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ROZEREM™
(rametteon) Tablets
INDICATIONS AND USAGE
ROZEREM is indicated for the treatment of insomnia charactenzed by
difficulty with sleep onset.
CONTRAINDICATIONS
ROZEREM is contraindicated in patients with a hypersensitivity to
ramelteon or any components of the ROZEREM formulation.
WARNINGS
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 a reasonable period 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. As with other hypnotics, exacerbation of insomnia and
emergence of cognitive and behavioral abnormalities were seen with
ROZEREM during the clinical development program.
ROZEREM should not be used by patients with severe hepatic impairment
ROZEREM should not be used in combination with fluvoxamine
(see PRECAUTIONS: Drug Interactions)
A variety of cognitive and behavior changes have been reported to occur
in association with the use of hypnotics, m primarily depressed patients,
worsening of depression, including suicidal ideation, has been reported in
association with the use of hypnotics.
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 shouki confine their activities to those
necessary to prepare for bed.
PRECAUTIONS
General
ROZEREM has not been studied in subjects with severe sleep apnea or
severe COPO and is not recommended for use in those populations
Patients should be advised to exercise caution if they consume alcohol in
combination with ROZEREM.
Use in Adolescents and Children
ROZEREM has been associated with an effect on reproductive hormones
in adults, e.g„ decreased testosterone levels and increased prolactin
levels, ft is not known what effect chronic or even chronic intermittent
use of ROZEREM may have on the reproductive axis in developing
humans (see Pediatric Use).
Information tor Patients
• Patients should be advised to take ROZEREM within 30 minutes prior
to going to bed and should confine their activities to those necessary
to prepare for bed.
• Patients should be advised to avoid engaging in hazardous activities
(such a motor vehicle or heavy machinery) after taking
• Patients should be advised that they should not take ROZEREM with or
immediately after a high-fat meal
• Patients should be advised to consult their health care provider if they
experience worsening of insomnia or any new behavioral signs or
symptoms of concern
• Patients should consult their hearth care provider if they experience
one of the following: cessation of menses or galactorrhea in females,
decreased libido, or problems with fertility.
Laboratory Tests
No standard monitoring is required.
For patients presenting with unexplained amenonhea, galactorrhea,
decreased libido, or problems with fertility, assessment of prolactin levels
and testosterone levels should be considered as appropriate.
Drug Interactions
ROZEREM has a highly variable intersubject pharmacokinetic profile
Pharmacist information : STRENGTH: Rozerem Bmg NDC: 64764-805-30
Pharmacist: For reimbursement, please submit to Patient Choice. The information printed below should be used when submitting for reimbursement.
For questions, please call the Help Desk at 1-800-422-5604
Voucher is good through 3/31/08. Void where prohibited by law. Not valid if reproduced. This offer is not valid if any part of your prescription is paid for by: (i) any federal or state healthcare program, including a
state medical or pharmaceutical assistance program (Medicare, Medicaid, VA, etc.), (ii) Medicare Prescription Drug Program (Part D Program), or (iii) insurance that is paying the entire cost of the prescription.
• This voucher is good for up to one 7-night supply before 3/31/08 * This voucher is for a free trial and does not require any purchase of any other product
• This voucher is valid for redemption in the USA at participating retail pharmacies only * No substitutions permitted
• Please dispense this product at no charge to the patient * This program may be cancelled at any time without notice
• This voucher must be accompanied by 1 prescription for up to 7 tablets of Rozerem • This offer is not valid where prohibited by law
• Limit 1 voucher per patient * Voucher not valid if reproduced
• For assistance filing this claim, please call 1-800-422-5604 * Not valid with any other coupon, discount or incentive involving Rozerem
I certify that I have received this voucher from an eligible patient and that I have dispensed Rozerem in accordance with the terms of this voucher and accompanying prescription. I have not submitted and will not
submit (i) a claim for reimbursement to the patient or any Third-Party Payor, governmental or otherwise, for the free product dispensed pursuant to this voucher, or (ii) any portion of the free product dispensed
pursuant to this voucher to a Third-Party Payor for purposes of counting it towards the patient’s out-of-pocket expenses (such as TrOOP under Medicare Part D, Medicaid, TriCARE). I certify that my participation
in this program is consistent with all applicable state laws and any obligations, contractual or otherwise, that I have as a pharmacy provider.
important information about your voucher
Eligibility Requirements: This offer is not valid if any part of your prescription is paid for by: (i) any federal or state healthcare program, including a state medical or pharmaceutical assistance program (Medicare,
Medicaid, VA, etc.), (ii) Medicare Prescription Drug Program (Part D Program), or (iii) insurance that is paying the entire cost of the prescription.
Terms and (Conditions: You must meet Eligibility Requirements. You may use this voucher only for a free trial of up to 7 pills of Rozerem. This voucher is for a free trial and does not require the purchase of
any other product. This voucher is redeemable one time only when presented with a valid, signed prescription for up to 7 tablets of the above-listed medication. Offer limited to 1 voucher per patient. This voucher
is good for use only with Rozerem at the time the prescription is filled by the pharmacist and dispensed to the patient. This offer is good only in the USA at participating retail pharmacies and cannot be redeemed
at government-subsidized clinics. This offer is not valid where prohibited by law. This voucher is not valid with any other program, discount, or incentive involving Rozerem. This offer may be rescinded, revoked, or
amended without notice. Voucher not valid if reproduced. The selling, purchasing, trading, or counterfeiting of this voucher is prohibited by law. No claim for product dispensed pursuant to terms of voucher shall be
submitted to any Third-Party Payor, public (e.g. Medicare, Medicaid, TriCARE) or private, for reimbursement. Offer valid until 3/31/08.
Rozerem,.. is a trademark of Takeda Pharmaceutical Company Limited and used under license by Takeda Phaimaceuticals North America, Inc.
LUVOX' (fluvoxamine) is a registered trademark of Solvay Pharmaceuticals, Inc.
©2007 Takeda Pharmaceuticals North America, Inc. RAM-01379
(approximately 100% coefficient of variation in Cm, and AUC). As noted
above. CYPIA2 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 CYPIA2 inhibitor): When fluvoxamine 100 mg twice
daily was administered for 3 days prior to single-dose co-administration
of ROZEREM 16 mg and fluvoxamine, the AUC** for ramelteon increased
approximately 190-fold, and the increased approximately 70-fotd.
compared to ROZEREM administered alone. ROZEREM should not be
used m combination with fluvoxamine (see WARNINGS). Other less
potent CYPIA2 inhibitors have not been adequately studied. ROZEREM
should be administered with caution to patients taking less strong
CYPIA2 inhibitors.
Rifampin (strong CYP enzyme inducer): Administration of rifampin 600 mg
once daily for 11 days resulted in a mean decrease of approximately
80% (40% to 90%) in total exposure to rametteon and metabolite M-11.
(both AUCo-rt and Cm*) after a single 32 mg dose of ROZEREM. Efficacy
may be reduced when ROZEREM is used in combination with strong CYP
enzyme inducers such as rifampin.
Ketoconazole (strong CYP3A4 inhibitor): The AUC 0 . rt and Cm* of
ramelteon increased by approximately 84% and 36%. respectively, when
a single 16 mg dose of ROZEREM was administered on the fourth day of
ketoconazole 200 mg twice daily administration, compared to administration
of ROZEREM alone. Similar increases were seen in M-ll pharmacokinetic
variables. ROZEREM should be administered with caution in subjects
taking strong CYP3A4 inhibitors such as ketoconazole
Fluconazole (strong CYP2C9 inhibitor): The total and peak systemic
exposure (AUC O .*< and CnJ of ramelteon after a single 16 mg dose of
ROZEREM was increased by approximately 150% when administered
with fluconazole. Similar increases were also seen in M-ll exposure.
ROZEREM should be administered with caution in subjects taking strong
CYP2C9 inhibitors such as fluconazole
Interaction studies of concomitant administration of ROZEREM with
fluoxetine (CYP2D6 inhibitor), omeprazole (CYPIA2 inducer/CYP2CI9
inhibitor), theophylline (CYPIA2 substrate), and dextromethorphan
(CYP2D6 substrate) did not produce clinically meaningful changes in
either peak or total exposures to ramelteon or the M-ll metabolite.
Effects of ROZEREM on Metabolism of Other Drugs
Concomitant administration of ROZEREM with omeprazole (CYP2CI9
substrate), dextromethorphan (CYP2O6 substrate), midazolam (CYP3A4
substrate), theophyine (CYPIA2 substrate), digoxin (p-tfycoprotem substrate),
and warfarin (CYP2C9 (SJ/CYPIA2 [R] substrate) did not produce clinically
meaningful changes in peak and total exposures to these drugs.
Effect of Alcohol on Rozerem
Alcohol: 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.
Drug/Laboratory Test Interactions
ROZEREM is not known to interfere wth commonly used clinical
laboratory tests. In addition, in vitro data indicate that ramelteon does not
cause false-positive results for benzodiazepines, opiates, barbiturates,
cocaine, cannabmoids. or amphetamines in two standard urine drug
screening methods in vitro.
Carcinogenesis, Mutagenesis, and Impairment at Fertility
Carcinogenesis
In a two-year caranogematy study. B6C3F- mice were administered
ramelteon at doses of 0,30.100,300, or 1000 mg/kg/day by oral gavage.
Male mice exhibited a dose-related increase in the incidence of hepatic
tumors at dose levels 2 100 mg/kg/day including hepatic adenoma,
hepatic carcinoma, and hepatoblastoma Female mice developed a
dose-related increase in the incidence of hepatic adenomas at dose
levels > 300 mg/kg/day and hepatic carcinoma at the 1000 mg/kg/day
dose level. The no-effect level for hepatic tumors in male mice was
30 mg/kg/day (103-times and 3-times the therapeutic exposure to
ramelteon and the active metabolite M-H, respectively, at the maximum
recommended human dose [MRHD] based on an area under the
concentration-time curve [AUC] companson). The no-effect level for
hepatic tumors in female mice was 100 mg/kg/day (827-times and
12-times the therapeutic exposure to ramelteon and M-11, respectively,
at the MRHD based on AUC).
In a two-year carcinogenicity study conducted in the Sprague-Dawley
rat, male and female rats were administered ramelteon at doses of
0,15.60.250 or 1000 mg/kg/day by oral gavage Male rats exhibited a
dose-related increase in the incidence of hepatic adenoma and benign
Leydig cell tumors of the testis at dose levels 2 250 mg/kg/day and
hepatic carcinoma at the 1000 mg/kg/day dose level. Female rats
exhibited a dose-related increase in the incidence of hepatic adenoma
at dose levels 2 60 mg/kg/day and hepatic carcinoma at the
1000 mg/kg/day dose level. The no-effect level for hepatic tumors and
benign Leydig cell tumors in male rats was 60 mg/kg/day (1.429-times
and 12-times the therapeutic exposure to ramelteon and M-11, respectively,
at the MRHD based on AUC). The no-effect level for hepatic tumors in
female rats was 15 mg/kg/day (472-times and 16-times the therapeutic
exposure to ramelteon and M-H, respectively, at the MRHD based on AUC).
The development of hepatic tumors m rodents following chronic treatment
with non-genotoxic compounds may be secondary to microsomal
enzyme induction, a mechanism for tumor generation not thought to
occur in humans. Leydig cell tumor development following treatment
with non-genotoxic compounds in rodents has been linked to reductions
in circulating testosterone levels with compensatory increases m luteinizing
hormone release, which is a known proliferative stimulus to Leydig cells
in the rat testis. Rat Leydig cells are more sensitive to the stimulatory
effects of luteinizing hormone than human Leydig cells. In mechanistic
studies conducted in the rat. daily ramelteon administration at 250 and
1000 mg/kg/day for 4 weeks was associated with a reduction in plasma
testosterone levels. In the same study, luteinizing hormone levels were
elevated over a 24-hour period after the last ramelteon treatment;
however, the durability of this luteinizing hormone finding and its support
for the proposed mechanistic explanation was not clearty established.
Although the rodent tumors observed following rametteon treatment
occurred at ptosma levels of rametteon and M-H in excess of mean dtnical
plasma concentrations at the MRHD, the relevance of both rodent hepatic
tumors and benign rat Leydig cell tumors to humans is not known.
Mutagenesis
Ramelteon was not genotoxic in the following: in vitro bacterial reverse
mutation (Ames) assay; in vitro mammalian cell gene mutation assay
using the mouse lymphoma TK + /' ceH line; in vivo/in vitro unscheduled
DNA synthesis assay in rat hepatocytes; and in in wvo micronucleus
assays conducted in mouse and rat Ramelteon was positive in the
chromosomal aberration aisay in Chinese hamster lung cells in the
presence of S 9 metabolic activation.
Separate studies indicated that the concentration of the M-H metabolite
formed by the rat liver S 9 fraction used in the in vitro genetic toxicology
studies described above, exceeded the concentration of rametteon;
therefore, the genotoxic potential of the M-H metabolite was also
assessed in these studies.
Impairment of FertHity
Ramelteon was administered to male and female Sprague-Dawley rats
in an initial fertility and early embryonic development study at dose
levels of 6,60, or 600 mg/kg/day. No effects on male or female mating or
fertility were observed with a rametteon dose up to 600 mg/kg/day
(786-times higher than the MRHD on a mg/m* basis). Irregular estrus
cycles, reduction in the number of implants, and reduction in the number
of live embryos were noted with closing females at > 60 mg/kg/day
(79-times higher than the MRHD on a mg/m* basis). A reduction in the
number of corpora lutea occurred at the 600 mg/kg/day dose level.
Administration of rametteon up to 600 mg/kg/day to male rats for
7 weeks had no effect on sperm quality and when the treated male
rats were mated with untreated female rats there was no effect on
implants or embryos, hi a repeat of this study using oral administration
of ramelteon at 20.60 or 200 mg/kg/day for the same study duration,
females demonstrated irregular estrus cycles with doses 2 60 mg/kg/day,
but no effects were seen on implantation or embryo viaMity. The no-effect
dose tor fertility endpoints was 20 mg/kg/day m females (26-times the
MRHD on a mg/m* basis) and 600 mg/kg/day m males (786-times higher
than the MRHD on a mg/m* basis) when considenng all studies.
Pregnancy: Pregnancy Category C
Ramelteon has been shown to be a developmental teratogen in the rat
when given in doses 197 times higher than the maximum recommended
human dose [MRHD] on a mg/m* basis. There are no adequate and well
controlled studies in pregnant women. Rametteon should be used dunng
pregnancy only if the potential benefit justifies the potential risk to the fetus.
The effects of ramelteon on embryo-fetal development were assessed in
both the rat and rabbit. Pregnant rats were administered ramelteon by oral
gavage at doses of 0.10,40,150, or 600 mg/kg/day during gestation days
6 -17, which is the period of organogenesis in tins species. Evidence of
maternal toxicity and fetal teratogenicity was observed at doses greater
than or equal to 150 mg/kg/day. Maternal toxicity was chiefly charactenzed
by decreased body weight and. at 600 mg/kg/day. ataxia and decreased
spontaneais movement At matemalfy toxic doses 050 mg/kg/day or greater),
the fetuses demonstrated visceral malformations consisting of diaphragmatic
hernia and minor anatomical variations of the skeleton (irregularly
shaped scapula). At 600 mg/kg/day. reductions in fetal body weights and
malformations including cysts on the external genitalia were additionally
observed. The no-effect level for teratogenicity in this study was
40 mg/kg/day (1,892-times and 45-times higher than the therapeutic
exposure to ramelteon and the active metabolite M-11. respectively, at the
MRHD based on an area under the concentration-time curve [AUC]
comparison). Pregnant rabbits were administered ramelteon by oral
gavage at doses of 0,12.60, or 300 mg/kg/day during gestation days
6-18, which is the period of organogenesis in this species. Although
maternal toxicity was apparent with a ramelteon dose of 300 mg/kg/day,
no evidence of fetal effects or teratogenicity was associated with any
dose level. The no-effect level for teratogenicity was. therefore,
300 mg/kg/day (11,862-times and 99-times higher than the therapeutic
exposure to rametteon and M-H. respectively, at the MRHD based on AUC).
The effects of ramelteon on pre- and post-natal development in the rat
were studied by administration of rametteon to the pregnant rat by ora!
gavage at doses of 0,30,100, or 300 mg/kg/day from day 6 of gestation
through parturition to postnatal (lactation) day 21, at which time offspring
were weaned. Maternal toxicity was noted at doses of 100 mg/kg/day or
greater and consisted of reduced body weight gam and increased
adrenal gland weight. Reduced body weight dunng the post-weaning
period was also noticed m the offspnng of the groups given
100 mg/kg/day and higher. Offspnng in the 300 mg/kg/day group
demonstrated physical and developmental delays including delayed
eruption of the lower incisors, a delayed acquisition of the righting reflex,
and an alteration of emotional response. These delays are often observed
in the presence of reduced offspring body weight but may still be indcative
of developmental delay. An apparent decrease m the viability of offspnng
in the 300 mg/kg/day group was likely due to altered maternal behavior
and function observed at this dose level. Offspring of the 300 mg/kg/day
group also showed evidence of diaphragmatic hernia, a finding observed
in the embryo-fetal development study previously described. There were
no effects on the reproductive capacity of offspnng and the resulting
progeny were not different from those of vehide-treated offspnng. The
no-effect level for pre- and post-natal development in this study was
30 mg/kg/day (39-times higher than the MRHD on a mg/m* basis).
Labor and Delivery
The potential effects of ROZEROVI 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.
Nursaig Motors
Rametteon is secreted into the milk of lactatmg rats. It is not known
whether this drug is excreted in human No clinical studies in nursmg
mothers have been performeo. The use of ROZEREM in nursmg mothers
is not recommended
Pediatric Use
Safety and effectiveness of ROZEREM m pedatnc patients have not been
established. Further study is needed prior to determining that ttvs product may
be used safety n pre-pubescent art pubescent patent