Ramelteon

Ramelteon is used to help patients who have sleep-onset insomnia (difficulty falling asleep) fall asleep more quickly. Ramelteon is in a class of medications called melatonin receptor agonists. It works similarly to melatonin, a natural substance in the brain that is needed for sleep.

Ramelteon should only be taken at bedtime. If you did not take ramelteon at bedtime and you are unable to fall asleep, you may take ramelteon if you will be able to remain in bed for 7 to 8 hours afterward. Do not take ramelteon if you are not ready to go to sleep and stay asleep for at least 7 to 8 hours.

Mechanism of Action

ROZEREM (ramelteon) is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors and selectivity over the MT3 receptor. Ramelteon demonstrates full agonist activity in vitro in cells expressing human MT1 or MT2 receptors.

The activity of ramelteon at the MT1 and MT2 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 active and has approximately one tenth and one fifth the binding affinity of the parent molecule for the human MT1 and MT2 receptors, respectively, and is 17- to 25fold less potent than ramelteon in in vitro functional assays. Although the potency of M-II at MT1 and MT2 receptors is lower than the parent drug, M-II circulates at higher concentrations than the parent producing 20- to 100-fold greater mean systemic exposure when compared to ramelteon. M-II has weak affinity for the serotonin 5-HT2B receptor, but no appreciable affinity for other receptors or enzymes. 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.

Pharmacokinetics

The pharmacokinetic profile of ROZEREM (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 (Cmax) 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.

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.

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 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.

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 post-dose.

Repeated once daily dosing with ROZEREM (ramelteon) does not result in significant accumulation owing to the short elimination half-life of ramelteon (on average, approximately 1 to 2.6 hours).

The half-life of M-II is 2 to 5 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.

When administered with a high-fat meal, the AUC0-inf for a single 16 mg dose of ROZEREM (ramelteon) was 31% higher and the Cmax was 22% lower than when given in a fasted state. Median Tmax was delayed by approximately 45 minutes when ROZEREM (ramelteon) was administered with food. Effects of food on the AUC values for M-II were similar. It is therefore recommended that ROZEREM (ramelteon) not be taken with or immediately after a high-fat meal [see DOSAGE AND ADMINISTRATION].

Pharmacokinetics in Special Populations

In a group of 24 elderly subjects aged 63 to 79 years administered a single ROZEREM (ramelteon) 16 mg dose, the mean Cmax and AUC0-inf values were 11.6 ng/mL (SD, 13.8) and 18.7 ng·hr/mL (SD, 19.4), respectively. The elimination half-life was 2.6 hours (SD, 1.1). Compared with younger adults, the total exposure (AUC0-inf) and Cmax of ramelteon were 97% and 86% higher, respectively, in elderly subjects. The AUC0-inf and Cmax of M-II were increased by 30% and 13%, respectively, in elderly subjects.

There are no clinically meaningful gender-related differences in the pharmacokinetics of ROZEREM (ramelteon) or its metabolites.

Exposure to ROZEREM (ramelteon) was increased almost 4-fold in subjects with mild hepatic impairment after 7 days of dosing with 16 mg/day; exposure was further increased (more than 10-fold) in subjects with moderate hepatic impairment. Exposure to M-II was only marginally increased in mildly and moderately impaired subjects relative to healthy matched controls. The pharmacokinetics of ROZEREM (ramelteon) have not been evaluated in subjects with severe hepatic impairment (Child-Pugh Class C). ROZEREM (ramelteon) should be used with caution in patients with moderate hepatic impairment [see WARNINGS AND PRECAUTIONS].

The pharmacokinetic characteristics of ROZEREM (ramelteon) were studied after administering a 16 mg dose to subjects with mild, moderate, or severe renal impairment based on pre-dose creatinine clearance (53 to 95, 35 to 49, or 15 to 30 mL/min/1.73 m², respectively), and in subjects who required chronic hemodialysis. Wide intersubject variability was seen in ROZEREM (ramelteon) exposure parameters. However, no effects on Cmax or AUC0-t of parent drug or M-II were seen in any of the treatment groups; the incidence of adverse events was similar across groups. These results are consistent with the negligible renal clearance of ramelteon, which is principally eliminated via hepatic metabolism. No adjustment of ROZEREM (ramelteon) dosage is required in patients with renal impairment, including patients with severe renal impairment (creatinine clearance of ≤ 30 mL/min/1.73 m²) and patients who require chronic hemodialysis.

Drug-Drug Interactions

ROZEREM (ramelteon) has a highly variable intersubject pharmacokinetic profile (approximately 100% coefficient of variation in Cmax and AUC). As noted above, CYP1A2 is the major isozyme involved in the metabolism of ROZEREM (ramelteon) ; the CYP2C subfamily and CYP3A4 isozymes are also involved to a minor degree.

Fluvoxamine (strong CYP1A2 inhibitor): When fluvoxamine 100 mg twice daily was administered for 3 days prior to single-dose co-administration of ROZEREM 16 mg and fluvoxamine, the AUC0-inf for ramelteon increased approximately 190-fold, and the Cmax increased approximately 70-fold, compared to ROZEREM (ramelteon) administered alone. ROZEREM (ramelteon) should not be used in combination with fluvoxamine. Other less strong CYP1A2 inhibitors have not been adequately studied. ROZEREM (ramelteon) should be administered with caution to patients taking less strong CYP1A2 inhibitors [see CONTRAINDICATIONS, DRUG INTERACTIONS].

Rifampin (strong CYP enzyme inducer): Administration of rifampin 600 mg once daily for 11 days resulted in a mean decrease of approximately 80% (40% to 90%) in total exposure to ramelteon and metabolite M-II, (both AUC0-inf and Cmax) after a single 32 mg dose of ROZEREM (ramelteon) . Efficacy may be reduced when ROZEREM (ramelteon) is used in combination with strong CYP enzyme inducers such as rifampin [see DRUG INTERACTIONS].

Ketoconazole (strong CYP3A4 inhibitor): The AUC0-inf and Cmax of ramelteon increased by approximately 84% and 36%, respectively, when a single 16 mg dose of ROZEREM (ramelteon) was administered on the fourth day of ketoconazole 200 mg twice daily administration, compared to administration of ROZEREM (ramelteon) alone. Similar increases were seen in M-II pharmacokinetic variables. ROZEREM (ramelteon) should be administered with caution in subjects taking strong CYP3A4 inhibitors such as ketoconazole [see DRUG INTERACTIONS].

Fluconazole (strong CYP2C9 inhibitor): The total and peak systemic exposure (AUC0-inf and Cmax) of ramelteon after a single 16 mg dose of ROZEREM (ramelteon) was increased by approximately 150% when administered with fluconazole. Similar increases were also seen in M-II exposure. ROZEREM (ramelteon) should be administered with caution in subjects taking strong CYP2C9 inhibitors such as fluconazole [see DRUG INTERACTIONS].

Donepezil: Administration of donepezil 10 mg once daily for 26 days resulted in a mean increase of approximately 100% in overall exposure to ramelteon, (AUC0-inf) and a mean increase of approximately 87% in maximum exposure to ramelteon (Cmax) after a single 8 mg dose of ROZEREM (ramelteon) . No change was seen in M-II exposure. Patients should be closely monitored when ROZEREM (ramelteon) is coadministered with donepezil [see DRUG INTERACTIONS].

Doxepin: Administration of doxepin 10 mg once daily for 23 days resulted in a mean increase of approximately 66% in overall exposure to ramelteon, (AUC0-inf) and a mean increase of approximately 69% in maximum exposure to ramelteon (Cmax) after a single 8 mg dose of ROZEREM (ramelteon) . No change was seen in M-II exposure. Patients should be closely monitored when ROZEREM (ramelteon) is coadministered with doxepin [see DRUG INTERACTIONS].

Interaction studies of concomitant administration of ROZEREM (ramelteon) with fluoxetine (CYP2D6 inhibitor), omeprazole (CYP1A2 inducer/CYP2C19 inhibitor), theophylline (CYP1A2 substrate), dextromethorphan (CYP2D6 substrate), sertraline, venlafaxine, escitalopram, gabapentin, and zolpidem did not produce clinically meaningful changes in either peak or total exposures to ramelteon or the M-II metabolite.

Zolpidem: Administration of ramelteon 8 mg once daily for 11 days resulted in an increase in median Tmax of zolpidem by approximately 20 minutes and exposure to zolpidem (both AUC0-inf and Cmax) was unchanged after a single 10 mg dose of zolpidem. Ordinarily zolpidem should not be given in a patient taking ROZEREM (ramelteon) .

Concomitant administration of ROZEREM (ramelteon) with omeprazole (CYP2C19 substrate), dextromethorphan (CYP2D6 substrate), midazolam (CYP3A4 substrate), theophylline (CYP1A2 substrate), digoxin (pglycoprotein substrate), warfarin (CYP2C9 [S]/CYP1A2 [R] substrate), venlafaxine, fluvoxamine, donepezil, doxepin, sertraline, escitalopram, and gabapentin did not produce clinically meaningful changes in peak and total exposures to these drugs.

With single-dose, daytime co-administration of ROZEREM (ramelteon) 32 mg and alcohol (0.6 g/kg), there were no clinically meaningful or statistically significant effects on peak or total exposure to ROZEREM (ramelteon) . However, an additive effect was seen on some measures of psychomotor performance (i.e., the Digit Symbol Substitution Test, the Psychomotor Vigilance Task Test, and a Visual Analog Scale of Sedation) at some post-dose time points. No additive effect was seen on the Delayed Word Recognition Test. Because alcohol by itself impairs performance, and the intended effect of ROZEREM (ramelteon) is to promote sleep, patients should be cautioned not to consume alcohol when using ROZEREM (ramelteon) .

Clinical Studies

Controlled Clinical Trials

Three randomized, double-blind trials in subjects with chronic insomnia employing polysomnography (PSG) were provided as objective support of Rozerem (ramelteon) 's effectiveness in sleep initiation.

One study enrolled younger adults (aged 18 to 64 years, inclusive) with chronic insomnia and employed a parallel design in which the subjects received a single, nightly dose of ROZEREM (ramelteon) (8 mg or 16 mg) or matching placebo for 35 days. PSG was performed on the first two nights in each of Weeks 1, 3, and 5 of treatment. ROZEREM (ramelteon) reduced the average latency to persistent sleep at each of the time points when compared to placebo. The 16 mg dose conferred no additional benefit for sleep initiation.

The second study employing PSG was a three-period crossover trial performed in subjects aged 65 years and older with a history of chronic insomnia. Subjects received ROZEREM (ramelteon) (4 mg or 8 mg) or placebo and underwent PSG assessment in a sleep laboratory for two consecutive nights in each of the three study periods. Both doses of ROZEREM (ramelteon) reduced latency to persistent sleep when compared to placebo.

The third study evaluated long term efficacy and safety in adults with chronic insomnia. Subjects received a single, nightly dose of ROZEREM (ramelteon) 8 mg or matching placebo for 6 months. PSG was performed on the first two nights of Week 1 and Months 1, 3, 5, and 6. ROZEREM (ramelteon) reduced sleep latency at each time point when compared to placebo. In this study, when the PSG results from nights 1 and 2 of Month 7 were compared to the results from nights 22 and 23 of Month 6, there was a statistically significant increase in LPS of 33% (9.5 minutes) in the ramelteon group. There was no increase in LPS in the placebo group when the same time periods were compared.

A randomized, double-blind, parallel group study was conducted in outpatients aged 65 years and older with chronic insomnia and employed subjective measures of efficacy (sleep diaries). Subjects received ROZEREM (ramelteon) (4 mg or 8 mg) or placebo for 35 nights. ROZEREM (ramelteon) reduced patient-reported sleep latency compared to placebo. A similarly designed study performed in younger adults (aged 18 - 64 years) using 8 mg and 16 mg of ramelteon did not replicate this finding of reduced patient-reported sleep latency compared to placebo.

While the 16 mg dose was evaluated as a potential treatment for adults, it was shown to confer no additional benefit for sleep initiation and was associated with higher incidences of fatigue, headache and next-day somnolence.

In a randomized, double-blind, parallel-group trial using a first-night-effect model, healthy adults received placebo or ROZEREM (ramelteon) before spending one night in a sleep laboratory and being evaluated with PSG. ROZEREM (ramelteon) demonstrated a decrease in mean latency to persistent sleep as compared to placebo.

Studies Pertinent to Safety Concerns for Sleep- promoting Drugs

A human laboratory abuse potential study was performed in 14 subjects with a history of sedative/hypnotic or anxiolytic drug abuse. Subjects received single oral doses of ROZEREM (ramelteon) (16, 80, or 160 mg), triazolam (0.25, 0.50, or 0.75 mg) or placebo. All subjects received each of the 7 treatments separated by a wash-out period and underwent multiple standard tests of abuse potential. No differences in subjective responses indicative of abuse potential were found between ROZEREM (ramelteon) and placebo at doses up to 20 times the recommended therapeutic dose. The positive control drug, triazolam, consistently showed a dose-response effect on these subjective measures, as demonstrated by the differences from placebo in peak effect and overall 24-hour effect.

In order to evaluate potential next-day residual effects, the following scales were used: a Memory Recall Test, a Word List Memory Test, a Visual Analog Mood and Feeling Scale, the Digit-Symbol Substitution Test, and a post-sleep questionnaire to assess alertness and ability to concentrate. There was no evidence of next-day residual effect seen after 2 nights of ramelteon use during the crossover studies.

In a 35-night, double-blind, placebo-controlled, parallel-group study in adults with chronic insomnia, measures of residual effects were performed at three time points. Overall, the magnitudes of any observed differences were small. At Week 1, patients who received 8 mg of ROZEREM (ramelteon) had a mean VAS score (46 mm on a 100 mm scale) indicating more fatigue in comparison to patients who received placebo (42 mm).

At Week 3, patients who received 8 mg of ROZEREM (ramelteon) had a lower mean score for immediate recall (7.5 out of 16 words) compared to patients who received placebo (8.2 words); and the patients treated with ROZEREM (ramelteon) had a mean VAS score indicating more sluggishness (27 mm on a 100 mm VAS) in comparison to the placebo-treated patients (22 mm). Patients who received ROZEREM (ramelteon) did not have next-morning residual effects that were different from placebo at Week 5.

Rebound Insomnia/Withdrawal: Potential rebound insomnia and withdrawal effects were assessed in four studies in which subjects received ROZEREM (ramelteon) or placebo for up to 6 months; 3 were 35-day studies, one was a 6 month study. These studies included a total of 2533 subjects, of whom 854 were elderly.

Tyrer Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ): The BWSQ is a self-report questionnaire that solicits specific information on 20 symptoms commonly experienced during withdrawal from benzodiazepine receptor agonists; ROZEREM (ramelteon) is not a benzodiazepine receptor agonist.

In two of the three 35-day insomnia studies, the questionnaire was administered one week after completion of treatment; in the third study, the questionnaire was administered on Days 1 and 2 after completion. In all three of the 35-day studies, subjects receiving ROZEREM (ramelteon) 4 mg, 8 mg, or 16 mg daily reported BWSQ scores similar to those of subjects receiving placebo.

In the 6 month study, there was no evidence of withdrawal from the 8 mg dose as measured by the BWSQ.

Rebound Insomnia: Rebound insomnia was assessed in the 35-day studies by measuring sleep latency after abrupt treatment discontinuation. One of these studies employed PSG in younger adult subjects receiving ROZEREM (ramelteon) 8 mg or 16 mg; the other two studies employed subjective measures of sleep-onset insomnia in elderly subjects receiving ROZEREM (ramelteon) 4 mg or 8 mg, and in younger adult subjects receiving ROZEREM (ramelteon) 8 mg or 16 mg. There was no evidence that ROZEREM (ramelteon) caused rebound insomnia during the post-treatment period.

Studies to Evaluate Effects on Endocrine Function

Two controlled studies evaluated the effects of ROZEREM (ramelteon) on endocrine function.

In the first trial, ROZEREM (ramelteon) 16 mg once daily or placebo was administered to 99 healthy volunteer subjects for 4 weeks. This study evaluated the thyroid axis, adrenal axis and reproductive axis. No clinically significant endocrinopathies were demonstrated in this study. However, the study was limited in its ability to detect such abnormalities due to its limited duration.

In the second trial, ROZEREM (ramelteon) 16 mg once daily or placebo was administered to 122 subjects with chronic insomnia for 6 months. This study evaluated the thyroid axis, adrenal axis and reproductive axis. There were no significant abnormalities seen in either the thyroid or the adrenal axes. Abnormalities were, however, noted within the reproductive axis. Overall, the mean serum prolactin level change from baseline was 4.9 mcg/L (34% increase) for women in the ROZEREM (ramelteon) group compared with -0.6 mcg/L (4% decrease) for women in the placebo group (p=0.003). No differences between active- and placebo-treated groups occurred among men. Thirty-two percent of all patients who were treated with ramelteon in this study (women and men) had prolactin levels that increased from normal baseline levels compared to 19% of patients who were treated with placebo. Subject-reported menstrual patterns were similar between the two treatment groups.

In a 12-month, open-label study in adult and elderly patients, there were two patients who were noted to have abnormal morning cortisol levels, and subsequent abnormal ACTH stimulation tests. A 29-year-old female patient was diagnosed with a prolactinoma. The relationship of these events to ROZEREM (ramelteon) therapy is not clear.

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

• Severe anaphylactic and anaphylactoid reactions [see WARNINGS AND PRECAUTIONS]
• Abnormal thinking, behavior changes, and complex behaviors [see WARNINGS AND PRECAUTIONS]
• CNS effects [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

The data described in this section reflect exposure to ROZEREM (ramelteon) in 5373 subjects, including 722 exposed for 6 months or longer, and 448 subjects for one year.

Six percent of the 5373 individual subjects exposed to ROZEREM (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 ROZEREM (ramelteon) were somnolence, dizziness, nausea, fatigue, headache, and insomnia; all of which occurred in 1% of the patients or less.

Table 1 displays the incidence of adverse events reported by the 2861 patients with chronic insomnia who participated in placebo-controlled trials of ROZEREM (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

Read the entire FDA prescribing information for Rozerem (Ramelteon)

Ramelteon may be found in some form under the following brand names:

• Rozerem

You should not use ramelteon if you are also taking fluvoxamine (Luvox), or if you have severe liver disease.

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Take ramelteon 30 minutes before your normal bedtime. After you take ramelteon, avoid doing anything other than getting ready for bed.

Do not crush, chew, or break the tablet. Swallow it whole.

Avoid taking ramelteon together with or just after eating a high-fat meal. This will make it harder for your body to absorb the medication.

Call your doctor if your symptoms do not improve after 7 to 10 days of using ramelteon.

Store at room temperature away from moisture and heat. Keep the bottle tightly closed when not in use.

Since ramelteon is usually taken as needed, you may not be on a dosing schedule. Ramelteon should be taken only within 30 minutes of your normal bedtime. Do not take extra medicine to make up a missed dose.

• Exhibits high affinity for melatonin MT1 and MT2 receptors.1 2 Agonist activity at these receptors may contribute to the drug’s sleep-inducing properties.1 2

• Demonstrates lower selectivity for melatonin MT3 receptors than for MT1 and MT2 receptors.1 Has no appreciable affinity for the GABA receptor complex or for receptors that bind neuropeptides, cytokines, serotonin, dopamine, norepinephrine, acetylcholine, or opiates.1

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of low mood (depression), thoughts of killing yourself, nervousness, emotional ups and downs, thinking that is not normal, anxiety, or lack of interest in life.
• Feeling confused.
• Change in how you act.
• Hallucinations (seeing or hearing things that are not there).
• Bad dreams.
• Memory problems or loss.
• Upset stomach or throwing up.
• For women, no period.
• Nipple discharge.
• Lowered interest in sex.
• Trouble getting pregnant.
• A very bad reaction called angioedema has happened with ramelteon. Sometimes, this may be life-threatening. Signs may include swelling of the hands, face, lips, eyes, tongue, or throat; trouble breathing; trouble swallowing; or unusual hoarseness. Talk with the doctor.

• Rozerem

Potent, selective agonist of melatonin receptors MT1 and MT2 (with little affinity for MT3) within the suprachiasmic nucleus of the hypothalamus, an area responsible for determination of circadian rhythms and synchronization of the sleep-wake cycle. Agonism of MT1 is thought to preferentially induce sleepiness, while MT2 receptor activation preferentially influences regulation of circadian rhythms. Ramelteon is eightfold more selective for MT1 than MT2 and exhibits nearly sixfold higher affinity for MT1 than melatonin, presumably allowing for enhanced effects on sleep induction (Hatta 2014).

Absorption

Rapid; high-fat meal delays Tmax and increases AUC (~31%)

Distribution

74 L

Metabolism

Extensive first-pass effect; oxidative metabolism primarily through CYP1A2 and to a lesser extent through CYP2C and CYP3A4; forms active metabolite (M-II)

Excretion

Primarily as metabolites: Urine (84%); feces (4%)

AUC is 97% higher and Cmax is 86% higher than in younger adults. AUC and Cmax of M-II metabolite increased 30% and 13%, respectively.

Abiraterone Acetate: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Analgesics (Opioid): CNS Depressants may enhance the CNS depressant effect of Analgesics (Opioid). Management: Avoid concomitant use of opioid analgesics and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Monitor therapy

CYP2C9 Inhibitors (Strong): May increase the serum concentration of Ramelteon. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Ramelteon. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Ramelteon. Monitor therapy

Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Fluconazole: May increase the serum concentration of Ramelteon. Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

FluvoxaMINE: May increase the serum concentration of Ramelteon. Avoid combination

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Melatonin: May enhance the sedative effect of Hypnotics (Nonbenzodiazepine). Monitor therapy

Methotrimeprazine: May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Obeticholic Acid: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Peginterferon Alfa-2b: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Sodium Oxybate: Hypnotics (Nonbenzodiazepine) may enhance the CNS depressant effect of Sodium Oxybate. Avoid combination

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Vemurafenib: May increase the serum concentration of CYP1A2 Substrates. Management: Consider alternatives to such combinations whenever possible, particularly if the CYP1A2 substrate has a relatively narrow therapeutic index. Consider therapy modification

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, dizziness, or loss of strength and energy. Have patient report immediately to prescriber signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), confusion, behavioral changes, hallucinations, nightmares, memory impairment, nausea, vomiting, angioedema, amenorrhea, nipple discharge, decreased libido, or infertility (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

8 mg orally within 30 minutes of going to bed

Maximum Dose: 8 mg per day

Comments: This drug should not be taken with or immediately after a high-fat meal.

Use: Treatment of insomnia characterized by difficulty with sleep onset

No adjustment recommended.

Administration Advice:
-The drug tablet should be swallowed whole; tablets should not be broken.

Storage Requirements:
-The container should be kept tightly closed to protect from moisture and humidity.

General:
-This drug does not appear to produce physical dependence; treatment discontinuation after chronic administration did not produce withdrawal signs in humans or in animals.
-If overdosage occurs, general symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate and IV fluids as needed.

Patient Advice:
-Do not drink alcohol while taking this drug.
-Do not take other medications that can make you sleepy while taking this drug.
-Do not take this drug with food or right after a meal.
-Do not take this drug unless you are able to get a full night's sleep before you must be active again.
-After taking this drug, avoid driving and other activities that require concentration such as operating machinery; limit your activities to those necessary to prepare for bed.
-Consult your healthcare provider if your insomnia worsens or is not better within 7 to 10 days.

This drug should be used during pregnancy only if the potential benefit justifies the possible risk to the fetus. US FDA pregnancy category: C Comments: -This drug has been associated with an effect on reproductive hormones, such as decreased testosterone levels and increased prolactin levels. -It is not known what effect chronic or chronic intermittent use of this drug may have on the reproductive axis in developing humans.

Animal studies have revealed evidence of developmental toxicity and teratogenic effects at doses much greater than the recommended human dose (RHD). Growth retardation, developmental delay, and behavioral changes were observed in animal offspring at doses greater than 30 mg/kg/day; increased incidences of fetal structural abnormalities occurred at doses greater than 40 mg/kg/day; increased incidences of malformation and death among offspring were seen at 300 mg/kg/day. Animal fertility studies show alterations in estrus cyclicity and decreased numbers of corpora lutea, implantations, and live embryos at doses greater than 20 mg/kg/day; no effects on sperm quality or reproductive performance in males were observed. The potential effects of this drug on the duration of labor and/or delivery for either the mother or fetus have not been studied. There are no controlled data in human pregnancy. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.