PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Melatonin Receptor Agonists

    DEA CLASS

    Rx

    DESCRIPTION

    Selective melatonin receptor agonist
    Used for the treatment of transient or chronic sleep onset insomnia
    Watch for sleep-related behaviors or behavioral changes; use of alcohol or other CNS depressants may increase risks

    COMMON BRAND NAMES

    Rozerem

    HOW SUPPLIED

    Rozerem Oral Tab: 8mg

    DOSAGE & INDICATIONS

    For the treatment of chronic or transient insomnia characterized by difficulty with sleep onset.
    Oral dosage
    Adults

    8 mg PO taken within 30 minutes of going to bed. Ramelteon should not be taken with or immediately after a high fat meal. Results from clinical trials have demonstrated efficacy for up to 6 months of use.

    Geriatric Adults

    8 mg PO taken within 30 minutes of going to bed. Ramelteon should not be taken with or immediately after a high fat meal. Results from clinical trials have demonstrated efficacy for up to 6 months of use. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of sedative/hypnotics in long-term care facility (LTCF) residents. Max: 8 mg/night PO in residents meeting the criteria for treatment. All sleep medications should be used in accordance with approved product labeling. If the sleep agent is used routinely and is beyond the manufacturer's recommendations for duration of use, the facility should attempt a quarterly taper, unless clinically contraindicated as defined in the OBRA guidelines.

    MAXIMUM DOSAGE

    Adults

    8 mg/day PO.

    Elderly

    8 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Use of ramelteon is not recommended in patients with severe hepatic impairment (Child-Pugh Class C). Ramelteon should be used with caution in patients with mild or moderate liver disease; although specific dosage adjustment recommendations are not available.

    Renal Impairment

    No dose adjustment is required in patients with any degree of renal impairment.
     
    Intermittent hemodialysis
    Supplemental dosing is not required following hemodialysis.
     
    Continuous hemodialysis (CAVHD, CVVHD)
    Supplemental dosing is not required following hemodialysis.

    ADMINISTRATION

    Oral Administration

    Do not take ramelteon with or immediately after a high-fat meal; doing so would slow absorption and is expected to reduce the effect on sleep latency.
    Administer within 30 minutes of going to bed. Once administered, activities should be limited to those necessary to get ready for bed.

    STORAGE

    Rozerem:
    - Avoid excessive humidity
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    NOTE: Although melatonin and ramelteon share similar pharmacologic receptor sites, it is not known if precautions that apply to melatonin would also apply to ramelteon.

    Angioedema

    Ramelteon is contraindicated in patients with ramelteon hypersensitivity or hypersensitivity to any components of the ramelteon formulation. Similarly, use is contraindicated in patients who have ramelteon-induced angioedema. Reactions including anaphylaxis or angioedema may become evident as early as the initial dose. Patients should be instructed on the appropriate action in the event of an allergic reaction.

    Hepatic disease

    Use ramelteon with caution in patients with mild to moderate hepatic disease (Child Pugh Class A and B). Ramelteon should not be used in patients with severe hepatic disease (Child Pugh Class C) due to the potential for significantly increased ramelteon exposure and risk of resultant toxicity. Patients with moderate liver impairment had more than 10-fold elevations in exposure to ramelteon and patients with mild liver impairment had elevations in exposure of 4-fold; the drug is reported to have a wide therapeutic range.

    Sleep apnea

    Ramelteon has not been studied in patients with severe obstructive sleep apnea; its use is not recommended in such patients. Use caution when using ramelteon in patients with mild to moderate sleep apnea. Treatment with a single dose of ramelteon did not exacerbate mild to moderate obstructive sleep apnea in a clinical study (n = 26). There was no difference compared with placebo on the Apnea/Hypopnea Index (the primary outcome variable), apnea index, hypopnea index, central apnea index, mixed apnea index, and obstructive apnea index. There is no available information on the respiratory effects of multiple doses of the drug in patients with sleep apnea. The effects on exacerbation in patients with mild to moderate sleep apnea cannot be definitively known from the single-dose study. Treatment with a single dose of ramelteon had no demonstrable respiratory depressant effects in adults with mild to severe chronic obstructive pulmonary disease (COPD), as measured by arterial O2 saturation (SaO2). There is no available information on the respiratory effects of multiple doses of the drug in patients with COPD, but not particular precautions are noted by the manufacturer for use in COPD patients.

    Behavioral changes, depression, suicidal ideation

    A variety of cognitive and behavioral changes have been reported to occur in association with the use of hypnotics. In primarily depressed patients, a 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. 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.

    Coadministration with other CNS depressants, driving or operating machinery, ethanol ingestion, sleep-related behaviors

    Alcohol impairs psychomotor performance and an additive effect on some measures of psychomotor performance may be seen if ramelteon is combined with ethanol. Caution patients to avoid ethanol ingestion when using ramelteon. Patients should avoid engaging in hazardous activities that require concentration (such as driving or operating machinery) after taking ramelteon; patients should confine their activities to those necessary to prepare for bed. Sedative-hypnotic medications have the potential to cause sleep-related behaviors such as sleep-driving, a state of driving after ingestion of a sedative-hypnotic while not fully awake and having no memory of the event. Other sleep-related behaviors may include making phone calls or eating while asleep. The use of alcohol and coadministration with other CNS depressants (including other sedative-hypnotics) may increase the risk of such behaviors. The exact incidences of sleep-related behaviors among various sedative products are unknown; however patients should be informed of the risks prior to receiving any medication from this class.

    Labor, obstetric delivery, pregnancy

    There are no adequate and well-controlled studies of ramelteon use during pregnancy. Ramelteon should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In animal studies, ramelteon produced evidence of developmental toxicity, including teratogenic effects, in rats at doses much greater than the recommended human dose (RHD) of 8 mg/day. Ramelteon has not been studied for effects on labor or delivery in the mother or the fetus; the drug has no established use in labor or obstetric delivery.

    Breast-feeding

    It is not known whether ramelteon is excreted into the milk of breast-feeding women, and caution is advisable when administering ramelteon during lactation. Ramelteon is excreted into the milk of lactating rats.

    Hyperprolactinemia, infertility

    It is not known what effect chronic or even chronic intermittent use of ramelteon may have on the reproductive axis. Use of ramelteon has been associated with decreased testosterone concentrations and increased prolactin concentrations. Significant hyperprolactinemia has been reported in women receiving ramelteon. For patients taking ramelteon who present with unexplained amenorrhea or menstrual irregularity, galactorrhea, decreased libido, or infertility or reported fertility problems, assessment of prolactin concentrations and testosterone concentrations should be considered as appropriate. It is clear that endogenous melatonin plays an important role in the regulation of endocrine functions in the body, and the effect of ramelteon on endocrine function requires more study. In one study, ramelteon (16 mg/day given for 4 weeks) the effects on thyroid axis, adrenal axis and reproductive axis were evaluated, and no clinically significant endocrinopathies were demonstrated. However, the limited duration of the study limited its ability to detect issues. In a second trial, ramelteon (16 mg/day) 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 ramelteon group (clinically significant vs. placebo). Subject-reported menstrual patterns were similar between the 2 female treatment groups. Thirty-two percent of all patients who were treated with ramelteon in this study (women and men) had increased prolactin levels above normal baseline levels vs. 19% of those given placebo. No reproductive axis differences between active- and placebo-treated groups occurred among men. In a 12-month, open-label study in adult and elderly patients, there were 2 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 ramelteon therapy is not clear.

    Children, infants

    The safety and effectiveness of the use of ramelteon in children and adolescents less than 18 years of age has not been established. There is no known use of ramelteon in infants. Use in pediatric patients may be of special concern based on the fact that ramelteon has been associated with decreased testosterone concentrations and increased prolactin concentrations in adults. It is not known what effect chronic or even chronic intermittent use of melatonin analogs may have on the reproductive axis in developing humans. While melatonin has been used as a dietary supplement for children with circadian-related sleep-wake disorders, the use of melatonin-receptor agonists like ramelteon in pediatric patients has remained controversial and there is a lack of data to support safety and efficacy; more study in the context of clinical trials is necessary.

    Dementia, geriatric

    Ramelteon has been proven effective in reducing sleep latency in geriatric patients with sleep onset insomnia (SOI); no differences in safety or efficacy in geriatric patients vs. younger adults has been observed at recommended dosing. Guidelines state that benefits of ramelteon treatment generally outweigh harms in appropriately selected patients with SOI. In geriatric subjects with insomnia (n = 33), a single 8 mg ramelteon dose did not impair middle of the night balance, mobility, or memory functions compared to placebo. The effect of multiple-night dosing has not been studied. Use with caution in the older patient with dementia; one guideline recommends against use of melatonin and melatonin agonists in geriatric patients with dementia with irregular sleep-wake rhythm disorder (ISWRD), due to weak evidence of efficacy and some data that suggest detrimental effects on daytime mood and functioning in this sub-population. According to the Beers Criteria, sedative-hypnotics are considered potentially inappropriate medications (PIMs) in geriatric patients with delirium or at high risk of delirium and should be avoided because new-onset or worsening delirium may occur. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to the OBRA guidelines, factors potentially causing insomnia should be evaluated before initiating a sedative (e.g., sleep environment, inadequate physical activity, provision of care disruptions, caffeine or medications, pain and discomfort, or other underlying conditions that cause insomnia). Most cases of insomnia are associated with other underlying conditions. It is expected that non-pharmacologic interventions and maximized treatment of underlying conditions (if applicable) are implemented to address the causative factor(s). Initiation of sleep induction or maintenance medication should be preceded or accompanied by other interventions to attempt sleep improvement. All sleep medications should be used in accordance with approved product labeling. The use of sedating medications for individuals with diagnosed sleep apnea requires careful assessment, documented clinical rationale, and close monitoring. Exceptions to the OBRA provisions include: single dose sedative use for a dental or medical procedure or short-term sedative use during initiation of treatment for depression, pain, or other comorbid condition until symptoms improve or the underlying causative factor can be identified and/or effectively treated. OBRA provides dosing guidance for most sedatives, including ramelteon. When a drug is being used to induce sleep or treat a sleep disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity in accordance with OBRA guidelines.

    ADVERSE REACTIONS

    Severe

    suicidal ideation / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    adrenocortical insufficiency / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    hallucinations / Early / Incidence not known
    mania / Early / Incidence not known
    hyperprolactinemia / Delayed / Incidence not known
    sleep-related behaviors / Early / Incidence not known
    hepatitis / Delayed / Incidence not known

    Mild

    dizziness / Early / 4.0-4.0
    insomnia / Early / 3.0-3.0
    fatigue / Early / 3.0-3.0
    drowsiness / Early / 3.0-3.0
    nausea / Early / 3.0-3.0
    headache / Early / Incidence not known
    agitation / Early / Incidence not known
    somnambulism / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Acetaminophen; Butalbital; Caffeine: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Acetaminophen; Codeine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Oxycodone: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Tramadol: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Alfentanil: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Alprazolam: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
    Amiodarone: (Moderate) Caution is recommended during concomitant use of ramelteon and amiodarone. Because ramelteon is metabolized by CYP3A4 and CYP1A2, use with CYP3A4 and CYP1A2 inhibitors, such as amiodarone, may increase exposure to ramelteon and the potential for adverse effects. If amiodarone must be administered with ramelteon, monitor the patient closely for toxicity due to increased ramelteon concentrations.
    Amitriptyline; Chlordiazepoxide: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
    Amoxicillin; Clarithromycin; Lansoprazole: (Moderate) Use caution with concurrent use of ramelteon and strong inhibitors of CYP3A4, such as clarithromycin. Because ramelteon is partially metabolized via CYP3A4, an increase in exposure of ramelteon is expected. An increase in ramelteon AUC by approximately 84% and Cmax by 36% was noted when coadministered with a strong CYP3A4 inhibitor (ketoconazole). Similar increases were noted in M-II pharmacokinetics. Patients should be monitored for increased ramelteon side effects. Also use caution with concurrent use of combinations containing clarithromycin, such as amoxicillin; clarithromycin; lansoprazole or amoxicillin; clarithromycin; omeprazole.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Use caution with concurrent use of ramelteon and strong inhibitors of CYP3A4, such as clarithromycin. Because ramelteon is partially metabolized via CYP3A4, an increase in exposure of ramelteon is expected. An increase in ramelteon AUC by approximately 84% and Cmax by 36% was noted when coadministered with a strong CYP3A4 inhibitor (ketoconazole). Similar increases were noted in M-II pharmacokinetics. Patients should be monitored for increased ramelteon side effects. Also use caution with concurrent use of combinations containing clarithromycin, such as amoxicillin; clarithromycin; lansoprazole or amoxicillin; clarithromycin; omeprazole.
    Anxiolytics; Sedatives; and Hypnotics: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
    Apraclonidine: (Minor) No specific drug interactions were identified with systemic agents and apraclonidine during clinical trials. Theoretically, apraclonidine might potentiate the effects of CNS depressant drugs such as the anxiolytics, sedatives, and hypnotics, including barbiturates or benzodiazepines.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if ramelteon and aprepitant, fosaprepitant are used concurrently, and monitor for an increase in ramelteon-related adverse effects for several days after administration of a multi-day aprepitant regimen. Ramelteon is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of ramelteon. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Aprepitant is also a CYP2C9 inducer and ramelteon is a CYP2C9 substrate. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant.
    Aripiprazole: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics.
    Asenapine: (Moderate) Drugs that can cause CNS depression, if used concomitantly with asenapine, may increase adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when asenapine is given in combination with anxiolytics, sedatives, and hypnotics.
    Aspirin, ASA; Butalbital; Caffeine: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Atazanavir; Cobicistat: (Moderate) Monitor for an increase in ramelteon-related adverse reactions if coadministration with cobicistat is necessary. Ramelteon is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ramelteon exposure by 84%.
    Barbiturates: (Major) Barbiturates can induce CYP1A2, the major metabolic pathway for ramelteon, and may eventually accelerate the clearance (and, thus, reduce the sedative properties) of ramelteon. Administration of multiple doses of a potent CYP inducer (rifampin) resulted in a mean decrease of approximately 80% in total exposure to ramelteon and its metabolite M-II. Additive CNS depression may also occur. The induction of ramelteon metabolism would likely require several days of barbiturate administration while additive drowsiness would appear immediately. Caution should be exercised during concomitant use of any CNS-depressant drugs and any barbiturate; dosage reduction of one or both agents may be necessary. If the medications must be used together, monitor for the effectiveness of ramelteon. Hypnotic barbiturates are best avoided during ramelteon therapy; the manufacturer warns against using other medications for sleep concurrently with ramelteon.
    Belladonna; Opium: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Benzodiazepines: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Coadministration of ramelteon with inhibitors of CYP2C9, such as metronidazole, may lead to increases in the serum concentrations of ramelteon.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Coadministration of ramelteon with inhibitors of CYP2C9, such as metronidazole, may lead to increases in the serum concentrations of ramelteon.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering ramelteon with boceprevir due to an increased potential for ramelteon-related adverse events. If ramelteon dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of ramelteon. Ramelteon is partially metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated ramelteon plasma concentrations.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Buprenorphine: (Moderate) If concurrent use of ramelteon and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Buprenorphine; Naloxone: (Moderate) If concurrent use of ramelteon and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Buspirone: (Moderate) Due to pharmacodynamic additive effects, also use caution when combining ramelteon with buspirone.
    Caffeine: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Caffeine; Ergotamine: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Cannabidiol: (Moderate) Consider a dose adjustment of ramelteon as clinically appropriate when administered with cannabidiol. Increased or decreased ramelteon exposure is possible. Additive somnolence and sedation may occur. Ramelteon is a CYP2C9 substrate and a sensitive CYP1A2 substrate. In vitro data predicts inhibition of CYP2C9 and inhibition or induction of CYP1A2 by cannabidiol potentially resulting in clinically significant interactions.
    Capecitabine: (Moderate) Use caution if coadministration of capecitabine with ramelteon is necessary, and monitor for an increase in ramelteon-related adverse reactions. Ramelteon is a CYP2C9 substrate; capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. The AUC of ramelteon (single dose, 16 mg) was elevated > 150% when administered with a strong CYP2C9 inhibitor, fluconazole; similar increases were seen in regard to the active metabolite, M-II. Patients should be monitored closely for ramelteon side effects even though ramelteon has a wide therapeutic index.
    Carbamazepine: (Moderate) Efficacy of ramelteon may be reduced when it is used in combination with strong CYP1A2 enzyme inducers such as carbamazepine.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Cariprazine: (Moderate) Due to the CNS effects of cariprazine, caution should be used when cariprazine is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics like ramelteon.
    Chloral Hydrate: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
    Chloramphenicol: (Moderate) The AUC and Cmax of ramelteon may be increased by strong CYP3A4 inhibitors such as chloramphenicol.
    Chlordiazepoxide: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
    Chlordiazepoxide; Clidinium: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Cimetidine: (Major) Caution is recommended during concurrent use of ramelteon and cimetidine. Because ramelteon is metabolized via CYP3A4 and CYP1A2, use with CYP3A4 and CYP1A2 inhibitors, such as cimetidine, may increase exposure to ramelteon and the potential for adverse reactions. Other CYP1A2 inhibitors have been shown to have significant interactions with ramelteon, leading to elevated AUC of ramelteon > 190-fold and Cmax > 70 fold. If cimetidine must be administered with ramelteon, monitor the patient closely for toxicity due to elevated ramelteon serum concentrations. Alternatives to cimetidine may be considered, such as famotidine or nizatidine.
    Ciprofloxacin: (Major) Ramelteon should be administered with caution to patients taking CYP1A2 inhibitors, such as systemic ciprofloxacin. Strong CYP1A2 inhibitors have been shown to have significant interactions with ramelteon, leading to elevated AUC of ramelteon > 190-fold and Cmax > 70-fold. If ciprofloxacin must be administered with ramelteon, monitor the patient closely for toxicity due to elevated ramelteon serum concentrations. Consider if an alternative fluoroquinolone with no CYP1A2 inhibition, like levofloxacin, could be utilized, or, if ramelteon therapy could be temporarily halted during use of ciprofloxacin. Non-systemic ciprofloxacin formulas, like ear drops, do not interact.
    Clarithromycin: (Moderate) Use caution with concurrent use of ramelteon and strong inhibitors of CYP3A4, such as clarithromycin. Because ramelteon is partially metabolized via CYP3A4, an increase in exposure of ramelteon is expected. An increase in ramelteon AUC by approximately 84% and Cmax by 36% was noted when coadministered with a strong CYP3A4 inhibitor (ketoconazole). Similar increases were noted in M-II pharmacokinetics. Patients should be monitored for increased ramelteon side effects. Also use caution with concurrent use of combinations containing clarithromycin, such as amoxicillin; clarithromycin; lansoprazole or amoxicillin; clarithromycin; omeprazole.
    Clonazepam: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
    Clopidogrel: (Moderate) Coadministration of ramelteon with inhibitors of CYP2C9, such as clopidogrel, may lead to increases in the serum concentrations of ramelteon.
    Clorazepate: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
    Cobicistat: (Moderate) Monitor for an increase in ramelteon-related adverse reactions if coadministration with cobicistat is necessary. Ramelteon is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ramelteon exposure by 84%.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for an increase in ramelteon-related adverse reactions if coadministration with cobicistat is necessary. Ramelteon is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ramelteon exposure by 84%.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in ramelteon-related adverse reactions if coadministration with cobicistat is necessary. Ramelteon is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ramelteon exposure by 84%.
    Codeine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Codeine; Guaifenesin: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Codeine; Promethazine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Conivaptan: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as ramelteon, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2-3 times). Theoretically, similar pharmacokinetic effects could be seen with ramelteon. Treatment with ramelteon may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Cyclobenzaprine: (Moderate) Cyclobenzaprine may cause additive CNS depression if used concomitantly with other CNS depressants, such as anxiolytics, sedatives, and hypnotics. Combination therapy can cause additive effects of sedation and dizziness, which can impair the patient's ability to undertake tasks requiring mental alertness. Dosage adjustments of either or both medications may be necessary.
    Cyclosporine: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as cyclosporine, may lead to increases in the serum concentrations of ramelteon.
    Darunavir; Cobicistat: (Moderate) Monitor for an increase in ramelteon-related adverse reactions if coadministration with cobicistat is necessary. Ramelteon is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ramelteon exposure by 84%.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for an increase in ramelteon-related adverse reactions if coadministration with cobicistat is necessary. Ramelteon is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ramelteon exposure by 84%.
    Delavirdine: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as delavirdine, may lead to increases in the serum concentrations of ramelteon.
    Deutetrabenazine: (Moderate) Advise patients that concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as ramelteon, may have additive effects and worsen drowsiness or sedation.
    Diazepam: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Diltiazem: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as diltiazem, may lead to increases in the serum concentrations of ramelteon.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Disulfiram: (Moderate) Coadministration of ramelteon with inhibitors of CYP2C9, such as disulfiram, may lead to increases in the serum concentrations of ramelteon.
    Donepezil: (Moderate) Concurrent use of donepezil and ramelteon results in increased ramelteon exposure. If these agents are used together, monitor the patient closely for adverse effects. Use of donepezil 10 mg/day for 26 days and ramelteon as a single 8 mg dose resulted in increased mean AUC and Cmax of ramelteon of approximately 100% and 87%, respectively. No change was observed with regard to the active metabolite, M-II. Clinically meaningful changes in peak and total exposure of donepezil have not been observed.
    Donepezil; Memantine: (Moderate) Concurrent use of donepezil and ramelteon results in increased ramelteon exposure. If these agents are used together, monitor the patient closely for adverse effects. Use of donepezil 10 mg/day for 26 days and ramelteon as a single 8 mg dose resulted in increased mean AUC and Cmax of ramelteon of approximately 100% and 87%, respectively. No change was observed with regard to the active metabolite, M-II. Clinically meaningful changes in peak and total exposure of donepezil have not been observed.
    Doxepin: (Moderate) Concurrent use of doxepin and ramelteon results in increased ramelteon exposure. If these agents are used together, monitor the patient closely for adverse effects. Use of doxepin 10 mg/day for 23 days and ramelteon as a single 8 mg dose resulted in increased mean AUC and Cmax of ramelteon of approximately 66% and 69%, respectively. No change was observed with regard to the active metabolite, M-II. Clinically meaningful changes in peak and total exposure of doxepin have not been observed.
    Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Ramelteon is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Droperidol: (Moderate) Due to pharmacodynamic additive effects, also use caution when combining ramelteon with droperidol.
    Drospirenone; Ethinyl Estradiol: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as ethinyl estradiol, may lead to increases in the serum concentrations of ramelteon.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as ethinyl estradiol, may lead to increases in the serum concentrations of ramelteon.
    Elbasvir; Grazoprevir: (Moderate) Administering ramelteon with elbasvir; grazoprevir may result in elevated ramelteon plasma concentrations. Ramelteon is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Erythromycin: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as erythromycin, may lead to increases in the serum concentrations of ramelteon.
    Erythromycin; Sulfisoxazole: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as erythromycin, may lead to increases in the serum concentrations of ramelteon.
    Estazolam: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
    Eszopiclone: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
    Ethanol: (Major) Because alcohol by itself impairs psychomotor performance, and the intended effect of ramelteon is to promote sleep, patients should be cautioned not to consume alcohol when using ramelteon.
    Ethinyl Estradiol: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as ethinyl estradiol, may lead to increases in the serum concentrations of ramelteon.
    Ethinyl Estradiol; Desogestrel: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as ethinyl estradiol, may lead to increases in the serum concentrations of ramelteon.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as ethinyl estradiol, may lead to increases in the serum concentrations of ramelteon.
    Ethinyl Estradiol; Etonogestrel: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as ethinyl estradiol, may lead to increases in the serum concentrations of ramelteon.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as ethinyl estradiol, may lead to increases in the serum concentrations of ramelteon.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as ethinyl estradiol, may lead to increases in the serum concentrations of ramelteon.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as ethinyl estradiol, may lead to increases in the serum concentrations of ramelteon.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as ethinyl estradiol, may lead to increases in the serum concentrations of ramelteon.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as ethinyl estradiol, may lead to increases in the serum concentrations of ramelteon.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as ethinyl estradiol, may lead to increases in the serum concentrations of ramelteon.
    Ethinyl Estradiol; Norethindrone: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as ethinyl estradiol, may lead to increases in the serum concentrations of ramelteon.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as ethinyl estradiol, may lead to increases in the serum concentrations of ramelteon.
    Ethinyl Estradiol; Norgestimate: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as ethinyl estradiol, may lead to increases in the serum concentrations of ramelteon.
    Ethinyl Estradiol; Norgestrel: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as ethinyl estradiol, may lead to increases in the serum concentrations of ramelteon.
    Fenofibric Acid: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as ramelteon, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of ramelteon during coadministration with fenofibric acid.
    Fentanyl: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Fluconazole: (Moderate) The AUC and Cmax of ramelteon after a single 16 mg dose was increased by approximately 150% when administered with fluconazole (a CYP2C9 inhibitor). Ramelteon should be administered with caution in subjects taking strong CYP2C9 inhibitors such as fluconazole. The patient should be monitored closely for toxicity from ramelteon.
    Fluorouracil, 5-FU: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as fluorouracil, may lead to increases in the serum concentrations of ramelteon.
    Fluoxetine; Olanzapine: (Moderate) Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression including ramelteon.
    Flurazepam: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
    Fluvoxamine: (Severe) Ramelteon is contraindicated for use in combination with fluvoxamine, a strong CYP1A2 inhibitor; CYP1A2 is the major isozyme involved in the hepatic metabolism of ramelteon. When fluvoxamine 100 mg twice daily was administered for 3 days prior to single-dose co-administration of ramelteon 16 mg and fluvoxamine, the AUC for ramelteon increased roughly 190-fold, and the Cmax increased approximately 70-fold, compared to ramelteon administered alone.
    Food: (Major) Patients should avoid taking ramelteon with or immediately after a meal with high fat food, as the sleep promoting effects of ramelteon may be altered. After administration with a high fat meal, the systemic exposure of ramelteon was 31% higher, the maximum serum concentration (Cmax) was 22% lower, and the median time to the maximum serum concentration (Tmax) was 45 minutes longer as compared with the fasted state. Similar effects were noted with the pharmacokinetics of the active metabolite, M-II. In addition, ramelteon should likely not be taken with grapefruit juice; grapefruit juice might increase the risk for ramelteon side effects. Ramelteon is a high extraction ratio drug, and grapefruit inhibits enteric CYP3A4 activity.
    Grapefruit juice: (Major) Ramelteon should not taken with grapefruit or grapefruit juice. Ramelteon is a high extraction ratio drug, and grapefruit inhibits enteric CYP3A4 activity.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Haloperidol: (Moderate) An enhanced CNS depressant effect may occur when haloperidol is combined with other CNS depressants including sedating h1-blockers.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking ramelteon. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydromorphone: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Ibuprofen; Oxycodone: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with ramelteon, a CYP3A substrate, as ramelteon toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Imatinib: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as imatinib, may lead to increases in the serum concentrations of ramelteon.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with ramelteon may result in increased serum concentrations of ramelteon. Ramelteon is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isocarboxazid: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including ramelteon.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Administration of rifampin, a potent CYP1A2 enzyme inducer, may result in a decrease in total exposure to ramelteon. Efficacy may be reduced when ramelteon is used in combination with strong CYP1A2 enzyme inducers such as rifampin.
    Isoniazid, INH; Rifampin: (Moderate) Administration of rifampin, a potent CYP1A2 enzyme inducer, may result in a decrease in total exposure to ramelteon. Efficacy may be reduced when ramelteon is used in combination with strong CYP1A2 enzyme inducers such as rifampin.
    Itraconazole: (Moderate) Monitor for adverse reactions related to ramelteon if coadministration of itraconazole is necessary. A reduced dose of ramelteon may be necessary. Ramelteon is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC and Cmax of ramelteon by approximately 84% and 36%.
    Ivacaftor: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as ramelteon. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; ramelteon is partially metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates, such as ramelteon, can theoretically increase ramelteon exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Kava Kava, Piper methysticum: (Major) In general, patients taking ramelteon should avoid use of kava kava; the manufacturer advises avoidance of other medications that can have additive sedative effects.The German Commission E warns that any substances that act on the CNS, including ramelteon, may interact with kava kava, Piper methysticum. While the interactions can be pharmacodynamic in nature, kava kava has been reported to inhibit many CYP isozymes including CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A9/11; important pharmacokinetic interactions might occur with ramelteon, which is metabolized primarily by CYP1A2. If ramelteon and kava kava are taken together, the patient should immediately report any unusual side effects, as increased ramelteon serum concentrations could theoretically occur.
    Ketoconazole: (Moderate) Ramelteon should be used cautiously in combination with systemic ketoconazole, which is a strong CYP3A4 inhibitor. When ketoconazole 200 mg twice daily was administered for 3 days prior to single-dose coadministration of ramelteon 16 mg, the AUC and Cmax of ramelteon increased by approximately 84% and 36%, respectively. Similar increases were seen in regard to the active metabolite of ramelteon, M-II. The patient should be monitored closely for toxicity from ramelteon if coadministration cannot be avoided.Topical ketoconazole products are not expected to interact.
    Leflunomide: (Moderate) Coadministration of ramelteon with inhibitors of CYP2C9, such as leflunomide, may lead to increases in the serum concentrations of ramelteon.
    Letermovir: (Moderate) Plasma concentrations of ramelteon could be increased when administered concurrently with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. If these drugs are given together, closely monitor for reduced ramelteon efficacy and ramelteon-related adverse events. Ramelteon is a substrate of CYP3A4. Letermovir a moderate inhibitor of CYP3A4. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, administration of ramelteon with another strong CYP3A4 inhibitor increased the exposure and maximum plasma concentration of ramelteon by approximately 84% and 36%, respectively.
    Levorphanol: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Lithium: (Moderate) Because lithium has the potential to impair cognitive and motor skills, caution is advisable during concurrent use of other medications with centrally-acting effects including anxiolytics, sedatives, and hypnotics.
    Lofexidine: (Moderate) Monitor for excessive sedation during coadministration of lofexidine and ramelteon. Lofexidine can potentiate the effects of CNS depressants.
    Lorazepam: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
    Lumacaftor; Ivacaftor: (Minor) Concomitant use of ramelteon and lumacaftor; ivacaftor may alter ramelteon exposure; caution and close monitoring are advised if these drugs are used together. Ramelteon is a minor substrate of CYP3A4 and CYP2C9. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce and and/or inhibit CYP2C9. Although induction of ramelteon through the secondary CYP3A pathway may lead to decreases in drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear.
    Lumacaftor; Ivacaftor: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as ramelteon. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; ramelteon is partially metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates, such as ramelteon, can theoretically increase ramelteon exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Lurasidone: (Moderate) Due to the CNS effects of lurasidone, caution should be used when lurasidone is given in combination with other centrally acting medications such as anxiolytics, sedatives, and hypnotics.
    Melatonin: (Major) Because of pharmacologic similarities in action as melatonin-receptor agonists, melatonin should not be coadministered with ramelteon. The actions would be expected to be duplicative, and might result in additive side effects, such as somnolence, headache, unusual behaviors or moods, memory impairment, or balance and coordination issues. In a clinical trial, there was clear evidence for a transitory pharmacodynamic interaction between melatonin and another hypnotic agent one hour following co-dosing. Concomitant administration resulted in increased impairment of attention, memory and coordination compared to the hypnotic agent alone. Use of more than one agent for hypnotic purposes may increase the risk for over-sedation, CNS effects, or sleep-related behaviors. Be alert for unusual changes in moods or behaviors. Patients should be advised to avoid dietary supplements containing melatonin.
    Meperidine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Meperidine; Promethazine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Meprobamate: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
    Methadone: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Metoclopramide: (Minor) Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.
    Metronidazole: (Moderate) Coadministration of ramelteon with inhibitors of CYP2C9, such as metronidazole, may lead to increases in the serum concentrations of ramelteon.
    Mexiletine: (Major) Coadministration of ramelteon with inhibitors of CYP1A2, such as mexiletine, may lead to increases in the serum concentrations of ramelteon.
    Midazolam: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
    Mifepristone: (Moderate) Ramelteon should be administered with caution in subjects taking strong CYP3A4 inhibitors. Because ramelteon is partially metabolized via CYP3A4, an increase in exposure of ramelteon is expected. An increase in ramelteon AUC by approximately 84% and Cmax by 36% was noted when coadministered with a strong CYP3A4 inhibitor (ketoconazole). Similar increases were noted in M-II pharmacokinetics. Patients should be monitored for increased ramelteon side effects. Examples of CYP3A4 inhibitors include: chloramphenicol, conivaptan, cyclosporine, dalfopristin; quinupristin, delavirdine, diltiazem, erythromycin, ethinyl estradiol, imatinib, STI-571, itraconazole, systemic miconazole, mifepristone, troleandomycin, verapamil, voriconazole, and zafirlukast. This list is not inclusive of all CYP3A4 inhibitors. Imatinib, voriconazole, and zafirlukast are also CYP2C9 inhibitors, and when administered with ramelteon may result in multiple hepatic enzyme inhibition interactions, although the significance of these interactions has not been studied. The patient should be monitored closely for ramelteon-associated toxicity.
    Mitotane: (Major) Use caution if mitotane and ramelteon are used concomitantly, and monitor for decreased efficacy of ramelteon and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and ramelteon is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of ramelteon. Administration of another strong CYP inducer, rifampin, for 11 days resulted in a mean decrease of approximately 80% (40% to 90%) in total exposure to ramelteon and metabolite M-II, (both AUC and Cmax) after a single 32 mg dose of ramelteon.
    Monoamine oxidase inhibitors: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including ramelteon.
    Morphine: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Morphine; Naltrexone: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Nabilone: (Moderate) Concomitant use of nabilone with other CNS depressants can potentiate the effects of nabilone on respiratory depression.
    Norfloxacin: (Major) Theoretically, ramelteon should be administered with caution to patients taking CYP1A2 inhibitors, such as norfloxacin. Other CYP1A2 inhibitors have been shown to have significant interactions with ramelteon, leading to elevated ramelteon AUC > 190-fold and Cmax > 70-fold. If norfloxacin must be administered with ramelteon, monitor the patient closely for toxicity due to elevated ramelteon serum concentrations.
    Obeticholic Acid: (Major) Ramelteon should be administered with caution to patients taking CYP1A2 inhibitors. Strong CYP1A2 inhibitors have been shown to have significant interactions with ramelteon, leading to elevated AUC of ramelteon > 190-fold and Cmax > 70-fold. Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as ramelton. Co-administer ramelteon with caution and monitor for ramelteon-associated side effects.
    Olanzapine: (Moderate) Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression including ramelteon.
    Oritavancin: (Moderate) Coadministration of oritavancin and ramelteon may result in increases or decreases in ramelteon exposure and may increase side effects or decrease efficacy of ramelteon. Ramelteon is metabolized by CYP3A4 and CYP2C9. Oritavancin weakly induces CYP3A4, while weakly inhibiting CYP2C9. If these drugs are administered concurrently, monitor the patient for signs of toxicity or lack of efficacy.
    Oxazepam: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
    Oxycodone: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Oxymorphone: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and ramelteon, a CYP3A4 substrate, may cause an increase in systemic concentrations of ramelteon. Use caution when administering these drugs concomitantly.
    Perampanel: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as ramelteon.
    Phenelzine: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including ramelteon.
    Phenicol Derivatives: (Moderate) The AUC and Cmax of ramelteon may be increased by strong CYP3A4 inhibitors such as chloramphenicol.
    Phentermine; Topiramate: (Major) Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering.
    Posaconazole: (Moderate) Posaconazole and ramelteon should be coadministered with caution due to an increased potential for ramelteon-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of ramelteon. These drugs used in combination may result in elevated ramelteon plasma concentrations, causing an increased risk for ramelteon-related adverse events.
    Pregabalin: (Moderate) The concomitant use of pregabalin with ramelteon may augment the CNS depressant effect of pregabalin and/or ramelteon.
    Protease inhibitors: (Moderate) The serum concentrations of ramelteon may increase when ramelteon is administered with strong CYP3A4 inhibitors like the anti-retroviral protease inhibitors. Because there is the potential for multiple CYPP450 enzyme inhibition interactions between protease inhibitors and ramelteon, caution should be used if these 2 drugs are coadministered. The patient should be monitored closely for toxicity even though ramelteon has a wide therapeutic index.
    Quazepam: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
    Rasagiline: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including anxiolytics, sedatives, and hypnotics, including ramelteon, a melatonin-receptor agonist used to induce sleep. Use these drugs cautiously with MAOIs; warn patients to not drive or perform other hazardous activities until they know how a particular drug combination affects them. In some cases, the dosages of the CNS depressants may need to be reduced.
    Remifentanil: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Ribociclib: (Moderate) Monitor for an increase in ramelteon-related adverse reactions if coadministration with ribociclib is necessary. Ramelteon is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ramelteon exposure by 84%.
    Ribociclib; Letrozole: (Moderate) Monitor for an increase in ramelteon-related adverse reactions if coadministration with ribociclib is necessary. Ramelteon is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ramelteon exposure by 84%.
    Rifabutin: (Moderate) Administration of rifabutin, a CYP1A2 enzyme inducer, may theoretically result in decreased exposure to ramelteon. Monitor the patient closely if rifabutin therapy is initiated or stopped in patients receiving ramelteon.
    Rifampin: (Moderate) Administration of rifampin, a potent CYP1A2 enzyme inducer, may result in a decrease in total exposure to ramelteon. Efficacy may be reduced when ramelteon is used in combination with strong CYP1A2 enzyme inducers such as rifampin.
    Rotigotine: (Moderate) Concomitant use of rotigotine with other CNS depressants, such as ramelteon, can potentiate the sedation effects of rotigotine.
    Rucaparib: (Moderate) Monitor for an increase in ramelteon-related adverse reactions if coadministration with rucaparib is necessary. Ramelteon is a CYP1A2 substrate and rucaparib is a moderate CYP1A2 inhibitor.
    Safinamide: (Moderate) Dopaminergic medications, including safinamide, may cause a sudden onset of somnolence which sometimes has resulted in motor vehicle accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. Because of possible additive effects, advise patients about the potential for increased somnolence during concurrent use of safinamide with other sedating medications, such as Ramelteon.
    Sedating H1-blockers: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as ramelteon.
    Selegiline: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including ramelteon.
    Simeprevir: (Moderate) Simeprevir, a mild CYP1A2 inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of ramelteon, which is a CYP1A2 and CYP3A4 substrate. Monitor patients for adverse effects of ramelteon, such as CNS effects.
    Sufentanil: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Ramelteon should be administered with caution to patients taking CYP2C9 inhibitors, such as sulfamethoxazole. The AUC and Cmax of ramelteon have been elevated > 150% when administered with other CYP2C9 inhibitors. The patient should be monitored closely for toxicity even though ramelteon has a wide therapeutic index.
    Sulfinpyrazone: (Moderate) Coadministration of ramelteon with inhibitors of CYP2C9, such as sulfinpyrazone, may lead to increases in the serum concentrations of ramelteon.
    Suvorexant: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. These agents include any other sedatives and hypnotics. Ramelteon and suvorexant would be considered duplicate treatments and use together should generally be avoided.
    Tacrine: (Severe) Concurrent use of ramelteon and strong inhibitors of CYP1A2, such as tacrine, is not advised. CYP1A2 is the major isozyme involved in the hepatic metabolism of ramelteon. Tacrine has a potent CYP1A2 inhibitory effect. Ramelteon should not be used with strong CYP1A2 inhibitors, as the ramelteon AUC and Cmax will be substantially increased. Coadministration with another strong CYP1A2 inhibitor, fluvoxamine, elevated the AUC of ramelteon > 190-fold and the Cmax > 70 fold; the combination is contraindicated.
    Tapentadol: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Tasimelteon: (Severe) Because of pharmacologic similarities in action as melatonin-receptor agonists, ramelteon should not be coadministered with tasimelteon. The actions would be expected to be duplicative, and might result in additive side effects, such as somnolence, headache, unusual behaviors or moods, memory impairment, or balance and coordination issues.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering ramelteon with telaprevir due to an increased potential for ramelteon-related adverse events. If ramelteon dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of ramelteon. Ramelteon is partially metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated ramelteon plasma concentrations.
    Telithromycin: (Moderate) Concentrations of ramelteon may be increased with concomitant use of telithromycin. Ramelteon is a CYP3A4 substrate and telithromycin is a strong CYP3A4 inhibitor. Patients should be monitored for increased side effects.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and ramelteon is necessary, as the systemic exposure of ramelteon may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of ramelteon; consider increasing the dose of ramelteon if necessary. Ramelteon is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Temazepam: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
    Tezacaftor; Ivacaftor: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as ramelteon. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; ramelteon is partially metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates, such as ramelteon, can theoretically increase ramelteon exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Thalidomide: (Major) Avoid the concomitant use of thalidomide with anxiolytics, sedatives, and hypnotics due to the potential for additive sedative effects.
    Thiabendazole: (Major) Thiabendazole is a potent inhibitor of CYP1A2 hepatic enzymes. Concurrent use of ramelteon and strong inhibitors of CYP1A2, such as thiabendazole, should be avoided. CYP1A2 is the major isozyme involved in the hepatic metabolism of ramelteon. Ramelteon should not be used with strong CYP1A2 inhibitors, as the ramelteon AUC and Cmax will be substantially increased. Coadministration with a strong CYP1A2 inhibitor elevated the AUC of ramelteon > 190-fold and the Cmax > 70 fold.
    Tizanidine: (Moderate) Concurrent use of tizanidine and CNS depressants like ramelteon can cause additive CNS depression.
    Tobacco: (Moderate) Efficacy may be reduced when ramelteon is used in combination with strong CYP1A2 enzyme inducers such as tobacco smoking.
    Topiramate: (Major) Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering.
    Tramadol: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Trandolapril; Verapamil: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as verapamil, may lead to increases in the serum concentrations of ramelteon.
    Tranylcypromine: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including ramelteon.
    Trazodone: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS depressant effects, including possible respiratory depression or hypotension. A dose reduction of one or both drugs may be warranted.
    Triazolam: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
    Valerian, Valeriana officinalis: (Major) In general, patients taking ramelteon should avoid use of valerian; the manufacturer advises avoidance of other medications that can have additive sedative effects. It is not known if ramelteon interacts with valerian, Valeriana officinalis; however, additive pharmacodynamic effects mgiht occur. Any substances that act on the CNS may theoretically interact with valerian. The valerian derivative, dihydrovaltrate, binds at barbiturate binding sites; valerenic acid has been shown to inhibit enzyme-induced breakdown of GABA in the brain; the non-volatile monoterpenes (valepotriates) have sedative activity.
    Vemurafenib: (Moderate) Concomitant use of vemurafenib and ramelteon may result in altered concentrations of ramelteon. Vemurafenib is an inhibitor of CYP2C9 and CYP1A2 and an inducer of CYP3A4. Ramelteon is a substrate of CYP2C9, CYP1A2, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    Verapamil: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as verapamil, may lead to increases in the serum concentrations of ramelteon.
    Vigabatrin: (Moderate) Vigabatrin may cause somnolence and fatigue. Drugs that can cause CNS depression, if used concomitantly with vigabatrin, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when vigabatrin is given with ramelteon.
    Vilazodone: (Moderate) Due to the CNS effects of vilazodone, caution should be used when vilazodone is given in combination with other centrally acting medications such as anxiolytics, sedatives, and hypnotics.
    Voriconazole: (Moderate) Monitor for an increase in ramelteon-related adverse reactions if coadministration with voriconazole is necessary. Ramelteon is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ramelteon exposure by 84%.
    Zafirlukast: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as zafirlukast, may lead to increases in the serum concentrations of ramelteon.
    Zaleplon: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
    Zileuton: (Major) Ramelteon should be avoided in combination with potent CYP1A2 inhibitors, such as zileuton, if possible. CYP1A2 is the major isozyme involved in the metabolism of ramelteon. Strong CYP1A2 inhibitors have been shown to have significant interactions with ramelteon, leading to elevated ramelteon AUC > 190-fold and Cmax > 70-fold. If zileuton must be administered with ramelteon, monitor the patient closely for toxicity due to elevated ramelteon serum concentrations.
    Zolpidem: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.

    PREGNANCY AND LACTATION

    Pregnancy

    It is not known whether ramelteon is excreted into the milk of breast-feeding women, and caution is advisable when administering ramelteon during lactation. Ramelteon is excreted into the milk of lactating rats.

    MECHANISM OF ACTION

    Mechanism of Action: Ramelteon is the first in a new class of agents termed melatonin receptor agonists. Melatonin receptors belong to the 7 transmembrane G protein-coupled receptor family. The 3 subtypes of mammalian melatonin receptors that have been identified are MT1, MT2, and MT3. Ramelteon selectively targets the melatonin receptors MT1 and MT2, which are located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN functions as the body's internal clock and regulates the 24-hour sleep-wake cycle. The MT1 and MT2 receptors are believed to be involved in the promotion of sleep and the maintenance of the normal circadian rhythm (shift between day and night), respectively, when acted upon by endogenous melatonin. The activation of the MT1 and MT2 receptor sites is associated with the inhibition of adenylate cyclase and the resultant decrease in cAMP accumulation. Ramelteon has 3—16 times higher affinity for human MT1 and MT2 receptors than melatonin. Compared to exogenous melatonin, ramelteon may preferentially select MT1 over MT2 and, therefore, may be more suitable therapy for sleep-onset insomnia. Although the results from animal studies suggest that the MT1 and MT2 receptors have distinct functional roles in the SCN, there may be some overlap in function. In animal and human clinical trials, ramelteon appears to be modestly effective in both shortening the the delay to sleep onset and increasing the total amount of sleep time. MT3 receptors appear to be a form of quinone reductase. The importance of melatonin-binding to the MT3 receptor is not well-defined; ramelteon has limited affinity for this site.Unlike the benzodiazepines, ramelteon has not been shown to decrease rapid eye movement (REM) sleep. In animal studies, ramelteon has not been shown to exhibit the reward properties of benzodiazepines or morphine, which suggests that MT1 and MT2 receptor agonists have minimal abuse potential. Ramelteon has shown no affinity for the GABA-receptor complex, which is the primary target area for many of the current hypnotics on the market including the benzodiazepines and the newer agents zolpidem and zaleplon. Ramelteon also shows very low affinity for MT3 binding site, as well as receptors that bind neuropeptides, cytokines, serotonin, dopamine, noradrenaline, acetylcholine, and opiates.

    PHARMACOKINETICS

    Ramelteon is administered orally.  In vitro protein binding of ramelteon is roughly 82% with binding primarily to albumin. Ramelteon is not distributed selectively to red blood cells; however, the drug has a mean volume of distribution of 73.6 L after IV administration, which suggests substantial tissue distribution. Metabolized occurs primarily by oxidation and secondarily to form glucuronide conjugates. Ramelteon metabolites (M-I, M-II, M-III, and M-IV) are rapidly formed and eliminated (half-life of 1—3 h). M-II is the only major active metabolite; M-II has approximately one tenth and one fifth the binding affinity of the parent molecule for the human MT1 and MT2 receptors, respectively. The M-II metabolite is 17—25 fold 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—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. CYP1A2 is the major isozyme involved in the hepatic metabolism of ramelteon (see Drug Interactions); the CYP2C subfamily and CYP3A4 isozymes are involved to a minor degree. Drug elimination is 84% renal and 4% fecal; the metabolites account for the majority of the dose eliminated. Less than 0.1% of a ramelteon dose is eliminated unchanged. Repeat once daily dosing does not result in significant accumulation due to the short elimination half-life ranging from 1—2.6 hours. The half-life of the major metabolite, M-II, ranges from 2—5 hours and is independent of dose. Serum concentrations of ramelteon and the M-II metabolite are essentially undetectable at 24 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP2C9, CYP3A4
    Cytochrome P450 (CYP) 1A2 is the major isozyme involved in the hepatic metabolism of ramelteon; the CYP2C subfamily and CYP3A4 isozymes are also involved to a minor degree. In vitro studies have been undertaken to evaluate the effect of CYP inducers or inhibitors when ramelteon is acting as a substrate. Interaction studies with fluoxetine (CYP2D6 inhibitor), omeprazole (a CYP1A2 inducer and CYP2C19 inhibitor), theophylline (CYP1A2 substrate), and dextromethorphan (CYP2D6 substrate) have not revealed clinically meaningful changes in either peak (Cmax) or total (AUC) exposures to ramelteon or the M-II metabolite. Additionally, ramelteon has been evaluated for its effect as an inducer or inhibitor on different substrates. It did not cause clinically meaningful changes in either the peak or total exposure of omeprazole (CYP2C19 substrate), dextromethorphan (CYP2D6 substrate), midazolam (CYP3A4 substrate), theophylline (CYP1A2 substrate), digoxin (p-glycoprotein substrate), warfarin (CYP2C9 (S)/CYP1A2 (R) substrate), venlafaxine, sertraline, escitalopram, or gabapentin. It appears unlikely that ramelteon would act as an inducer or inhibitor of CYP hepatic enzymes; however, more study is needed.
     

    Oral Route

    Following oral administration, ramelteon (16 mg PO) is rapidly absorbed (tmax = 0.3 h) and exhibits linear pharmacokinetics. Median peak concentrations occur at roughly 0.75 hour (range 0.5—1.5 hours) after fasted oral administration. A high fat meal can alter the oral absorption of ramelteon and should be avoided during or immediately before the ramelteon dose. Although the total absorption of ramelteon is at least 84%, the absolute oral bioavailability following a single oral dose is low (1.8%) due to extensive first-pass metabolism. Extensive first-pass metabolism is evidenced by low concentrations of the unchanged compound in both urine and plasma. Maximal serum concentration (Cmax) and area under the concentration-time curve (AUC) data show substantial intersubject variability, which is consistent with the high first-pass effect; the coefficient of variation for these values is approximately 100%.

    Intravenous Route

    Although not clinically administered via IV injection, ramelteon has a mean volume of distribution after IV administration of 73.6 L, which suggests substantial tissue distribution.