RAMELTEON tablet, film coated

United States - English - NLM (National Library of Medicine)

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Active ingredient:
Ramelteon (UNII: 901AS54I69) (Ramelteon - UNII:901AS54I69)
Available from:
Upsher-Smith Laboratories, LLC
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Ramelteon tablets are indicated for the treatment of insomnia characterized by difficulty with sleep onset. The clinical trials performed in support of efficacy were up to six months in duration. The final formal assessments of sleep latency were performed after two days of treatment during the crossover study (elderly only), at five weeks in the six-month studies (adults and elderly), and at the end of the six-month study (adults and elderly) [see Clinical Studies (14)] . Patients who develop angioedema after treatment with ramelteon tablets should not be rechallenged with the drug. Patients should not take ramelteon tablets in conjunction with fluvoxamine [see Drug Interactions (7)] . Risk Summary Available data from postmarketing reports with ramelteon use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, ramelteon produced evidence of developmental toxicity, including teratogenic effects, in rats at
Product summary:
Ramelteon tablets are available as yellow, round shaped film coated tablets, debossed with "AC 414" on one side and plain on other side, in the following quantities: Store 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.
Authorization status:
Abbreviated New Drug Application
Authorization number:
0832-1250-11, 0832-1250-30

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MEDICATION GUIDE

Ramelteon (ra-mel-tee-on) Tablets

Read the Medication Guide that comes with ramelteon tablets before you start taking it and each time you

get a refill. There may be new information. This Medication Guide does not take the place of talking to

your doctor about your medical condition or treatment.

What is the most important information I should know about ramelteon tablets?

Ramelteon tablets may cause severe allergic reactions. Symptoms include swelling of the tongue or

throat, trouble breathing, and nausea and vomiting. Get emergency medical help if you get these

symptoms after taking ramelteon tablets.

After taking ramelteon tablets, you may get up out of bed while not being fully awake and do an activity

that you do not know you are doing. The next morning, you may not remember that you did anything

during the night. You have a higher chance for doing these activities if you drink alcohol or take other

medicines that make you sleepy with ramelteon tablets. Activities may include:

driving a car ("sleep-driving")

making and eating food

talking on the phone

having sex

sleep-walking

Call your doctor right away if you find out that you have done any of the above activities after taking

ramelteon tablets.

Important:

Take ramelteon tablets exactly as prescribed

Do not take more ramelteon tablets than prescribed.

Take ramelteon tablets within 30 minutes of going to bed, not sooner.

Do not take ramelteon tablets if you:

drink alcohol

take other medicines that can make you sleepy. Talk to your doctor about all of your

medicines. Your doctor will tell you if you can take ramelteon tablets with your other

medicines

cannot get a full night's sleep

What are ramelteon tablets?

Ramelteon tablets are a hypnotic (sleep) medicine. Ramelteon tablets are used in adults for the treatment

of the symptom of trouble falling asleep from insomnia.

Ramelteon tablets are not for children.

Who should not take ramelteon tablets?

Do not take ramelteon tablets if you are allergic to anything in it. See the end of this Medication Guide for

a complete list of ingredients in ramelteon tablets.

Do not take ramelteon tablets if you are currently taking Luvox (fluvoxamine).

Ramelteon tablets may not be right for you. Before starting ramelteon tablets, tell your doctor about all of

your health conditions, including if you:

have a history of depression, mental illness, or suicidal thoughts

have liver disease

have a lung disease or breathing problems

are pregnant, or planning to become pregnant

are breastfeeding or plan to breastfeed. Ramelteon tablets may cause somnolence in a breastfed

infant. You may consider interrupting breastfeeding and pumping and discarding breastmilk

during treatment and for 25 hours after administration of ramelteon tablets.

Tell your doctor about all of the medicines you take including prescription and nonprescription

medicines, vitamins and herbal supplements. Medicines can interact with each other, sometimes causing

serious side effects.

Do not take ramelteon tablets with:

other medicines that can make you sleepy

Luvox (fluvoxamine)

Know the medicines you take. Keep a list of your medicines with you to show your doctor and pharmacist

each time you get a new medicine.

How should I take ramelteon tablets?

Take ramelteon tablets exactly as prescribed. Do not take more ramelteon tablets than prescribed

for you.

Do not break the tablets. They should be swallowed whole.

Take ramelteon tablets within 30 minutes of going to bed. After taking ramelteon tablets only do

activities to get ready for bed.

Do not take ramelteon tablets with or right after a meal.

Do not take ramelteon tablets unless you are able to get a full night's sleep before you must be

active again.

Call your doctor if your insomnia worsens or is not better within 7 to 10 days. This may mean that

there is another condition causing your sleep problems.

If you take too much ramelteon tablets or overdose, call your doctor or poison control center right

away, or get emergency treatment.

What are the possible side effects of ramelteon tablets?

Possible serious side effects of ramelteon tablets include:

severe allergic reactions. Symptoms include swelling of the tongue or throat, trouble breathing,

and nausea and vomiting. Get emergency medical help if you get these symptoms after taking

ramelteon tablets.

getting out of bed while not being fully awake and do an activity that you do not know you are

doing. (See "What is the most important information I should know about ramelteon tablets?")

abnormal thoughts and behavior. Symptoms include worsening of depression, suicidal thoughts or

actions, nightmares, and hallucinations.

hormone effects. Ramelteon tablets can decrease testosterone levels and increase prolactin levels

in the blood. Symptoms of low testosterone or high prolactin levels are:

decreased interest in sex

problems getting pregnant

irregular menstrual periods or no menstrual periods

leakage of milk from the nipples of a person who is not breastfeeding

Call your doctor right away if you have any of the above side effects or any other side effects that worry

you while using ramelteon tablets. Call your doctor for medical advice about side effects. You may report

side effects to the FDA at 1-800-FDA-1088.

The most common side effects of ramelteon tablets are:

drowsiness

tiredness

dizziness

You may still feel drowsy the next day after taking ramelteon tablets. Do not drive or do other

dangerous activities after taking ramelteon tablets until you feel fully awake.

These are not all the side effects of ramelteon tablets. Ask your doctor or pharmacist for more

information.

How should I store ramelteon tablets?

Store ramelteon tablets at room temperature, 59˚ to 86˚ F (15˚ to 30˚C). Keep the container tightly

closed and protected from moisture and humidity.

Keep ramelteon tablets and all medicines out of reach of children.

General Information about ramelteon tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.

Do not use ramelteon tablets for a condition for which it was not prescribed.

Do not share ramelteon tablets with other people, even if you think they have the same symptoms

that you have. It may harm them.

This Medication Guide summarizes the most important information about ramelteon tablets. If you would

like more information, talk with your doctor. You can ask your doctor or pharmacist for information

about ramelteon tablets that is written for healthcare professionals. For more information about ramelteon

tablets, please call Upsher-Smith Laboratories, LLC at 1-855-899-9180 or go to www.upsher-smith.com

What are the ingredients in ramelteon tablets?

Active Ingredient: ramelteon

Inactive Ingredients: hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate,

polyethylene glycol, povidone, pregelatinized starch, titanium dioxide and yellow iron oxide.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

For Medication Guides, please visit www.upsher-smith.com or call 1-888-650-3789.

Distributed by

UPSHER-SMITH LABORATORIES, LLC

Maple Grove, MN 55369

All trademarks are property of their respective owners.

200371

Revised: 10/2020

Revised: 11/2020

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Version: 1

Effective Time: 20201112

Upsher-Smith Laboratories, LLC

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RAMELTEON- ramelteon tablet, film coated

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use RAMELTEON TABLETS safely and

effectively. See full prescribing information for RAMELTEON TABLETS.

RAMELTEON tablets, for oral use

Initial U.S. Approval: 2005

INDICATIONS AND USAGE

Ramelteon tablets are indicated for the treatment of insomnia characterized by difficulty with sleep onset. (1)

DOSAGE AND ADMINISTRATION

Adult dose: 8 mg taken within 30 minutes of going to bed. (2.1)

Should not be taken with or immediately after a high-fat meal. (2.1)

Total daily dose should not exceed 8 mg. (2.1)

DOSAGE FORMS AND STRENGTHS

8 mg tablets. (3)

CONTRAINDICATIONS

History of angioedema while taking ramelteon. (4)

Fluvoxamine (strong CYP1A2 inhibitor): Increases AUC for ramelteon and should not be used in combination. (7.1)

WARNINGS AND PRECAUTIONS

Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis have been reported. Do not rechallenge if

such reactions occur. (5.1)

Need to evaluate for comorbid diagnoses: Reevaluate if insomnia persists after 7 to 10 days of treatment. (5.2)

Abnormal thinking, behavioral changes, complex behaviors: May include "sleep-driving" and hallucinations.

Immediately evaluate any new onset behavioral changes. (5.3)

Depression: Worsening of depression or suicidal thinking may occur. (5.3)

CNS effects: Potential impairment of activities requiring complete mental alertness such as operating machinery or

driving a motor vehicle, after ingesting the drug. (5.4)

Reproductive effects: Include decreased testosterone and increased prolactin levels. Effect on reproductive axis in

developing humans is unknown. (5.5)

Patients with severe sleep apnea: Ramelteon tablets are not recommended for use in this population. (5.6)

ADVERSE REACTIONS

Most common adverse reactions (≥3% and more common than with placebo) are: somnolence, dizziness, fatigue, nausea,

and exacerbated insomnia. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Upsher-Smith Laboratories, LLC at 1-855-899-9180 or

FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Rifampin (strong CYP enzyme inducer): Decreases exposure to and effects of ramelteon. (7.1)

Ketoconazole (strong CYP3A4 inhibitor): Increases AUC for ramelteon; administer with caution. (7.1)

Fluconazole (strong CYP2C9 inhibitor): Increases systemic exposure of ramelteon; administer with caution. (7.1)

Donepezil: Increases systemic exposure of ramelteon; patients should be closely monitored when ramelteon is

coadministered with donepezil. (7.1)

Doxepin: Increases systemic exposure of ramelteon; patients should be closely monitored when ramelteon is

coadministered with doxepin. (7.1)

Alcohol: Causes additive psychomotor impairment; should not be used in combination. (7.2)

USE IN SPECIFIC POPULATIONS

Pediatric use: Safety and effectiveness not established. (8.4)

Geriatric use: No overall differences in safety and efficacy between elderly and younger adult subjects. (8.5)

Hepatic impairment: Is not recommended in patients with severe impairment; use with caution in moderate

impairment. (8.8)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 10/2020

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Dosage in Adults

2.2 Dosing in Patients with Hepatic Impairment

2.3 Administration with Other Medications

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Severe Anaphylactic and Anaphylactoid Reactions

5.2 Need to Evaluate for Comorbid Diagnoses

5.3 Abnormal Thinking and Behavioral Changes

5.4 CNS Effects

5.5 Reproductive Effects

5.6 Use in Patients with Concomitant Illness

5.7 Laboratory Tests

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

7 DRUG INTERACTIONS

7.1 Effects of Other Drugs on Ramelteon

7.2 Effect of Alcohol on Ramelteon

7.3 Drug/Laboratory Test Interactions

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Chronic Obstructive Pulmonary Disease

8.7 Sleep Apnea

8.8 Hepatic Impairment

8.9 Renal Impairment

9 DRUG ABUSE AND DEPENDENCE

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

12.4 Pharmacokinetics in Special Populations

12.5 Drug-Drug Interactions

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Controlled Clinical Trials

14.2 Studies Pertinent to Safety Concerns for Sleep-Promoting Drugs

14.3 Studies to Evaluate Effects on Endocrine Function

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Ramelteon tablets are indicated for the treatment of insomnia characterized by difficulty with sleep

onset.

The clinical trials performed in support of efficacy were up to six months in duration. The final formal

assessments of sleep latency were performed after two days of treatment during the crossover study

(elderly only), at five weeks in the six-month studies (adults and elderly), and at the end of the six-month

study (adults and elderly) [see Clinical Studies (14)].

2 DOSAGE AND ADMINISTRATION

2.1 Dosage in Adults

The recommended dose of ramelteon tablets is 8 mg taken within 30 minutes of going to bed. It is

recommended that ramelteon tablets not be taken with or immediately after a high-fat meal.

The total ramelteon tablets dose should not exceed 8 mg per day.

2.2 Dosing in Patients with Hepatic Impairment

Ramelteon tablets are not recommended in patients with severe hepatic impairment. Ramelteon tablets

should be used with caution in patients with moderate hepatic impairment [see Warnings and Precautions

(5.6), Clinical Pharmacology (12.4)].

2.3 Administration with Other Medications

Ramelteon tablets should not be used in combination with fluvoxamine. Ramelteon tablets should be

used with caution in patients taking other CYP1A2 inhibiting drugs [see Drug Interactions (7), Clinical

Pharmacology (12.5)].

3 DOSAGE FORMS AND STRENGTHS

Ramelteon tablets are available in an 8 mg strength tablet for oral administration.

Ramelteon tablets 8 mg are yellow, round shaped film-coated tablets, debossed with "AC 414" on one

side and plain on other side.

4 CONTRAINDICATIONS

Patients who develop angioedema after treatment with ramelteon tablets should not be rechallenged with

the drug.

Patients should not take ramelteon tablets in conjunction with fluvoxamine [see Drug Interactions (7)].

5 WARNINGS AND PRECAUTIONS

5.1 Severe Anaphylactic and Anaphylactoid Reactions

Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after

Sections or subsections omitted from the full prescribing information are not listed.

taking the first or subsequent doses of ramelteon. Some patients have had additional symptoms such as

dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required

medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx,

airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with

ramelteon tablets should not be rechallenged with the drug.

5.2 Need to Evaluate for Comorbid Diagnoses

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 7 to 10 days 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. Exacerbation of insomnia and

emergence of cognitive and behavioral abnormalities were seen with ramelteon during the clinical

development program.

5.3 Abnormal Thinking and Behavioral Changes

A variety of cognitive and behavior changes have been reported to occur in association with the use of

hypnotics. In primarily depressed patients, worsening of depression (including suicidal ideation and

completed suicides) has been reported in association with the use of hypnotics.

Hallucinations, as well as behavioral changes such as bizarre behavior, agitation and mania have been

reported with ramelteon use. Amnesia, anxiety and other neuro-psychiatric symptoms may also occur

unpredictably.

Complex behaviors such as "sleep-driving" (i.e., driving while not fully awake after ingestion of a

hypnotic) and other complex behaviors (e.g., preparing and eating food, making phone calls, or having

sex), with amnesia for the event, have been reported in association with hypnotic use. The use of

alcohol and other CNS depressants may increase the risk of such behaviors. These events can occur in

hypnotic-naive as well as in hypnotic-experienced persons. Complex behaviors have been reported with

the use of ramelteon tablets. Discontinuation of ramelteon tablets should be strongly considered for

patients who report any complex sleep behavior.

5.4 CNS Effects

Patients should avoid engaging in hazardous activities that require concentration (such as operating a

motor vehicle or heavy machinery) after taking ramelteon.

After taking ramelteon tablets, patients should confine their activities to those necessary to prepare for

bed.

Patients should be advised not to consume alcohol in combination with ramelteon tablets as alcohol and

ramelteon may have additive effects when used in conjunction.

5.5 Reproductive Effects

Ramelteon has been associated with an effect on reproductive hormones in adults, e.g., decreased

testosterone levels and increased prolactin levels. It is not known what effect chronic or even chronic

intermittent use of ramelteon may have on the reproductive axis in developing humans [see Clinical Trials

(14.3)].

5.6 Use in Patients with Concomitant Illness

Ramelteon has not been studied in subjects with severe sleep apnea and is not recommended for use in

this population [see Use in Specific Populations (8.7)].

Ramelteon should not be used by patients with severe hepatic impairment [see Clinical Pharmacology

(12.4)].

5.7 Laboratory Tests

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

Ramelteon is not known to interfere with commonly used clinical laboratory tests. In addition, in vitro

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 in

vitro.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections:

Severe anaphylactic and anaphylactoid reactions [see Warnings and Precautions (5.1)]

Abnormal thinking, behavior changes, and complex behaviors [see Warnings and Precautions (5.3)]

CNS effects [see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience

Adverse Reactions Resulting in Discontinuation of Treatment

The data described in this section reflects exposure to ramelteon in 5,373 subjects, including 722

exposed for six months or longer, and 448 subjects for one year.

Six percent of the 5,373 individual subjects exposed to ramelteon in clinical studies discontinued

treatment owing to an adverse event, compared with 2% of the 2,279 subjects receiving placebo. The

most frequent adverse events leading to discontinuation in subjects receiving ramelteon tablets were

somnolence, dizziness, nausea, fatigue, headache, and insomnia; all of which occurred in 1% of the

patients or less.

Ramelteon Most Commonly Observed Adverse Events

Table 1 displays the incidence of adverse events reported by the 2,861 patients with chronic insomnia

who participated in placebo-controlled trials of ramelteon.

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.

Table 1. Incidence (% of subjects) of Treatment-Emergent Adverse Events

MedDRA Preferred Term

Placebo (n=1,456)

Ramelteon 8 mg (n=1,405)

Somnolence

Fatigue

Dizziness

Nausea

Insomnia exacerbated

7 DRUG INTERACTIONS

7.1 Effects of Other Drugs on Ramelteon

Fluvoxamine (strong CYP1A2 inhibitor)

for ramelteon increased approximately 190-fold, and the C

increased approximately 70-

fold upon coadministration of fluvoxamine and ramelteon, compared to ramelteon administered alone.

Ramelteon should not be used in combination with fluvoxamine [see Contraindications (4), Clinical

Pharmacology (12.5)]. Other less strong CYP1A2 inhibitors have not been adequately studied.

Ramelteon should be administered with caution to patients taking less strong CYP1A2 inhibitors.

Rifampin (strong CYP enzyme inducer)

Administration of multiple doses of rifampin resulted in a mean decrease of approximately 80% in total

exposure to ramelteon and metabolite M-II. Efficacy may be reduced when ramelteon is used in

combination with strong CYP enzyme inducers such as rifampin [see Clinical Pharmacology (12.5)].

Ketoconazole (strong CYP3A4 inhibitor)

The AUC

and C

of ramelteon increased by approximately 84% and 36% upon coadministration

of ketoconazole with ramelteon. Ramelteon should be administered with caution in subjects taking

strong CYP3A4 inhibitors such as ketoconazole [see Clinical Pharmacology (12.5)].

Fluconazole (strong CYP2C9 inhibitor)

The AUC

and C

of ramelteon was increased by approximately 150% when ramelteon was

coadministered with fluconazole. Ramelteon should be administered with caution in subjects taking

strong CYP2C9 inhibitors such as fluconazole [see Clinical Pharmacology (12.5)].

Donepezil

The AUC

and C

of ramelteon increased by approximately 100% and 87%, respectively upon

coadministration of donepezil with ramelteon. Patients should be closely monitored when ramelteon is

coadministered with donepezil [see Clinical Pharmacology (12.5)].

Doxepin

The AUC

and C

of ramelteon increased by approximately 66% and 69%, respectively, upon

coadministration of doxepin with ramelteon. Patients should be closely monitored when ramelteon is

coadministered with doxepin [see Clinical Pharmacology (12.5)].

7.2 Effect of Alcohol on Ramelteon

Alcohol by itself impairs performance and can cause sleepiness. Since the intended effect of ramelteon

is to promote sleep, patients should be cautioned not to consume alcohol when using ramelteon [see

Clinical Pharmacology (12.5)]. Use of the products in combination may have an additive effect.

7.3 Drug/Laboratory Test Interactions

Ramelteon is not known to interfere with commonly used clinical laboratory tests. In addition, in vitro

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 in

vitro.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available data from postmarketing reports with ramelteon use in pregnant women have not identified a

0-inf

0-inf

0-inf

0-inf

0-inf

drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In

animal studies, ramelteon produced evidence of developmental toxicity, including teratogenic effects, in

rats at doses greater than 36 times the recommended human dose (RHD) of 8 mg/day based on body

surface area (mg/m ) (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is

unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In

the U.S. general population, the estimated background risk of major birth defects and miscarriage in

clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

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 based on mg/m . 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 based on mg/m ).

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 based on mg/m .

Increased incidences of malformation and death among offspring were seen at the highest dose.

8.2 Lactation

Risk Summary

There are no data regarding the presence of ramelteon or its metabolites in human milk, the effects on

the breastfed infant, or the effects on milk production. Ramelteon and/or its metabolites are present in rat

milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk.

Because of the mechanism of action of ramelteon, there is a potential risk for somnolence in a breastfed

infant (see Clinical Considerations). The developmental and health benefits of breastfeeding should be

considered along with the mother's clinical need for ramelteon and any potential adverse effects on the

breastfed infant from ramelteon tablets or from the underlying maternal condition.

Clinical Considerations

Infants exposed to ramelteon through breastmilk should be monitored for somnolence and feeding

problems. A lactating woman may consider interrupting breastfeeding and pumping and discarding breast

milk during treatment and for 25 hours (approximately 5 elimination half-lives) after ramelteon tablets

administration in order to minimize drug exposure to a breastfed infant.

8.4 Pediatric Use

Safety and effectiveness of ramelteon in pediatric patients have not been established. Further study is

needed prior to determining that this product may be used safely in prepubescent and pubescent patients.

8.5 Geriatric Use

A total of 654 subjects in double-blind, placebo-controlled, efficacy trials who received ramelteon

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 ramelteon 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 ramelteon tablets 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.

8.6 Chronic Obstructive Pulmonary Disease

The respiratory depressant effect of ramelteon 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 ramelteon 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 <70%, and a FEV <80% of predicted with <12% reversibility to albuterol. Treatment with a single

dose of ramelteon 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 ramelteon in patients with COPD. The respiratory depressant

effects in patients with COPD cannot be definitively known from this study.

8.7 Sleep Apnea

The effects of ramelteon 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 ramelteon

tablets 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 ramelteon does not exacerbate mild to

moderate obstructive sleep apnea. There is no available information on the respiratory effects of

multiple doses of ramelteon in patients with sleep apnea. The effects on exacerbation in patients with

mild to moderate sleep apnea cannot be definitively known from this study.

Ramelteon has not been studied in subjects with severe obstructive sleep apnea; use of ramelteon is not

recommended in such patients.

8.8 Hepatic Impairment

Exposure to ramelteon was increased by four-fold in subjects with mild hepatic impairment and by more

than ten-fold in subjects with moderate hepatic impairment. Ramelteon should be used with caution in

patients with moderate hepatic impairment [see Clinical Pharmacology (12.4)].

Ramelteon is not recommended in patients with severe hepatic impairment.

8.9 Renal Impairment

No effects on C

and AUC

of parent drug or M-II were seen. No adjustment of ramelteon tablets

dosage is required in patients with renal impairment [see Clinical Pharmacology (12.4)].

9 DRUG ABUSE AND DEPENDENCE

Ramelteon tablets are not a controlled substance.

Discontinuation of ramelteon in animals or in humans after chronic administration did not produce

withdrawal signs. Ramelteon does not appear to produce physical dependence.

Human Data

A laboratory abuse potential study was performed with ramelteon [see Clinical Studies (14.2)].

Animal Data

Ramelteon did not produce any signals from animal behavioral studies indicating that the drug produces

rewarding effects. Monkeys did not self-administer ramelteon and the drug did not induce a conditioned

place preference in rats. There was no generalization between ramelteon and midazolam. Ramelteon did

not affect rotorod performance, an indicator of disruption of motor function, and it did not potentiate the

ability of diazepam to interfere with rotorod performance.

10 OVERDOSAGE

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 ramelteon. Therefore, the use of dialysis in the

treatment of overdosage is not appropriate.

Poison Control Center

As with the management of all overdosage, the possibility of multiple drug ingestion should be

considered. Contact a poison control center for current information on the management of overdosage.

11 DESCRIPTION

Ramelteon is an orally active hypnotic chemically designated as (S)-N-[2-(1,6,7,8- tetrahydro-2H-

indeno-[5,4-b]furan-8-yl)ethyl]propionamide and containing one chiral center. The compound is

produced as the (S)-enantiomer, with an empirical formula of C

H NO , molecular weight of 259.34,

and the following chemical structure:

Ramelteon is freely soluble in methanol and practically insoluble in water.

Each ramelteon tablet contains the following inactive ingredients: hydroxypropyl cellulose,

hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, povidone, pregelatinized

starch, titanium dioxide and yellow iron oxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT and MT receptors

and relative selectivity over the MT receptor.

The activity of ramelteon at the MT and MT 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 major metabolite of ramelteon, M-II, is pharmacologically active and has approximately one tenth

and one fifth the binding affinity of the parent molecule for the human MT and MT receptors,

respectively. However, M-II circulates at higher concentrations than the parent producing 20- to 100-

fold greater mean systemic exposure when compared to ramelteon. 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.

12.3 Pharmacokinetics

The pharmacokinetic profile of ramelteon 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 protein binding of ramelteon is approximately 82% in human serum, independent of

concentration. Binding to albumin accounts for most of that binding, since 70% of the drug is bound in

human serum albumin. Ramelteon is not distributed selectively to red blood cells.

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 postdose.

Repeated once daily dosing with ramelteon does not result in significant accumulation owing to the

short elimination half-life of ramelteon (on average, approximately one to 2.6 hours).

The half-life of M-II is two to five 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 ramelteon 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 ramelteon was administered with food. Effects of food on the AUC

values for M-II were similar. It is therefore recommended that ramelteon not be taken with or

0-inf

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