✅ Uses & Indications
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 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. ( 1 )
📏 Dosage & Administration
2 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 ) 2.1 Dosage in Adults The recommended dose of ramelteon tablets are 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) ].
💊 Side Effects
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) ] 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 Aurobindo Pharma USA, Inc. at 1-866-850-2876 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 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 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 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 2861 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=1456) Ramelteon 8 mg (n=1405) Somnolence 2% 3% Fatigue 2% 3% Dizziness 3% 4% Nausea 2% 3% Insomnia exacerbated 2% 3%
⚠️ Warnings & Precautions
5 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 is 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. 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 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. Discontinuation of ramelteon 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, patients should confine their activities to those necessary to prepare for bed. Patients should be advised not to consume alcohol in combination with ramelteon 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 .
🔄 Drug Interactions
7 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 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, 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 0-inf and C max 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 0-inf and C max 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 0-inf and C max 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 0-inf and C max 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 .
🚫 Contraindications
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 )
📦 Storage & Handling
16 HOW SUPPLIED/STORAGE AND HANDLING Ramelteon Tablets 8 mg are available as pale yellow colored, round, biconvex film-coated tablets, debossed with “RT” on one side and “8” on the other side. They are supplied as follows: Bottles of 30 NDC 59651-505-30 Bottles of 100 NDC 59651-505-01 Store at 20° to 25°C (68° to 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.