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Rozerem
Overview
What is Rozerem?
ROZEREM (ramelteon) is an orally active hypnotic chemically designated as ()--[2-(1,6,7,8-tetrahydro-2-indeno-[5,4-]furan-8-yl)ethyl]propionamide and containing one chiral
center. The compound is produced as the ()-enantiomer, with an empirical formula of CHNO,
molecular weight of 259.34, and the following chemical structure:
Ramelteon is freely soluble in organic solvents, such as methanol, ethanol,
and dimethyl sulfoxide; soluble in 1-octanol and acetonitrile; and very slightly
soluble in water and in aqueous buffers from pH 3 to pH 11.
Each ROZEREM tablet includes the following inactive ingredients: lactose
monohydrate, starch, hydroxypropyl cellulose, magnesium stearate, hypromellose,
copovidone, titanium dioxide, yellow ferric oxide, polyethylene glycol 8000, and
ink containing shellac and synthetic iron oxide black.
What does Rozerem look like?
What are the available doses of Rozerem?
ROZEREM is available in an 8 mg strength tablet for oral
administration.
ROZEREM 8 mg tablets are round, pale orange-yellow, film-coated, with “TAK”
and “RAM-8” printed on one side.
What should I talk to my health care provider before I take Rozerem?
Pregnancy Category 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/m) 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/m 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/m basis. Increased incidences of malformation and death among
offspring were seen at the highest dose.
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.
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.
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.
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.
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 (FEV)/forced vital capacity ratio of less than 70%,
and a FEV
less than 80% of predicted
with less than 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.
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.
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.
No effects on C and AUC of parent drug or M-II were seen. No adjustment of ROZEREM
dosage is required in patients with renal impairment
.
How should I use Rozerem?
ROZEREM is indicated for the treatment of insomnia characterized
by difficulty with sleep onset.
The
clinical trials performed in support of efficacy were up to 6 months in
duration. The final formal assessments of sleep latency were performed after 2
days of treatment during the crossover study (elderly only), at 5 weeks in the
6-week studies (adults and elderly), and at the end of the 6-month study (adults
and elderly)
.
The recommended dose of ROZEREM is 8 mg taken within 30 minutes
of going to bed. It is recommended that ROZEREM not be taken with or immediately
after a high-fat meal.
The total ROZEREM dose should not exceed 8 mg per day.
ROZEREM is not recommended in patients with severe hepatic
impairment. ROZEREM should be used with caution in patients with moderate
hepatic impairment [see , ].
ROZEREM should not be used in combination with fluvoxamine.
ROZEREM should be used with caution in patients taking other CYP1A2 inhibiting
drugs
What interacts with Rozerem?
Sorry No Records found
What are the warnings of Rozerem?
Sorry No Records found
What are the precautions of Rozerem?
Sorry No Records found
What are the side effects of Rozerem?
Sorry No records found
What should I look out for while using Rozerem?
Patients who develop angioedema after treatment with ROZEREM
should not be rechallenged with the drug.
Patients should not take ROZEREM in conjunction with fluvoxamine (Luvox)
.
What might happen if I take too much Rozerem?
General symptomatic and supportive measures should be used, along
with immediate gastric lavage where appropriate. Intravenous fluids should be
administered as needed. As in all cases of drug overdose, respiration, pulse,
blood pressure, and other appropriate vital signs should be monitored, and
general supportive measures employed.
Hemodialysis does not effectively reduce exposure to ROZEREM. Therefore, the
use of dialysis in the treatment of overdosage is not appropriate.
Poison
Control Center
:
How should I store and handle Rozerem?
Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP] .ROZEREM is available as round, pale orange-yellow, film-coated, 8 mg tablets, with “TAK” and “RAM-8” printed on one side, in the following quantities:NDC 54868-5649-0 Bottles of 30Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP controlled room temperature]. Keep container tightly closed and protected from moisture and humidity.ROZEREM is available as round, pale orange-yellow, film-coated, 8 mg tablets, with “TAK” and “RAM-8” printed on one side, in the following quantities:NDC 54868-5649-0 Bottles of 30Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP controlled room temperature]. Keep container tightly closed and protected from moisture and humidity.ROZEREM is available as round, pale orange-yellow, film-coated, 8 mg tablets, with “TAK” and “RAM-8” printed on one side, in the following quantities:NDC 54868-5649-0 Bottles of 30Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP controlled room temperature]. Keep container tightly closed and protected from moisture and humidity.
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
ROZEREM (ramelteon) is a melatonin receptor agonist with both
high affinity for melatonin MT and MTreceptors and selectivity over the MT receptor.
Ramelteon demonstrates full agonist activity
in cells expressing human MT
or MT receptors.
The activity of ramelteon at the MT and MTreceptors 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 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
MT and MT receptors,
respectively, and is 17- to 25-fold less potent than ramelteon in
functional assays.
Although the potency of M-II at MT and MT receptors is lower than the parent drug, M-II circulates at
higher concentrations than the parent producing 20- to 100-fold greater mean
systemic exposure when compared to ramelteon. M-II has weak affinity for the
serotonin 5-HT 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.
The pharmacokinetic profile of ROZEREM has been evaluated in
healthy subjects as well as in subjects with hepatic or renal impairment. When
administered orally to humans in doses ranging from 4 to 64 mg, ramelteon
undergoes rapid, high first-pass metabolism, and exhibits linear
pharmacokinetics. Maximal serum concentration (C) and
area under the concentration-time curve (AUC) data show substantial intersubject
variability, consistent with the high first-pass effect; the coefficient of
variation for these values is approximately 100%. Several metabolites have been
identified in human serum and urine.
Absorption
Ramelteon is absorbed rapidly, with median peak concentrations occurring at
approximately 0.75 hour (range, 0.5 to 1.5 hours) after fasted oral
administration. Although the total absorption of ramelteon is at least 84%, the
absolute oral bioavailability is only 1.8% due to extensive first-pass
metabolism.
Distribution
In vitro
Ramelteon has a mean volume of distribution after intravenous administration
of 73.6 L, suggesting substantial tissue distribution.
Metabolism
Metabolism of ramelteon consists primarily of oxidation to hydroxyl and
carbonyl derivatives, with secondary metabolism producing glucuronide
conjugates. CYP1A2 is the major isozyme involved in the hepatic metabolism of
ramelteon; the CYP2C subfamily and CYP3A4 isozymes are also involved to a minor
degree.
The rank order of the principal metabolites by prevalence in human serum is
M-II, M-IV, M-I, and M-III. These metabolites are formed rapidly and exhibit a
monophasic decline and rapid elimination. The overall mean systemic exposure of
M-II is approximately 20- to 100-fold higher than parent drug.
Elimination
Following oral administration of radiolabeled ramelteon, 84% of total
radioactivity was excreted in urine and approximately 4% in feces, resulting in
a mean recovery of 88%. Less than 0.1% of the dose was excreted in urine and
feces as the parent compound. Elimination was essentially complete by 96 hours
post-dose.
Repeated once daily dosing with ROZEREM does not result in significant
accumulation owing to the short elimination half-life of ramelteon (on average,
approximately 1- 2.6 hours).
The half-life of M-II is 2 to 5 hours and independent of dose. Serum
concentrations of the parent drug and its metabolites in humans are at or below
the lower limits of quantitation within 24 hours.
Effect of Food
When administered with a high-fat meal, the AUC
for a single 16 mg dose of ROZEREM was 31% higher and the C was 22% lower than when given in a fasted state. Median
T was delayed by approximately 45 minutes when ROZEREM
was administered with food. Effects of food on the AUC values for M-II were
similar. It is therefore recommended that ROZEREM not be taken with or
immediately after a high-fat meal
.
Age
:
Gender
:
Hepatic Impairment
:
Renal Impairment
:
ROZEREM has a highly variable intersubject pharmacokinetic
profile (approximately 100% coefficient of variation in C and AUC). As noted above, CYP1A2 is the major isozyme
involved in the metabolism of ROZEREM; the CYP2C subfamily and CYP3A4 isozymes
are also involved to a minor degree.
Effects of Other Drugs on ROZEREM
Metabolism
Fluvoxamine (strong CYP1A2 inhibitor):
Rifampin (strong CYP enzyme inducer):
Ketoconazole (strong CYP3A4 inhibitor):
Fluconazole (strong CYP2C9 inhibitor):
Interaction studies of concomitant administration of ROZEREM with fluoxetine
(CYP2D6 inhibitor), omeprazole (CYP1A2 inducer/CYP2C19 inhibitor), theophylline
(CYP1A2 substrate), and dextromethorphan (CYP2D6 substrate) did not produce
clinically meaningful changes in either peak or total exposures to ramelteon or
the M-II metabolite.
Effects of ROZEREM on Metabolism of Other
Drugs
Concomitant administration of ROZEREM with omeprazole (CYP2C19 substrate),
dextromethorphan (CYP2D6 substrate), midazolam (CYP3A4 substrate), theophylline
(CYP1A2 substrate), digoxin (p-glycoprotein substrate) and warfarin (CYP2C9
[S]/CYP1A2 [R] substrate) did not produce clinically meaningful changes in peak
and total exposures to these drugs.
Effect of Alcohol on ROZEREM
With single-dose, daytime co-administration of ROZEREM 32 mg and alcohol (0.6
g/kg), there were no clinically meaningful or statistically significant effects
on peak or total exposure to ROZEREM. However, an additive effect was seen on
some measures of psychomotor performance (i.e., the Digit Symbol Substitution
Test, the Psychomotor Vigilance Task Test, and a Visual Analog Scale of
Sedation) at some post-dose time points. No additive effect was seen on the
Delayed Word Recognition Test. Because alcohol by itself impairs performance,
and the intended effect of ROZEREM is to promote sleep, patients should be
cautioned not to consume alcohol when using ROZEREM.
Non-Clinical Toxicology
Patients who develop angioedema after treatment with ROZEREM should not be rechallenged with the drug.Patients should not take ROZEREM in conjunction with fluvoxamine (Luvox) .
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
ROZEREM is not known to interfere with commonly used clinical laboratory tests. In addition, 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 .
The following serious adverse reactions are discussed in greater detail in other sections:
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.
ROZEREM 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.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
While we update our database periodically, we cannot guarantee it is always updated to the latest version.
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