Ramelteon
Encyclopedia
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.
, 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 disorder.
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.
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 neuropeptide
s, cytokine
s, serotonin
, dopamine
, noradrenaline, acetylcholine
, and opiate
s. 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.
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.
, 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.
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.
Takeda Pharmaceutical Company
is the largest pharmaceutical company in Japan and Asia and a top 15 pharmaceutical company. The company has over 19,000 employees worldwide and achieved $15.7 billion USD in revenue during the 2008 fiscal year...
, is the first in a new class of sleep agents that selectively binds to the MT1 and MT2 receptors
Melatonin receptor
A melatonin receptor is a G protein-coupled receptor which binds melatonin.Three types of melatonin receptor have been cloned. The MT1 and MT2 receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype MT3 has been identified in amphibia and...
in the suprachiasmatic nucleus
Suprachiasmatic nucleus
The suprachiasmatic nucleus or nuclei, abbreviated SCN, is a tiny region on the brain's midline, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms...
(SCN), instead of binding to GABA A receptors, such as with drugs like zolpidem
Zolpidem
Zolpidem is a prescription medication used for the short-term treatment of insomnia, as well as some brain disorders. It is a short-acting nonbenzodiazepine hypnotic of the imidazopyridine class that potentiates gamma-aminobutyric acid , an inhibitory neurotransmitter, by binding to GABAA...
, eszopiclone
Eszopiclone
Eszopiclone, marketed by Sepracor under the brand-name Lunesta, is a nonbenzodiazepine hypnotic used as a treatment for insomnia. Eszopiclone is the active dextrorotatory stereoisomer of zopiclone, and belongs to the class of drugs known as cyclopyrrolones.Eszopiclone is a short acting...
, and zaleplon
Zaleplon
Zaleplon is a sedative/hypnotic, mainly used for insomnia. It is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class. In terms of adverse effects zaleplon appears to offer little improvement compared to both benzodiazepines and other non-benzodiazepine Z-drugs.Sonata is manufactured by...
. 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
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
, myorelaxant, and amnesic
Amnesia
Amnesia is a condition in which one's memory is lost. The causes of amnesia have traditionally been divided into categories. Memory appears to be stored in several parts of the limbic system of the brain, and any condition that interferes with the function of this system can cause amnesia...
effects.
Uses
ROZEREM (ramelteon), FDA Approved 07.04.05, can be used for insomniaInsomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, 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
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
modulators is not present in ramelteon. Some clinicians also use ramelteon for the treatment of Delayed sleep phase disorder.
Mechanism of action
Ramelteon is a melatonin receptor agonistAgonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
with both high affinity for melatonin MT1 and MT2 receptors
Melatonin receptor
A melatonin receptor is a G protein-coupled receptor which binds melatonin.Three types of melatonin receptor have been cloned. The MT1 and MT2 receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype MT3 has been identified in amphibia and...
and selectivity
Functional Selectivity
Functional selectivity is the ligand-dependent selectivity for certain signal transduction pathways in one and the same receptor. This can be present when a receptor has several possible signal transduction pathways...
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.
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 neuropeptide
Neuropeptide
Neuropeptides are small protein-like molecules used by neurons to communicate with each other. They are neuronal signaling molecules, influence the activity of the brain in specific ways and are thus involved in particular brain functions, like analgesia, reward, food intake, learning and...
s, cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s, serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
, dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
, noradrenaline, acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
, and opiate
Opiate
In medicine, the term opiate describes any of the narcotic opioid alkaloids found as natural products in the opium poppy plant.-Overview:Opiates are so named because they are constituents or derivatives of constituents found in opium, which is processed from the latex sap of the opium poppy,...
s. 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
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
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
Melatonin
Melatonin , also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring compound found in animals, plants, and microbes...
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.
Clinical efficacy
In a double-blind multicenter trial, 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 hyperprolactinaemiaHyperprolactinaemia
Hyperprolactinaemia or hyperprolactinemia is the presence of abnormally-high levels of prolactin in the blood. Normal levels are less than 500 mIU/L for women, and less than 450 mIU/L for men....
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: omeprazoleOmeprazole
Omeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease , gastroesophageal reflux disease , laryngopharyngeal reflux and Zollinger–Ellison syndrome...
, theophylline
Theophylline
Theophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD and asthma under a variety of brand names. Because of its numerous side-effects, the drug is now rarely administered for clinical use. As a member of the xanthine family, it...
, dextromethorphan
Dextromethorphan
Dextromethorphan is an antitussive drug. It is one of the active ingredients in many over-the-counter cold and cough medicines, such as Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, and others, including generic labels. Dextromethorphan has also found other uses in medicine, ranging...
, and midazolam
Midazolam
Midazolam is a short-acting drug in the benzodiazepine class developed by Hoffmann-La Roche in the 1970s. The drug is used for treatment of acute seizures, moderate to severe insomnia, and for inducing sedation and amnesia before medical procedures. It possesses profoundly potent anxiolytic,...
, digoxin
Digoxin
Digoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin...
and warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
. 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
Fluvoxamine
Fluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder...
should not be coadministered.
Ramelteon should be administered with caution in patients taking other CYP1A2
CYP1A2
Cytochrome P450 1A2 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body...
inhibitors, strong CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
inhibitors such as ketoconazole
Ketoconazole
Ketoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
, and strong CYP2C9
CYP2C9
Cytochrome P450 2C9 is a protein that in humans is encoded by the CYP2C9 gene.- Function :CYP2C9 is an important cytochrome P450 enzyme with a major role in the oxidation of both xenobiotic and endogenous compounds. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes...
inhibitors such as fluconazole
Fluconazole
Fluconazole is a triazole antifungal drug used in the treatment and prevention of superficial and systemic fungal infections. In a bulk powder form, it appears as a white crystalline powder, and it is very slightly soluble in water and soluble in alcohol. It is commonly marketed under the trade...
.
Efficacy may be reduced when ramelteon is used in combination with potent CYP
Cytochrome P450 oxidase
The cytochrome P450 superfamily is a large and diverse group of enzymes. The function of most CYP enzymes is to catalyze the oxidation of organic substances. The substrates of CYP enzymes include metabolic intermediates such as lipids and steroidal hormones, as well as xenobiotic substances...
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 insomniacInsomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
chatting with Abraham Lincoln
Abraham Lincoln
Abraham Lincoln was the 16th President of the United States, serving from March 1861 until his assassination in April 1865. He successfully led his country through a great constitutional, military and moral crisis – the American Civil War – preserving the Union, while ending slavery, and...
and a talking beaver
Beaver
The beaver is a primarily nocturnal, large, semi-aquatic rodent. Castor includes two extant species, North American Beaver and Eurasian Beaver . Beavers are known for building dams, canals, and lodges . They are the second-largest rodent in the world...
over a chess
Chess
Chess is a two-player board game played on a chessboard, a square-checkered board with 64 squares arranged in an eight-by-eight grid. It is one of the world's most popular games, played by millions of people worldwide at home, in clubs, online, by correspondence, and in tournaments.Each player...
board, while a hard-hat diver
Standard diving dress
A standard diving dress consists of a metallic diving helmet, an airline or hose from a surface supplied diving air pump, a canvas diving suit, diving knife and boots...
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.