FDA approved a REMS for ramelteon to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page ([Web]) or the ASHP REMS Resource Center ([Web]).
Management of insomnia characterized by difficulty with sleep onset.
Decreases sleep latency in patients with transient insomnia. Decreases sleep latency in patients with chronic insomnia receiving therapy for up to 35 days.
Dosage and Administration
Administration
Oral Administration
Administer orally within 30 minutes of bedtime.
Avoid administration with or immediately after a high-fat meal because of potentially decreased rate of absorption. (See Food under Pharmacokinetics.)
Dosage
Adults
Insomnia
Oral
8 mg.
Special Populations
Hepatic Impairment
Increased exposure to drug and active metabolite. (See Special Populations under Pharmacokinetics.) No specific dosage recommendations at this time. However, use with caution in patients with moderate hepatic impairment; avoid use in patients with severe hepatic impairment.
Renal Impairment
No dosage adjustment necessary in patients with mild, moderate, or severe renal impairment or in those requiring chronic hemodialysis.
Failure of insomnia to remit after a reasonable treatment period, exacerbation of insomnia, and/or emergence of new cognitive or behavioral abnormalities may indicate the presence of an underlying psychiatric or physical disorder requiring further patient evaluation.
Complex Sleep-related Behaviors
Potential risk of complex sleep-related behaviors such as sleep-driving (i.e., driving while not fully awake after ingesting a sedative-hypnotic drug, with no memory of the event), making phone calls, or preparing and eating food while asleep.
Sensitivity Reactions
Potential risk of anaphylaxis and angioedema; may occur as early as with the first dose of drug.
Major Toxicities
Psychiatric Effects
Cognitive and behavioral changes reported. In primarily depressed patients, exacerbation of depression and suicidal ideation reported following use of hypnotics.
Immediately evaluate any new psychiatric abnormalities.
Endocrine Effects
Increased prolactin concentrations reported in patients with chronic insomnia receiving ramelteon 16 mg daily for 6 months.
Abnormal morning cortisol concentrations (resulting in abnormal corticotropin [ACTH] stimulation test results) reported in 2 patients and prolactinoma reported in 1 patient receiving long-term (up to 12 months) therapy; causal relationship to drug not established.
If unexplained amenorrhea, galactorrhea, decreased libido, or fertility problems occur, consider evaluating prolactin or testosterone concentrations.
Abuse Potential and Dependence
No evidence of abuse potential detected following administration of doses up to 20 times the recommended hypnotic dose in patients with a history of drug abuse or dependence.
No evidence of physical dependence.
Withdrawal
No evidence of a withdrawal syndrome, including rebound insomnia, following discontinuance of long-term therapy (4, 8, or 16 mg daily for up to 35 days).
Residual Effects
Next-day residual effects (reduced immediate/delayed memory recall and increased sluggishness, fatigue, and irritation) detected at weeks 1 and 3 but not week 5 of therapy in adult patients receiving ramelteon 8 mg daily. Residual effects not detected in a similar study in geriatric patients receiving ramelteon 4 or 8 mg daily.
General Precautions
Long-term Safety
No clinically meaningful changes in laboratory parameters, endocrine tests, vital signs, ECG recordings, or intensity of menstrual bleeding detected in patients with chronic insomnia following up to 1 year of therapy. Rebound insomnia not observed following 1 year of therapy.
Concomitant Diseases
No respiratory depressant effect in patients with mild to moderate COPD. Effects in patients with severe COPD (e.g., those with elevated pCO2, those requiring nocturnal oxygen therapy) not studied; use in these patients not recommended.
No differences in measures of apnea indices observed in patients with mild to moderate obstructive sleep apnea. Effects in patients with severe obstructive sleep apnea not studied; use in these patients not recommended.
Specific Populations
Pregnancy
Category C.
Lactation
Distributed into milk in rats; not known whether distributed into human milk. Use not recommended.
Pediatric Use
Safety and efficacy not established in pediatric patients.
Geriatric Use
Increased exposure to drug and active metabolite. (See Special Populations under Pharmacokinetics.) However, no overall differences in safety or efficacy relative to younger adults.
Hepatic Impairment
Use with caution in patients with moderate hepatic impairment; avoid use in patients with severe hepatic impairment. (See Special Populations under Pharmacokinetics.)
Metabolized principally by CYP1A2 and, to a lesser extent, by the CYP2C subfamily and by CYP3A4.
Drugs Affecting Hepatic Microsomal Enzymes
Inhibitors of CYP1A2: Potential pharmacokinetic interaction (substantially increased serum ramelteon concentrations). Avoid concomitant use with strong CYP1A2 inhibitors; caution if used concomitantly with less potent CYP1A2 inhibitors.
Inhibitors of CYP3A4 and CYP2C9: Potential pharmacokinetic interaction (increased serum concentrations of ramelteon and active metabolite). Caution if used concomitantly with potent inhibitors of CYP3A4 or CYP2C9.
Inducers of CYP isoenzymes: Potential pharmacokinetic interaction (decreased serum concentrations of ramelteon and active metabolite). Possibly reduced ramelteon efficacy when used concomitantly with potent CYP inducers.
Drugs Metabolized by Hepatic Microsomal Enzymes
Substrates of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, and 3A4: Pharmacokinetic interaction unlikely.
Rapidly absorbed; following oral administration in fasting state, peak serum concentrations occur at approximately 0.75 hour.
Total absorption is ≥84%; however, absolute oral bioavailability is 1.8% because of extensive first-pass metabolism.
Food
High-fat meal delays time to peak serum concentration by 45 minutes, reduces peak serum concentration by 22%, and increases AUC by 31%. (See Oral Administration under Dosage and Administration.)
Special Populations
In geriatric patients, peak serum concentrations and AUC of ramelteon are increased by 86 and 97%, respectively. Peak serum concentrations and AUC of active metabolite also are increased, but to a lesser extent.
In patients with mild or moderate hepatic impairment, exposure to ramelteon is increased 4- or 10-fold, respectively. Exposure to active metabolite is marginally increased. Pharmacokinetic parameters not evaluated in patients with severe hepatic impairment (Child-Pugh class C). (See Hepatic Impairment under Cautions.)
Pharmacokinetic parameters not altered in patients with renal impairment or in those requiring chronic hemodialysis.
Distribution
Extent
Extensively distributed into tissues; not distributed selectively to red blood cells.
Plasma Protein Binding
Approximately 82% (mainly [70%] albumin).
Elimination
Metabolism
Metabolized principally by CYP1A2 and, to a lesser extent, by the CYP2C subfamily and by CYP3A4 to active (M-II) and inactive metabolites.
Elimination Route
Excreted in urine (84%) and feces (4%), principally as metabolites.
Half-life
1–2.6 hours (for ramelteon) and 2–5 hours (for active metabolite).
Stability
Storage
Oral
Capsules
Tightly-closed containers at 25°C (may be exposed to 15–30°C). Protect from moisture and humidity.
Actions
Exhibits high affinity for melatonin MT1 and MT2 receptors. Agonist activity at these receptors may contribute to the drug’s sleep-inducing properties.
Demonstrates lower selectivity for melatonin MT3 receptors than for MT1 and MT2 receptors. Has no appreciable affinity for the GABA receptor complex or for receptors that bind neuropeptides, cytokines, serotonin, dopamine, norepinephrine, acetylcholine, or opiates.
Advice to Patients
Necessity of administering within 30 minutes of bedtime and limiting activities to only those necessary to prepare for bed. Avoid administration with or immediately after a high-fat meal.
Necessity of avoiding driving, operating machinery, or performing hazardous tasks following administration. Importance of avoiding alcohol during therapy.
Importance of consulting a clinician if worsening insomnia or emergence of new behavioral manifestations occurs.
Importance of consulting a clinician if cessation of menses or galactorrhea (in women), decreased libido, or problems with fertility occur.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
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