RAMELTEON- ramelteon tablet, film coated
i3 Pharmaceuticals, LLC
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)].
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 8 mg tablets are round, yellow, film coated debossed with “I3” on one side and “5” on the other side.
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 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
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.
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 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
Ramelteon 8 mg
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