Ramelteon
Drug Info:
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Ramelteon
Brand names: Rozerem™
Chemical formula:
- Drug Forms:
- Ramelteon tablets (below)
- Ramelteon Oral tablet
- Espa�ol:
- Ramelteon, Tableta oral
Ramelteon tablets
What are Ramelteon tablets?
RAMELTEON (Rozerem™) is used to help you fall asleep faster if you experience sleeplessness (insomnia). It is specifically used to help people who have trouble falling asleep, rather than those who might wake up too early or too often at night. Sleep medicines should not be taken for long periods of time, except on your prescriber's advice. Do not share your medicine with anyone else. Generic ramelteon tablets are not yet available.What should I tell my health care provider before I take this medicine?
They need to know if you have any of these conditions:• are a frequent user of alcohol or have a history of drug abuse
• attempted suicide or thoughts of harming yourself
• breathing difficulty, such as chronic obstructive pulmonary disease (COPD), untreated asthma, or sleep apnea
• depression, bipolar disease (manic depression), or other mental health or behavior disorders
• difficulty staying asleep
• increased prolactin concentrations (hyperprolactinemia)
• lactose intolerant
• liver disease or a history of liver disease
• an unusual reaction to ramelteon, other medicines, foods, dyes, or preservatives
• pregnant or trying to get pregnant
• breast-feeding
How should this medicine be used?
Only take this medicine within 30 minutes before you are ready to go to bed. After you take ramelteon, limit your activities to those required to get ready for bed.
Avoid taking ramelteon with or immediately after eating any high fat meals or snacks. High fat foods may alter the absorption of ramelteon into your blood stream. The sleep promoting effects of ramelteon may be affected. Do not drink alcoholic beverages with ramelteon. Do not drive, operate machinery or engage in other dangerous activities after you have taken ramelteon prior to bedtime.
Contact your pediatrician or health care professional regarding the use of this medicine in children. Special care may be needed.
What if I miss a dose?
This does not apply. Ramelteon should only be taken immediately before getting into bed or after getting in bed and having trouble falling asleep. Do not take double or extra doses. Do not take an extra dose in the middle of the night if you wake up after falling asleep.What drug(s) may interact with Ramelteon?
Do not take ramelteon with this medicine:
• fluvoxamine (Luvox®)
Other medicines that may interact with ramelteon:
• alcohol and alcoholic beverages
• amiodarone
• antiretroviral protease inhibitors (medicines used for HIV, AIDS)
• barbiturate medicines for inducing sleep or treating seizures (convulsions)
• chloramphenicol
• ciprofloxacin, erythromycin, enoxacin, norfloxacin (antibiotics)
• clopidogrel
• cyclosporine
• dalfopristin; quinupristin
• diltiazem
• disulfiram
• ethinyl estradiol (in some birth control pills)
• kava kava
• fluconazole, itraconazole, ketoconazole, miconazole, voriconazole (antifungals)
• fluorouracil, 5-FU
• gemfibrozil
• imatinib, STI-571
• isoniazid, INH
• leflunomide
• melatonin
• metronidazole
• mexiletine
• mifepristone, RU-486
• rifampin
• some sulfonamide medications
• tacrine
• troleandomycin
• valerian
• verapamil
• zileuton
• certain medications for depression, anxiety, or other emotional or psychiatric problems
Tell your prescriber or health care professional about all other medicines you are taking, including non-prescription medicines, nutritional supplements, or herbal products. Also tell your prescriber or health care professional if you are a frequent user of drinks with caffeine or alcohol, if you smoke, or if you use illegal drugs. These may affect the way your medicine works. Check with your health care professional before stopping or starting any of your medicines.
What should I watch for while taking Ramelteon?
In women: If you experience any irregularities in your menstrual cycle (your monthly period) or if your periods stop, contact your health care provider. If you experience galactorrhea (breast milk), you should also contact your prescriber.
If you experience a decreased sexual drive (decreased libido) or problems with fertility, you should contact your health care provider.
Do not drive, use machinery, or do anything that needs mental alertness until you know how ramelteon affects you. To reduce dizzy or fainting spells, do not sit or stand up quickly, especially if you are an older patient. Alcohol can increase the drowsy or dizzy effects. Avoid alcoholic drinks.
If you are going to have surgery, tell your prescriber or health care professional that you are taking ramelteon.
If you smoke tobacco, you may affect the amount of ramelteon in your body. Ask your prescriber or health care professional for help to stop smoking.
What side effects may I notice from receiving Ramelteon?
Side effects that you should report to your prescriber or health care professional as soon as possible:• breast milk production or discharge from nipples
• decreased sex drive
• extreme tiredness or weakness
• joint or muscle pain
• mental depression or worsening of depression
• missed monthly period (for women)
• suicidal thoughts
• trouble breathing or shortness of breath
• worsening of insomnia
Side effects that usually do not require medical attention (report to your prescriber or health care professional if they continue or are bothersome):
• bad taste
• daytime sleepiness
• diarrhea
• dizziness
• headache
• nausea
Where can I keep my medicine?
Keep out of the reach of children in a container that small children cannot open.Store at room temperature between 15—30 degrees C (59—86 degrees F) in the original container. Keep the container tightly closed and protected from moisture and humidity. Throw away any unused medicine after the expiration date.
Last updated: 7/25/2005 4:57:00 PM
Important Disclaimer: The drug information provided here is for educational purposes only. It is intended to supplement, not substitute for, the diagnosis, treatment and advice of a medical professional. This drug information does not cover all possible uses, precautions, side effects and interactions. It should not be construed to indicate that this or any drug is safe for you. Consult your medical professional for guidance before using any prescription or over the counter drugs.
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Ramelteon
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Ramelteon
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| Systematic (IUPAC) name | |
| (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b] furan-8-yl)ethyl]propionamide |
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| Clinical data | |
| Trade names | Rozerem |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a605038 |
| Pregnancy cat. | C (US) |
| Legal status | ℞-only (US) |
| Routes | Oral |
| Pharmacokinetic data | |
| Bioavailability | 1.8% |
| Protein binding | ~82% |
| Metabolism | Hepatic (CYP1A2-mediated) |
| Half-life | 1-2.6 hours |
| Excretion | Renal (84%) and fecal (4%) |
| Identifiers | |
| CAS number | 196597-26-9  |
| ATC code | N05CH02 |
| PubChem | CID 10858193 |
| IUPHAR ligand | 1356 |
| DrugBank | DB00980 |
| ChemSpider | 9033484 |
| UNII | 901AS54I69 |
| KEGG | D02689 |
| ChEMBL | CHEMBL133775 |
| Chemical data | |
| Formula | C16H21NO2 |
| Mol. mass | 259.343 g/mol |
| SMILES | eMolecules & PubChem |
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Ramelteon, marketed as Rozerem by Takeda Pharmaceuticals North America, is the first in a new class of sleep agents that selectively binds to the MT1 and MT2 receptors in the suprachiasmatic nucleus (SCN), instead of binding to GABA A receptors, such as with drugs like zolpidem, eszopiclone, and zaleplon. Ramelteon is approved by the U.S. Food and Drug Administration (FDA) for long-term use.
Ramelteon does not show any appreciable binding to GABAA receptors, which are associated with anxiolytic, myorelaxant, and amnesic effects.
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Contents
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Uses
ROZEREM (ramelteon), FDA Approved 07.04.05, can be 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 GABA modulators is not present in ramelteon. Some clinicians also use ramelteon for the treatment of Delayed sleep phase syndrome.
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 MT1 and MT2 receptors compared to the MT3 receptor.[1]
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, in humans, is more or less safe or effective than the hormone melatonin which it mimics; melatonin is much less expensive and is widely available over-the-counter in the US and Canada. The biological action of melatonin is similar to that of ramelteon. Ramelteon has been directly compared to melatonin in cats, and Ramelteon had a significant (3x) longer effect and had a more profound effect on the EEG of the sleeping cats.[2]
Clinical efficacy
In a double-blind multicenter trial[3], ramelteon did reduce the time to fall asleep by approximately 15-20 minutes, at 8 mg and 16 mg doses after four weeks compared to placebo (approx. 29-32 versus 48 minutes) Total sleep time improved about 40 minutes, however, this was identical to improvement with placebo at the end of trial. Subjective reported sleep time was greater in ramelteon treated persons. The main thing to note is ramelteon compared to placebo had a much faster onset of effects, one or two weeks, but the effects were roughly equivalent to placebo at four weeks.
Adverse effects
Ramelteon caused hyperprolactinaemia two to three times more often than placebo in clinical trials. Studies of rats and mice showed a dose-dependent increase in cancer. The long-term safety in humans is unknown. Ramelteon was teratogenic in rats.
Drug interactions
Ramelteon has been evaluated for potential drug interactions with the following medications and showed no significant effects: omeprazole, theophylline, dextromethorphan, and midazolam, 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.
Advertising campaign
Rozerem has become known for the surreal humor of its television advertisements, particularly one involving an insomniac chatting with Abraham Lincoln and a talking beaver over a chess board, while a hard-hat diver stands silently in the background. As of October, 2007, the most recent spot was framed as a late-night talk show, with the beaver as host, Lincoln as sidekick, a Rozerem expert as guest, and the diver as bandleader.
Synthesis
Chilman-Blair, K.; Castañer, J.; Silvestre, J.S.; Bayés, M. (2003). "TAK-375". Drugs of the Future 28 (10): 950. doi:10.1358/dof.2003.028.10.763214.
See also
References
- ^ Owen RT (April 2006). "Ramelteon: profile of a new sleep-promoting medication". Drugs Today 42 (4): 255–63. doi:10.1358/dot.2006.42.4.970842. PMID 16703122.
- ^ Miyamoto M, Nishikawa H, Doken Y, Hirai K, Uchikawa O, Ohkawa S (November 2004). "The sleep-promoting action of ramelteon (TAK-375) in freely moving cats". Sleep 27 (7): 1319–25. PMID 15586784.
- ^ Zammit G, Erman M, Wang-Weigand S, Sainati S, Zhang J, Roth T (August 2007). "Evaluation of the Efficacy and Safety of Ramelteon in Subjects with Chronic Insomnia". J Clin Sleep Med 3 (5): 495–504. PMC 1978328. PMID 17803013. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1978328.
Sources and external links
- Rozerem Official Website
- Prescribing Information Data Sheet
- RxList.com
- Clinical Pharmacokinetic Monitoring of Midazolam in Critically Ill Patients in relation to midazolam as a drug-drug interaction to Rozerem
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