Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING Ramelteon Tablets are available as round, yellow, film coated tablets debossed with "I3" on one side and "5" on the other side in the following quantities: NDC 72319-005-01 Bottles of 30 NDC 72319-005-04 Bottles of 100 NDC 72319-005-05 Bottles of 500 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.; PRINCIPAL DISPLAY PANELS - 8 mg Bottle Labels NDC 72319-005-01 30 Tablets Ramelteon Tablets 8 mg Each film-coated tablet contains 8 mg of ramelteon. Dispense the accompanying Medication Guide to each patient. i3 Pharmaceuticals, LLC Rx Only NDC 72319-005-04 100 Tablets Ramelteon Tablets 8 mg Each film-coated tablet contains 8 mg of ramelteon. Dispense the Medication Guide provided separately to each patient. i3 Pharmaceuticals, LLC Rx Only NDC 72319-005-05 500 Tablets Ramelteon Tablets 8 mg Each film-coated tablet contains 8 mg of ramelteon. Dispense the Medication Guide provided separately to each patient. i3 Pharmaceuticals, LLC Rx Only image description image description image description
- 16 HOW SUPPLIED/STORAGE AND HANDLING Ramelteon Tablets are available as round, yellow, film coated tablets debossed with "I3" on one side and "5" on the other side in the following quantities: NDC 72319-005-01 Bottles of 30 NDC 72319-005-04 Bottles of 100 NDC 72319-005-05 Bottles of 500 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.
- PRINCIPAL DISPLAY PANELS - 8 mg Bottle Labels NDC 72319-005-01 30 Tablets Ramelteon Tablets 8 mg Each film-coated tablet contains 8 mg of ramelteon. Dispense the accompanying Medication Guide to each patient. i3 Pharmaceuticals, LLC Rx Only NDC 72319-005-04 100 Tablets Ramelteon Tablets 8 mg Each film-coated tablet contains 8 mg of ramelteon. Dispense the Medication Guide provided separately to each patient. i3 Pharmaceuticals, LLC Rx Only NDC 72319-005-05 500 Tablets Ramelteon Tablets 8 mg Each film-coated tablet contains 8 mg of ramelteon. Dispense the Medication Guide provided separately to each patient. i3 Pharmaceuticals, LLC Rx Only image description image description image description
Overview
Ramelteon Tablets are an orally active hypnotic chemically designated as ( S )- N -[2-(1,6,7,8-tetrahydro-2 H -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 16 H 21 NO 2 , 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 Ramelteon Tablet includes the following inactive ingredients: lactose monohydrate, pregelatinized starch, hydroxypropyl cellulose, crospovidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc and iron oxide yellow. image description
Indications & 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 week studies (adults and elderly), and at the end of the six month study (adults and elderly) [see Clinical Studies (14) ]. Ramelteon Tablets are indicated for the treatment of insomnia characterized by difficulty with sleep onset.
Dosage & 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 ) 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) ] . 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) ] .
Warnings & 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 ) 5.1 Severe Anaphylactic and Anaphylactoid Reactions Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of Ramelteon Tablets. 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 Tablets 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 Tablets 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 Tablets. 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 Tablets may have additive effects when used in conjunction. 5.5 Reproductive Effects Ramelteon Tablets have 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 Tablets may have on the reproductive axis in developing humans [see Clinical Trials (14.3) ]. 5.6 Use in Patients with Concomitant Illness Ramelteon Tablets have 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 Tablets 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 Tablets are 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 . 5.1 Severe Anaphylactic and Anaphylactoid Reactions Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of Ramelteon Tablets. 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 Tablets 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 Tablets 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 Tablets. 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 Tablets may have additive effects when used in conjunction. 5.5 Reproductive Effects Ramelteon Tablets have 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 Tablets may have on the reproductive axis in developing humans [see Clinical Trials (14.3) ]. 5.6 Use in Patients with Concomitant Illness Ramelteon Tablets have 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 Tablets should not be used by patients with severe hepatic impairment [see Clinical Pharmacology (12.4) ] .
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) ]. History of angioedema while taking Ramelteon Tablets. ( 4 ) Fluvoxamine (strong CYP1A2 inhibitor): Increases AUC for ramelteon and should not be used in combination. ( 7.1 )
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) ] 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 i3 Pharmaceuticals, LLC at 1-844-874-7353 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Adverse Reactions Resulting in Discontinuation of Treatment The data described in this section reflect exposure to Ramelteon Tablets in 5373 subjects, including 722 exposed for six months or longer, and 448 subjects for one year. Six percent of the 5373 individual subjects exposed to Ramelteon Tablets 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 Ramelteon Tablets were somnolence, dizziness, nausea, fatigue, headache, and insomnia; all of which occurred in 1% of the patients or less. Ramelteon Tablets 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 Ramelteon Tablets. 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=1456) Ramelteon 8 mg (n=1405) Somnolence 2% 3% Fatigue 2% 3% Dizziness 3% 4% Nausea 2% 3% Insomnia exacerbated 2% 3% 6.1 Clinical Trials Experience Adverse Reactions Resulting in Discontinuation of Treatment The data described in this section reflect exposure to Ramelteon Tablets in 5373 subjects, including 722 exposed for six months or longer, and 448 subjects for one year. Six percent of the 5373 individual subjects exposed to Ramelteon Tablets 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 Ramelteon Tablets were somnolence, dizziness, nausea, fatigue, headache, and insomnia; all of which occurred in 1% of the patients or less. Ramelteon Tablets 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 Ramelteon Tablets. 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=1456) Ramelteon 8 mg (n=1405) Somnolence 2% 3% Fatigue 2% 3% Dizziness 3% 4% Nausea 2% 3% Insomnia exacerbated 2% 3%
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 ) 7.1 Effects of Other Drugs on Ramelteon Tablets Fluvoxamine (strong CYP1A2 inhibitor) AUC 0-inf for ramelteon increased approximately 190-fold, and the C max increased approximately 70-fold upon coadministration of fluvoxamine and Ramelteon Tablets, compared to Ramelteon Tablets administered alone. Ramelteon Tablets 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 Tablets 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 Tablets are used in combination with strong CYP enzyme inducers such as rifampin [see Clinical Pharmacology (12.5) ]. Ketoconazole (strong CYP3A4 inhibitor) The AUC 0-inf and C max of ramelteon increased by approximately 84% and 36% upon coadministration of ketoconazole with Ramelteon Tablets. Ramelteon Tablets 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 0-inf and C max of ramelteon was increased by approximately 150% when Ramelteon Tablets were coadministered with fluconazole. Ramelteon Tablets should be administered with caution in subjects taking strong CYP2C9 inhibitors such as fluconazole [see Clinical Pharmacology (12.5) ]. Donepezil The AUC 0-inf and C max of ramelteon increased by approximately 100% and 87%, respectively upon coadministration of donepezil with Ramelteon Tablets. Patients should be closely monitored when Ramelteon Tablets are coadministered with donepezil [see Clinical Pharmacology (12.5) ]. Doxepin The AUC 0-inf and C max of ramelteon increased by approximately 66% and 69%, respectively, upon coadministration of doxepin with Ramelteon Tablets. Patients should be closely monitored when Ramelteon Tablets are coadministered with doxepin [see Clinical Pharmacology (12.5) ]. 7.2 Effect of Alcohol on Ramelteon Tablets Alcohol by itself impairs performance and can cause sleepiness. Since the intended effect of Ramelteon Tablets is to promote sleep, patients should be cautioned not to consume alcohol when using Ramelteon Tablets [see Clinical Pharmacology (12.5) ] . Use of the products in combination may have an additive effect. 7.3 Drug/Laboratory Test Interactions Ramelteon Tablets are 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. 7.1 Effects of Other Drugs on Ramelteon Tablets Fluvoxamine (strong CYP1A2 inhibitor) AUC 0-inf for ramelteon increased approximately 190-fold, and the C max increased approximately 70-fold upon coadministration of fluvoxamine and Ramelteon Tablets, compared to Ramelteon Tablets administered alone. Ramelteon Tablets 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 Tablets 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 Tablets are used in combination with strong CYP enzyme inducers such as rifampin [see Clinical Pharmacology (12.5) ]. Ketoconazole (strong CYP3A4 inhibitor) The AUC 0-inf and C max of ramelteon increased by approximately 84% and 36% upon coadministration of ketoconazole with Ramelteon Tablets. Ramelteon Tablets 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 0-inf and C max of ramelteon was increased by approximately 150% when Ramelteon Tablets were coadministered with fluconazole. Ramelteon Tablets should be administered with caution in subjects taking strong CYP2C9 inhibitors such as fluconazole [see Clinical Pharmacology (12.5) ]. Donepezil The AUC 0-inf and C max of ramelteon increased by approximately 100% and 87%, respectively upon coadministration of donepezil with Ramelteon Tablets. Patients should be closely monitored when Ramelteon Tablets are coadministered with donepezil [see Clinical Pharmacology (12.5) ]. Doxepin The AUC 0-inf and C max of ramelteon increased by approximately 66% and 69%, respectively, upon coadministration of doxepin with Ramelteon Tablets. Patients should be closely monitored when Ramelteon Tablets are coadministered with doxepin [see Clinical Pharmacology (12.5) ]. 7.2 Effect of Alcohol on Ramelteon Tablets Alcohol by itself impairs performance and can cause sleepiness. Since the intended effect of Ramelteon Tablets is to promote sleep, patients should be cautioned not to consume alcohol when using Ramelteon Tablets [see Clinical Pharmacology (12.5) ] . Use of the products in combination may have an additive effect. 7.3 Drug/Laboratory Test Interactions Ramelteon Tablets are 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.
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