70%, and a FEV1 <80% of predicted with <12% reversibility to albuterol. Treatment with a single dose of ROZEREM has no demonstrable respiratory depressant effects in subjects with mild to severe COPD, as measured by arterial O2 saturation (SaO2). There is no available information on the respiratory effects of multiple doses of ROZEREM in patients with COPD. The respiratory depressant effects in patients with COPD cannot be definitively known from this study.
Administration and Monitoring
Administration
Oral
Monitoring
There is limited information regarding Ramelteon Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Ramelteon and IV administrations.
Overdosage
There is limited information regarding Ramelteon overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Ramelteon Pharmacology in the drug label.
Mechanism of Action
There is limited information regarding Ramelteon Mechanism of Action in the drug label.
Structure
There is limited information regarding Ramelteon Structure in the drug label.
Pharmacodynamics
There is limited information regarding Ramelteon Pharmacodynamics in the drug label.
Pharmacokinetics
There is limited information regarding Ramelteon Pharmacokinetics in the drug label.
Nonclinical Toxicology
There is limited information regarding Ramelteon Nonclinical Toxicology in the drug label.
Clinical Studies
There is limited information regarding Ramelteon Clinical Studies in the drug label.
How Supplied
There is limited information regarding Ramelteon How Supplied in the drug label.
Storage
There is limited information regarding Ramelteon Storage in the drug label.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
There is limited information regarding Ramelteon Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol by itself impairs performance and can cause sleepiness. Since the intended effect of ROZEREM is to promote sleep, patients should be cautioned not to consume alcohol when using ROZEREM. Use of the products in combination may have an additive effect.
Brand Names
There is limited information regarding Ramelteon Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Ramelteon Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.
| File:Ramelteon.svg | |
| File:Ramelteon3d.png | |
| Clinical data | |
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| Pregnancy category |
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| Routes of administration | Oral |
| ATC code | |
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| Pharmacokinetic data | |
| Bioavailability | 1.8% |
| Protein binding | ~82% |
| Metabolism | Hepatic (CYP1A2-mediated) |
| Elimination half-life | 1-2.6 hours |
| Excretion | Renal (84%) and fecal (4%) |
| Identifiers | |
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| CAS Number | |
| PubChem CID | |
| DrugBank | |
| E number | {{#property:P628}} |
| ECHA InfoCard | {{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value). |
| Chemical and physical data | |
| Formula | C16H21NO2 |
| Molar mass | 259.343 g/mol |
For patient information please see the page entitled Ramelteon (patient information)
Ramelteon, marketed as Rozerem by Takeda Pharmaceuticals North America, is the first in a new class of sleep agents that selectively binds to the melatonin receptors in the suprachiasmatic nucleus (SCN), versus binding to GABA A receptors, such as with drugs like zolpidem, eszopiclone, and zaleplon. Ramelteon is approved by the FDA for long-term use.
Ramelteon does not show any appreciable binding to GABAA receptors, which are associated with anxiolytic, myorelaxant, and amnesic effects.
Uses
Ramelteon is used for insomnia, particularly delayed sleep onset. Ramelteon has not been shown to produce dependence and has shown no potential for abuse, and the withdrawal and rebound insomnia that is typical with other GABA modulators is not present in ramelteon. It is currently the only non-scheduled prescription drug for the treatment of insomnia available in the United States.[1]
Mechanism of action
Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors and selectivity over the MT3 receptor. Ramelteon demonstrates full agonist activity in vitro in cells expressing human MT1 or MT2 receptors, and high selectivity for human MT 1 and MT2 receptors compared to the MT3 receptor.
The activity of ramelteon at the MT1 and MT2 receptors is believed to contribute to its sleep-promoting properties, as these receptors, acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle. Ramelteon has no appreciable affinity for the GABA receptor complex or for receptors that bind neuropeptides, cytokines, serotonin, dopamine, noradrenaline, acetylcholine, and opiates. Ramelteon also does not interfere with the activity of a number of selected enzymes in a standard panel.
The significance of ramelteon's lack of affinity for the MT3 receptor is not clear, despite the manufacturer's emphasis of this fact in commercial advertisements. The MT3 receptor appears almost exclusively in the gut and might not have any relationship to sleep or wakefulness.
The major metabolite of ramelteon, M-II, is active and has approximately one tenth and one fifth the binding affinity of the parent molecule for the human MT1 and MT2 receptors, respectively, and is 17 – 25-fold less potent than ramelteon in in vitro functional assays. Although the potency of M-II at MT1 and MT2 receptors is lower than the parent drug, M-II circulates at higher concentrations than the parent producing 20 – 100 fold greater mean systemic exposure when compared to ramelteon. M-II has weak affinity for the serotonin 5-HT2B receptor, but no appreciable affinity for other receptors or enzymes. Similar to ramelteon, M-II does not interfere with the activity of a number of endogenous enzymes.
All other known metabolites of ramelteon are inactive.
No published studies have indicated whether ramelteon is more or less safe or effective than melatonin, a much less expensive drug, widely available in the United States without a prescription. The biological action of melatonin is similar to that of ramelteon. The purported advantage of ramelteon is that the product and dosage is more likely to be pure and standardized, because it is a prescription drug that is monitored by the Food and Drug Administration (FDA).
Drug interactions
Ramelteon has been studied in combination with omeprazole, theophylline, dextromethorphan, midazolam (although one would probably not come across this medicine due to its high clearance and shorter half-life than other benzodiazepines. Thus, Intensive Care Units must assess the patient and carefully administer as needed. It is also used as a sedative before operations. Its half-life is less or greater than one hour. It is usually used in an Intensive Care Unit and administered via IV due to the destructive nature of first pass metabolism.) Other such drug-drug interactions include digoxin and warfarin. There were no clinically meaningful effects when ramelteon was coadministered with any of these drugs.
A drug interaction study showed that there were no clinically meaningful effects or an increase in adverse events when ramelteon and the SSRI Prozac (fluoxetine) were coadministered. Ramelteon and fluvoxamine should not be coadministered.
Ramelteon should be administered with caution in patients taking other CYP1A2 inhibitors, strong CYP3A4 inhibitors such as ketoconazole, and strong CYP2C9 inhibitors such as fluconazole.
Efficacy may be reduced when ramelteon is used in combination with potent CYP enzyme inducers such as rifampin, since ramelteon concentrations may be decreased.
References
Sources and external links
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