rozerem (ramelteon)
TRANSCRIPT
By Sirinoot Jantharangkul
Ramelteon (RozeremTM ) :melatonin receptor agonist
approved for insomnia
Ramelteon (RozeremTM ) :melatonin receptor agonist
approved for insomnia
Stages of sleep
Non-REM (Non-rapid eye movement)Stage 1: Initiates sleep ,15-30minStage 2: 50%of total sleep timeStage 3/4:15-20%of total sleep time
deep sleep REM (Rapid eye movement)
Dreming occurs
Sleep cycle
90min/cycle (4-5 cycles/night)
Normal sleep
Insomnia
InsomniaInsomnia: characterizes by one or
more of the following: Difficulty falling asleep
Waking up frequently during the night
with difficulty returning to sleep
Waking up too early in the morning
Unrefreshing sleep
Types of insomnia
Transient / Intermittent Insomnia Acute stress or illness Jet lag
Chronic Insomnia Primary or psychophysiological Secondary, refratory to treatment
of medical/ psychiatic disorder
Treatment
Non-pharmacologic therapySleep hygiene information
Stimulus control instructions
Chronotherapy
Treat underlying diseases or causes
Sedative-Hypnotics
Sedative-Hypnotics
Barbiturates
Benzodiazepines (BZDs)
Nonbenzodiazepine drugs
e.g zolpidem,zaleplon,eszopiclone
Characteristics of the ideal sleep agent
No physicaldependence
No tolerance
No effect on memory
Induction ofPhysiologicalSleep pattern
Rapidabsorption
Rapid sleepinduction
No residualsedation
Optimal half-lift
No reboundInsomnia orwithdrawal
No interactionWith alcohol
Ideal Sleep Agent
GABAA agonists
Ideal Sleep Agent
Rapidabsorption
No residualsedation
No reboundInsomnia orwithdrawal
Optimal half-lift
Rapid sleepinductionNo interaction
With alcohol
No physicaldependence
No tolerance
No effect on memory
Induction ofPhysiologicalSleep pattern
The Suprachiasmatic Nucleus (SCN)
SCN
Role of the SCN in the Sleep-Wake cycle
During the day, the SCN emitsan alerting signal that helps maintain Wakefulness.
At night, the alerting signalis attenuated, facilitating the onset of sleep.
Circadian control of melatonin production
SCNMEL
the activity of the SCN increases during the daymelatonin production is very low
SCN activity descends in the late daymelatonin production begins and reaches a peak very rapidly
DAY NIGHT
Melatonin
Melatonin is a hormone
(N-acetyl-5 methoxytryptamine)
Produced by the pineal gland
Regulate sleep-wake cycles
MT1MT2
MT2MT2
MT2
• Localized in hypothalamic suprachiasmatic nucleus and neural retina
•Diffuse expression in brain, liver,heart,kidneys
MT1 and MT2 receptors
Circadian control of melatonin production
MT1receptor
SCN
Melatonin
MT1 Agonists
Promote sleep via MT1Receptor in SCN regulating
Sleep/wake cycle
Physiological Sleep
MT1
Sleep promotion
melatonin receptor agonist
Ramelteon (RozeremTM )
:melatonin receptor agonist
RamelteonGeneric name: Ramelteon (ram el tee on)
Brand name: Rozerem
Company: Takeda Pharmaceuticals
North AmericaFDA Approval: 22 July, 2005
Treatment for: Insomnia
Molecular weight : 259.34 Freely soluble in organic solvents and
very slightly soluble in water
RamelteonRamelteon
Mechanism of action
melatonin receptor agonist with high affinity for melatonin (MT1) receptor
15time more potent than melatonin at MT1receptor
the MT1 receptor is believed to contribute to its sleep-promoting properties
the maintenance of the circadian rhythm underlying the normal sleep-wake cycle
Pharmacokinetics
Absorptionabsorbed rapidly from the GI tract
peak concentrations occurring at approximately 0.75 hour
bioavailability is only 1.8%
extensive first-pass metabolism.
Pharmacokinetics
DistributionIn vitro protein binding of ramelteon is approximately 82% in human serum
mean volume of distribution after intravenous administration of 73.6 L
Metabolismprimarily of oxidation to hydroxyl and carbonyl derivatives
through the cytochrome P (CYP)-450 system
major: the CYP1A2 isoenzyme
minor: the CYP2C subfamily and CYP3A4 isoenzyme
secondary metabolism producing glucuronide conjugates
Elimination84% in urine
4% in feces
T1/2 1 to 2.6 hours
Drug interactions
fluvoxamine and other CYP450 1A2 inhibitors
rifampin and other strong CYP450 inducer
ketoconazole and other strong CYP450 3A4
inhibitors
fluconazole and other strong CYP450 2C9
inhibitors
Contraindications
Hypersensitivity to ramelteon or any components of the ramelteon formulation.
Warning
Not for use in patients with severe hepatic impairment
Hypnotics have been associated with cognitive and behavior changes, including suicidal ideation
Not recommended in patients with severe sleep apnea or severe COPD
Warning
May decrease testosterone levels and increase prolactin level
Pregnancy: category C. development toratogen in the rat
Lactation: secreted into the milk of lactating rats
Adverse EventsRamelteon Placebo
Headache 7% 7% Somnolence 5% 3% Dizziness 5% 2% Fatigue 4% 3% Nausea 3% 2% Insomnia exacerbated 3% 2% URI 3% 2% Diarrhea 2% 2% Myalgia 2% 1% Depression 2% 1% Dysgeusia 2% 1% Arthralgia 2% 1% Influenza 1% 0 Blood cortisol decreased 1% 0
Dosage and administration
8 mg PO within 30 minutes of going to bed.
NOTE: Ramelteon should not be taken with or
immediately after a high fat meal.
Storage
Store at 25°C (77°F)
Keep container tightly closed
Protected from moisture and humidity.
Clinical studies 1
An efficacy, safety, and dose–response study of Ramelteon in patients with chronic primary insomnia
Milton Erman, David Seiden, Gary Zammit, Stephen Sainati, Jeffrey Zhang
Sleep Medicine xx (2005) 1–8
Purpose
To evaluate the efficacy, safety, and dose response of Ramelteon, a novel highly selective MT1/MT2 receptor agonist, in patients with chronic primary insomnia.
Patients and methods
A randomized, multicenter, double-blind, placebo-controlled, five-period crossover study design
107 patients, aged 18–64 years randomized into a dosing sequence that included
4, 8, 16, and 32 mg of ramelteon and placebo. 5- 12day washout period between treatments administered 30 min before habitual bedtime
Patients and methods
Polysomnographic monitoring Next-day residual effects
– VAS (mood and feeling)– DSST (digit symbol substitution test)– Word-list memory tests (immediate recall and
delayed recall– Post-sleep questionnaire(alertness and ability
to concentrate)
EfficacyTable 1 PSG and subjective sleep measures
Placebo Ramelteon Overall effect
4 mg 8 mg 16 mg 32 mg
PSG latency to persistentsleep(min) 37.7 24.0*** 24.3*** 24.0*** 22.9*** P<0.001Subjective sleep latency (min) 57.0 50.9 46.7 43.9* 46.5 P=0.040PSG total sleep time (min) 400.2 411.0* 412.9** 411.2* 418.2***P=0.001Subjective total sleep time (min)360.6 364.1 370.4 370.9 372.8 P=0.282Subjective sleep quality 3.8 3.6 3.7 3.7 3.7 P=0.525PSG WASO (min) 45.5 48.8 47.0 48.3 43.0 P=0.470
Note: All data presented here are least square (LS) means. LS means are from a mixed model witheffects for sequence, subject, period of treatment, with subject as a random effect and treatment as five groups.Subjective sleep quality was measured by the post-sleep questionnaire using a 7-point scale; a lower score is better. P values for pairwise comparisons were calculated by using Dunnetts t tests from the ANOVA model of the overall treatment comparison. ***P≤0.001 for comparison of active dose with placebo. **P≤0.010 for comparison of active dose with placebo. *P≤0.050 for comparison of active dose with placebo.
Table 3Next-day performance and alertness
Placebo Ramelteon
4 mg 8 mg 16 mg 32 mg DSST 47.4 47.3 46.5 47.7 47.5
Memory test-immediate recall 8.0 7.9 7.7 8.0 7.8
Memory test-delayed recall 4.9 5.0 5.4 5.1 5.2
Level of alertness 3.6 3.5 3.6 3.5 3.6
Ability to concentrate 3.6 3.5 3.5 3.5 3.6
Note: Values represent least squares means. There were no differences between placebo and any dose group for any measure. For the DSST, a higher score is better. For the word-list memory tests, a higher score is better. For the post-sleep questionnaire, a lower score is better.
Table 4Summary of most frequently reported adverse events (%)
Placebo Ramelteon
4 mg 8 mg 16 mg 32 mg
All adverse eventsa 19.4 25.2 18.3 19.6 21.4Headache 4.9 5.8 4.8 4.7 5.8Somnolence 1.0 0.0 1.9 3.7 1.9Pharyngolaryngeal pain 1.0 3.9 0.0 0.0 3.9Nasopharyngitis 2.9 1.0 0.0 1.9 1.0Nausea 1.9 2.9 1.0 0.9 1.0Dyspepsia 0.0 1.0 0.0 0.9 2.9Influenza 2.9 1.0 1.0 0.0 0.0Abdominal pain 1.0 1.0 1.0 0.9 0.0Dysmenorrhea 0.0 1.9 1.0 0.0 1.0Dry mouth 1.0 1.9 0.0 0.0 0.0Fatigue 0.0 0.0 1.0 0.9 1.9.
Conclusions
Ramelteon demonstrated a statistically significant reduction in LPS and a statistically significant increase in TST, with no apparent next-day residual effects, in patients with chronic primary insomnia.
Clinical studies 2
Ramelteon and triazolam in human: abuse potential (abstract)
Griffiths et al. Sleep 2005
Patients and methods
placebo-controlled, crossover clinical study 14 adults with a history of polydrug or multiple-
drug abuse 7 treatment separated by a wash-out period administered to patients in a randomly-assigned
sequence and included: -ramelteon (16 mg, 80 mg, 160 mg)-triazolam (0.25 mg, 0.50 mg, 0.75 mg)-placebo.
Drug-liking
Measures of "drug-liking," were assessed each day using questionnaires completed
at intervals between 0.5 hours predose, up to 24 hours after dose administration.
Drug Liking
0
0.5
1
1.5
2
2.5
PBO0.
25 0.5
0.75 16 80 16
0
PBO
Triazolam
Ramelteon
RamelteonTriazolam
( drug Effect Questionares Scale: 0-4 )
Dru
g l
ike
P<0.05
P<0.05
Results
Triazolam treatment (0.50 mg, 0.75 mg) produced a dose-related as compared to that of placebo
Ramelteon did not produce any significant changes in drug-liking comparative to that of placebo at any dose.
patients exhibited no abuse potential at up to 20 times the proposed therapeutic dose of ramelteon
Conclusions
Ramelteon: selective melatonin receptor agonist
Provides physiological sleep via activation of MT1 receptor play a role sleep/wake cycle
8mg tablets for the treatment of insomnia characterized by difficulty with sleep onset
has no serious adverse effects including dependence, abuse ability, memory impairment and motor impairment
THE END
GABAA Agonists
Amnesia,ataxia,toleranceDependence,abuse,residual effect
Rebound insomnia,etc.
Sedative Sleep
•Dependence•Abuse•Anti-anxiety
Sedation
•Anti-epilepsy
Ataxia
Amnesia
Task performance
variety of behavioral and cognitive tasks including :
DSST
Standing balance tasks memory tests
Self-report measures of subjective drug effects are collected from the subjects using structured questionnaires. The Single-Dose Questionnaire, developed by Fraser and his coworkers (Fraser, Isbell, Martin, Van Horn, & Wolbach, 1961) is among the most elegant psychometric instruments in its simplicity and predictive power.
It contains four scales: (a) the first asks whether the drug was felt and thereby determines whether the drug is psychoactive,
(b) the second is a 14-item list of substances from which the subject is asked which the administered compound is most like and thereby permits classification (the list includes blank and other),
(c) the third is a 14-item list of sensations (including normal and high) that characterizes and quantifies symptoms, and
(d) the fourth is a 5-point liking scale which is a measure of euphoria. A similar questionnaire is completed by staff observers
แสดงขบวนการส ังเคราะห์สาร Melatonin ใน pineal gland
MelatoninDietary supplements
used most commonly for disturbances
insomnia
jet lag
Cost
Drug Interactions
PRECAUTIONS➤Monitoring: For patients presenting with unexplained
amenorrhea,galactorrhea, decreased libido, or problems with fertility, considerassessment of prolactin levels and testosterone levels as
appropriate.➤Special risk: Ramelteon has not been studied in subjects withsevere sleep apnea or severe chronic obstructive pulmonary
disease(COPD) and is not recommended for use in those populations.➤Hazardous tasks: Avoid engaging in hazardous activities thatrequire concentration (eg, operating a motor vehicle or heavy machinery) after taking ramelteon. After taking ramelteon,
patientsshould confine their activities to those necessary to prepare for
bed.
PGS
EEG electrodes electromyogram (EMG), electrooculogram
(EOG, differential recording) electrocardiogram