Rozerem (ramelteon)

The recommended adult dosage of ramelteon for the management of insomnia is 8 mg within 30 minutes of bedtime.

Ramelteon is administered orally within 30 minutes of bedtime. The drug should not be administered with or immediately after a high-fat meal because of a potentially decreased rate of absorption. (See Description.)

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Ramelteon/Fluvoxamine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fluvoxamine may inhibit the metabolism of ramelteon by CYP1A2.(1)

CLINICAL EFFECTS: Concurrent use of fluvoxamine may result in elevated levels of and toxicity from ramelteon.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of ramelteon states that concurrent use of fluvoxamine is contraindicated.(1) The US manufacturer of fluvoxamine states that ramelteon should not be used with fluvoxamine.(2)

DISCUSSION: Pretreatment for 3 days with fluvoxamine (100 mg twice daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of ramelteon (16 mg) by 190-fold and 70-fold, respectively.(1,2) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Selected Cyp1a2 Substrates/Viloxazine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Viloxazine is a strong inhibitor of CYP1A2 and may increase the total exposure of sensitive CYP1A2 substrates.(1) The FDA defines strong inhibition as an increase in drug area-under-curve (AUC) greater than 5-fold.(2)

CLINICAL EFFECTS: Concurrent use of viloxazine with drugs primarily metabolized by CYP1A2 may lead to elevated drug levels and increase the risk of adverse reactions associated with the CYP1A2 substrate.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Drugs linked to this monograph have a narrow therapeutic window or are sensitive to CYP1A2 inhibition. Coadministration of viloxazine with sensitive CYP1A2 substrates or CYP1A2 substrates with a narrow therapeutic window is contraindicated.(1)

DISCUSSION: Concomitant use of viloxazine significantly increases the total exposure, but not peak exposure, of sensitive CYP1A2 substrates, which may increase the risk of adverse reactions associated with these CYP1A2 substrates. In a study, viloxazine increased the AUC of caffeine by almost 6-fold.(1) CYP1A2 substrates linked to this monograph include: agomelatine, alosetron, aminophylline, duloxetine, ramelteon, tasimelteon, and theophylline.(2,3)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Ramelteon; Suvorexant; Tasimelteon/Strong Cyp3a4 Inducers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of ramelteon, suvorexant or tasimelteon.(1-3)

CLINICAL EFFECTS: Concurrent use with strong inducers of CYP3A4 may result in substantially lower systemic concentrations and decreased efficacy of ramelteon, suvorexant or tasimelteon.(1-3)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Ramelteon: The manufacturer notes that ramelteon efficacy may be reduced when used in combination with a strong CYP3A4 inducer.(1) Suvorexant: If possible, use alternatives to strong CYP3A4 inducers in patients who require suvorexant therapy. Patients requiring concurrent therapy may need larger doses of suvorexant; however, the maximum daily dose of 20 mg should not be exceeded.(2) Tasimelteon: The manufacturer of tasimelteon recommends avoiding concurrent use with strong CYP3A4 inducers due to the potentially large decrease in tasimelteon exposure and reduced efficacy.(3)

DISCUSSION: Rifampin (600 mg daily for 11 days) decreased both maximum concentration (Cmax) and total exposure (area-under-curve or AUC) to ramelteon by 80%.(1) In an interaction study, rifampin substantially decreased levels of suvorexant. Suvorexant AUC and Cmax decreased by approximately 90% and 70%, respectively.(2) Rifampin (600 mg daily for 11 days) decreased exposure to tasimelteon by 90%.(3) Strong inducers of CYP3A4 include apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine and St. John's wort.(4-5)

Sleep Drugs/Opioids (Cough And Cold)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of opioids and sleep drugs or tranquilizers may result in additive CNS depression and sleep-related disorders.(1)

CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as sleep drugs or tranquilizers, may result in profound sedation, respiratory depression, coma, and/or death.(1) Concurrent use of opioids with eszopiclone, zaleplon, or zolpidem may increase the risk of sleep-related disorders including central sleep apnea and sleep-related hypoxemia, and complex sleep behaviors like sleepwalking, sleep driving, and other activities while not fully awake. Rarely, serious injuries or death have resulted from complex sleep behaviors.(2)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Avoid prescribing opioid-including cough medications for patients taking CNS depressants such as sleep drugs or tranquilizers.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(3) If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who have had a previous episode of complex sleep behavior.(2) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(4)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10) As of April 2019, the FDA had identified 66 cases of complex sleep behaviors with eszopiclone, zaleplon, or zolpidem, of which 20 cases resulted in death and the remainder resulted in serious injuries. It was not reported how many of the cases involved concomitant use of other CNS depressants.(2)

Sleep Drugs; Tranquilizers/Methadone (Cough And Cold)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of methadone and sleep drugs or tranquilizers may result in additive CNS depression and sleep-related disorders.(1)

CLINICAL EFFECTS: Concurrent use of methadone and other CNS depressants, such as sleep drugs or tranquilizers, may result in profound sedation, respiratory depression, coma, and/or death.(1) Concurrent use of methadone with eszopiclone, zaleplon, or zolpidem may increase the risk of sleep-related disorders including central sleep apnea and sleep-related hypoxemia, and complex sleep behaviors like sleepwalking, sleep driving, and other activities while not fully awake. Rarely, serious injuries or death have resulted from complex sleep behaviors.(2)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Avoid prescribing opioid-including cough medications for patients taking CNS depressants such as sleep drugs or tranquilizers.(1) If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who have had a previous episode of complex sleep behavior.(2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression. Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(5) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(6) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(7) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(8) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(9) As of April 2019, the FDA had identified 66 cases of complex sleep behaviors with eszopiclone, zaleplon, or zolpidem, of which 20 cases resulted in death and the remainder resulted in serious injuries. It was not reported how many of the cases involved concomitant use of other CNS depressants.(2)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Sleep Drugs/Opioids (Extended Release)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of opioids and sleep drugs may result in additive CNS depression and sleep-related disorders.(1)

CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as sleep drugs, may result in profound sedation, respiratory depression, coma, and/or death.(1) Concurrent use of opioids with eszopiclone, zaleplon, or zolpidem may increase the risk of sleep-related disorders including central sleep apnea and sleep-related hypoxemia and complex sleep behaviors like sleepwalking, sleep driving, and other activities while not fully awake. Rarely, serious injuries or death have resulted from complex sleep behaviors.(2)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as sleep drugs to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(3) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who have had a previous episode of complex sleep behavior.(2) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(4)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10) As of April 2019, the FDA had identified 66 cases of complex sleep behaviors with eszopiclone, zaleplon, or zolpidem, of which 20 cases resulted in death and the remainder resulted in serious injuries. It was not reported how many of the cases involved concomitant use of other CNS depressants.(2)

Sleep Drugs/Opioids (Immediate Release)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of opioids and sleep drugs may result in additive CNS depression and sleep-related disorders.(1)

CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as sleep drugs, may result in profound sedation, respiratory depression, coma, and/or death.(1) Concurrent use of opioids with eszopiclone, zaleplon, or zolpidem may increase the risk of sleep-related disorders including central sleep apnea and sleep-related hypoxemia and complex sleep behaviors like sleepwalking, sleep driving, and other activities while not fully awake. Rarely, serious injuries or death have resulted from complex sleep behaviors.(2)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as sleep drugs to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(3) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who have had a previous episode of complex sleep behavior.(2) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(4)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10) As of April 2019, the FDA had identified 66 cases of complex sleep behaviors with eszopiclone, zaleplon, or zolpidem, of which 20 cases resulted in death and the remainder resulted in serious injuries. It was not reported how many of the cases involved concomitant use of other CNS depressants.(2)

Sleep Drugs/Selected Opioids For Mat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of buprenorphine or diacetylmorphine and sleep drugs may result in additive CNS depression and sleep-related disorders.(1-3)

CLINICAL EFFECTS: Concurrent use of buprenorphine or diacetylmorphine and other CNS depressants, such as sleep drugs, may result in profound sedation, respiratory depression, coma, and/or death.(1-3) Concurrent use of opioids with eszopiclone, zaleplon, or zolpidem may increase the risk of sleep-related disorders including central sleep apnea and sleep-related hypoxemia, and complex sleep behaviors like sleepwalking, sleep driving, and other activities while not fully awake. Rarely, serious injuries or death have resulted from complex sleep behaviors.(4)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Medication assisted treatment (MAT) with buprenorphine or diacetylmorphine is not contraindicated in patients taking CNS depressants; however, discontinuation of CNS depressants is preferred in most cases. In some cases, monitoring at a higher level of care may be appropriate. In others, gradual tapering or decreasing to the lowest effective dose of the CNS depressant is appropriate. Consider other medications and nonpharmacologic treatments to address anxiety or insomnia. Ensure that other health care providers prescribing other CNS depressants are aware of the patient's buprenorphine or diacetylmorphine treatment.(2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(5) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who have had a previous episode of complex sleep behavior.(4) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(6)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(7) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(8) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(9) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(10) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(11) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(12) While concomitant use of MAT with CNS depressants increases the risk of adverse reactions, barriers to MAT can pose a greater risk of morbidity and mortality due to opioid use disorder.(2) As of April 2019, the FDA had identified 66 cases of complex sleep behaviors with eszopiclone, zaleplon, or zolpidem, of which 20 cases resulted in death and the remainder resulted in serious injuries. It was not reported how many of the cases involved concomitant use of other CNS depressants.(4)

Sleep Drugs; Tranquilizers/Levomethadone; Methadone For Mat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of methadone and sleep drugs or tranquilizers may result in additive CNS depression and sleep-related disorders.(1,2) Levomethadone is an enantiomer of methadone.(3)

CLINICAL EFFECTS: Concurrent use of methadone and other CNS depressants, such as sleep drugs or tranquilizers, may result in profound sedation, respiratory depression, coma, and/or death.(1,2) Concurrent use of opioids with eszopiclone, zaleplon, or zolpidem may increase the risk of sleep-related disorders including central sleep apnea and sleep-related hypoxemia, and complex sleep behaviors like sleepwalking, sleep driving, and other activities while not fully awake. Rarely, serious injuries or death have resulted from complex sleep behaviors.(4)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Medication assisted treatment (MAT) with methadone is not contraindicated in patients taking CNS depressants; however, discontinuation of CNS depressants is preferred in most cases. In some cases, monitoring at a higher level of care may be appropriate. In others, gradual tapering or decreasing to the lowest effective dose of the CNS depressant is appropriate. Consider other medications and nonpharmacologic treatments to address anxiety or insomnia. Ensure that other health care providers prescribing other CNS depressants are aware of the patient's buprenorphine or methadone treatment.(2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression. Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who have had a previous episode of complex sleep behavior.(4) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(5)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(6) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(7) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(8) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(9) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(10) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(11) While concomitant use of MAT with CNS depressants increases the risk of adverse reactions, barriers to MAT can pose a greater risk of morbidity and mortality due to opioid use disorder.(2) As of April 2019, the FDA had identified 66 cases of complex sleep behaviors with eszopiclone, zaleplon, or zolpidem, of which 20 cases resulted in death and the remainder resulted in serious injuries. It was not reported how many of the cases involved concomitant use of other CNS depressants.(4)

Sleep Drugs;Tranquil/Levomethadone;Methadone (Immediate Rel)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of methadone and sleep drugs or tranquilizers may result in additive CNS depression and sleep-related disorders.(1) Levomethadone is an enantiomer of methadone.(2)

CLINICAL EFFECTS: Concurrent use of methadone and other CNS depressants, such as sleep drugs or tranquilizers, may result in profound sedation, respiratory depression, coma, and/or death.(1) Concurrent use of opioids with eszopiclone, zaleplon, or zolpidem may increase the risk of sleep-related disorders including central sleep apnea and sleep-related hypoxemia, and complex sleep behaviors like sleepwalking, sleep driving, and other activities while not fully awake. Rarely, serious injuries or death have resulted from complex sleep behaviors.(3)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as sleep drugs or tranquilizers to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(4) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who have had a previous episode of complex sleep behavior.(3) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(5)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(6) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(7) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(8) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(9) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(10) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(11) As of April 2019, the FDA had identified 66 cases of complex sleep behaviors with eszopiclone, zaleplon, or zolpidem, of which 20 cases resulted in death and the remainder resulted in serious injuries. It was not reported how many of the cases involved concomitant use of other CNS depressants.(2)

Hypersensitivity to ramelteon or any ingredient in the formulation.

There are no contraindication contraindications for this drug.

• Alcohol use disorder
• Suicidal ideation

• Complex sleep behavior
• Depression
• Disease of liver
• Hyperprolactinemia

Adverse effects reported in 2% or more of patients receiving ramelteon during clinical trials include headache, somnolence, fatigue, dizziness, nausea, exacerbation of insomnia, upper respiratory tract infection, diarrhea, myalgia, depression, dysgeusia, and arthralgia.

Less Frequent

• Depression

Rare or Very Rare

• Amenorrhea
• Anaphylaxis
• Angioedema
• Behavioral disorders
• Dyspnea
• Galactorrhea not associated with childbirth
• Libido changes

More Frequent

• Dizziness
• Drowsy
• Fatigue
• Headache disorder
• Nausea

Less Frequent

• Arthralgia
• Diarrhea
• Dysgeusia
• Myalgia
• Upper respiratory infection

Rare or Very Rare

• Acute cognitive impairment
• Androgen deficiency
• Ataxia
• Complex sleep behavior
• Hallucinations
• Hyperprolactinemia

No enhanced messaging available.

Safety and efficacy of ramelteon have not been established in pediatric patients.

Category C. (See Users Guide.) Ramelteon has no established use in labor or delivery.

Distributed into milk in rats; not known whether ramelteon is distributed into human milk. Use in nursing women is not recommended.

Increased exposure to ramelteon has been reported in geriatric patients. However, no substantial differences in safety and efficacy relative to younger adults have been observed.