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    Non-Benzodiazepine, Benzodiazepine Receptor Agonists (NBRA)s

    BOXED WARNING

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

    Sedative-hypnotics can cause complex sleep-related behaviors such as phone calls, sexual activity, preparing and eating food, or sleep driving while not fully awake and in some cases having no memory of the event. These behaviors appear to be more frequent with nonbenzodiazepine benzodiazepine-receptor agonists (NBRAs), such as zolpidem, than other sedative-hypnotics. Although rare, serious injuries or death have occurred; therefore, zolpidem and other NBRAs are contraindicated in patients with a history of drug-induced complex sleep-related behaviors. Patients should be informed of the risks before receiving any medication from this class, including instructions to discontinue the medication if they experience a sleep-related episode and to contact their healthcare provider immediately. Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of NBRAs to the FDA MedWatch Safety Information and Adverse Event Reporting Program.[64083] Because zolpidem has a rapid onset of action and causes CNS depressant activity, zolpidem products indicated for insomnia due to difficulty with sleep initiation should only be administered immediately before retiring and with at least 7 to 8 hours remaining before the planned time of waking. Zolpidem products indicated for difficulty returning to sleep after middle-of-the-night awakenings should only be taken while the patient is in bed and has at least 4 hours of bedtime remaining before the planned time of waking. Vehicle drivers and machine operators should be warned that hypnotics, such as zolpidem, have a possible risk of adverse reactions including drowsiness, prolonged reaction time, dizziness, sleepiness, blurred/double vision, reduced alertness and impaired driving, even the day after use. Patients should be instructed to avoid driving or operating machinery or performing other tasks requiring mental alertness for at least 8 hours after taking immediate-release formulations, and patients receiving the extended-release formulation should be alerted about the potential impact on such activities the full day after use. Patients receiving zolpidem for middle-of-the-night awakenings should wait for at least 4 hours after dosing and until they feel fully awake before driving or engaging in other activities requiring full mental alertness. Because zolpidem can cause drowsiness and a decreased level of consciousness, there is a higher risk of falls, particularly in the elderly, with the potential for subsequent severe injuries. Zolpidem use has been associated with severe injuries such as hip fractures and intracranial hemorrhage. Due to gender differences in the elimination of zolpidem, a lower initial dose is recommended in adult females (women). Plasma levels of zolpidem in some patients, particularly women, may be high enough the morning after use to impair activities requiring mental alertness, such as driving. The risk for next-morning impairment is higher if zolpidem products are taken without adherence to the proper hours for sleep recommended following use or if a higher than the recommended dose is taken. Risks for impairment are also increased during coadministration with other CNS depressants with zolpidem or with use of drugs that increase the blood levels of zolpidem. Concurrent alcohol or CNS depressant use increases the risk for CNS depression, impairment, complex sleep-related behaviors, and other additive effects. Patients taking zolpidem should avoid ethanol ingestion. Lower initial dosages of zolpidem should be considered in patients taking other CNS-depressant therapies. Anterograde amnesia may be particularly evident at zolpidem doses above 10 mg/day.[46915] [31451] [44125] [57789] [52842] [60089] [60090]

    DEA CLASS

    Rx, schedule IV

    DESCRIPTION

    Non-benzodiazepine sedative-hypnotic
    Primarily used for insomnia characterized by difficulties with sleep initiation or sleep maintenance; certain products may be used for middle-of-the night awakenings
    Zolpidem has been associated with sleep-related behaviors (e.g., talking, cooking, eating, or driving while not fully awake) and next-day psychomotor impairment; patients should be informed of these risks prior to treatment initiation

    COMMON BRAND NAMES

    Ambien, Ambien CR, Edluar, Intermezzo, Zolpimist

    HOW SUPPLIED

    Ambien CR/Zolpidem/Zolpidem Tartrate Oral Tab ER: 6.25mg, 12.5mg
    Ambien/Zolpidem/Zolpidem Tartrate Oral Tab: 5mg, 10mg
    Edluar/Intermezzo/Zolpidem/Zolpidem Tartrate Sublingual Tablet, SL: 1.75mg, 3.5mg, 5mg, 10mg
    Zolpimist Oropharyngeal Spray Met: 1actuation, 5mg

    DOSAGE & INDICATIONS

    For the treatment of insomnia.
    For the short-term treatment of insomnia characterized by difficulty with sleep initiation.
    Oral dosage (e.g., immediate-release oral tablets, such as Ambien)
    Adult Females

    Initially, 5 mg PO immediately before bedtime and with at least 7 to 8 hours remaining before the planned time of awakening; this is also the recommended dose for debilitated adults. Avoid co-use with other sedative-hypnotics, including other zolpidem products. During concurrent use of a CNS depressant, dosage adjustments of zolpidem and the CNS depressant may be necessary because of the potential for additive effects. Max: 10 mg/day if needed; however, the higher dose is more likely to cause next-day impairment. Use the lowest effective dose. Administer as a single dose and do not re-administer during the same night. The risk for next-morning impairment is higher if zolpidem is taken with less than a full night of sleep remaining (7 to 8 hours), if a higher than the recommended dose is taken, or if zolpidem is co-administered with other CNS depressants or drugs that increase the blood levels of zolpidem. A full night of sleep (7 to 8 hours) is recommended to minimize the risk of next-day impairment.

    Adult Males

    Initially, 5 to 10 mg PO immediately before bedtime and with at least 7 to 8 hours remaining before the planned time of awakening; 5 mg PO immediately before bedtime is the final dose recommended for debilitated adults. 5 mg PO at bedtime provides sufficient efficacy for many men, and this lower dosage should be considered. Use the lowest effective dose. Avoid co-use with other sedative-hypnotics, including other zolpidem products. During concurrent use of a CNS depressant, dosage adjustments of zolpidem and the CNS depressant may be necessary because of the potential for additive effects. Max: 10 mg/day if needed; however, the higher dose is more likely to cause next-day impairment. Administer as a single dose and do not re-administer during the same night. The risk for next-morning impairment is higher if zolpidem is taken with less than a full night of sleep remaining (7 to 8 hours), if a higher than the recommended dose is taken, or if zolpidem is co-administered with other CNS depressants or drugs that increase the blood levels of zolpidem. A full night of sleep (7 to 8 hours) is recommended to minimize the risk of next-day impairment.

    Geriatric Adults

    5 mg PO immediately before bedtime and with at least 7 to 8 hours remaining before the planned time of awakening. Use the lowest effective dose. Geriatric patients and debilitated adults are particularly sensitive to the effects of zolpidem. Avoid co-use with other sedative-hypnotics, including other zolpidem products. During concurrent use of a CNS depressant, dosage adjustments of zolpidem and the CNS depressant may be necessary because of the potential for additive effects. Administer as a single dose and do not re-administer during the same night. The risk for next-morning impairment is higher if zolpidem is taken with less than a full night of sleep remaining (7 to 8 hours), if a higher than the recommended dose is taken, or if zolpidem is co-administered with other CNS depressants or drugs that increase the blood levels of zolpidem. A full night of sleep (7 to 8 hours) is recommended to minimize the risk of next-day impairment. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of sedative/hypnotics in long-term care facility (LTCF) residents.Max: 5 mg/day PO in residents meeting the criteria for treatment, except when documentation is provided showing that higher doses are necessary to maintain or improve the resident's functional status. 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.

    Sublingual dosage (sublingual tablets; e.g., Edluar)
    Adult Females

    Initially, 5 mg sublingually immediately before bedtime and with at least 7 to 8 hours remaining before the planned time of awakening; this is also the recommended dose for debilitated adults. Avoid co-use with other sedative-hypnotics, including other zolpidem products. During concurrent use of a CNS depressant, dosage adjustments of zolpidem and the CNS depressant may be necessary because of the potential for additive effects. Use the lowest effective dose. Max: 10 mg/day if needed; however, the higher dose is more likely to cause next-day impairment. Administer as a single dose and do not re-administer during the same night. The risk for next-morning impairment is higher if zolpidem is taken with less than a full night of sleep remaining (7 to 8 hours), if a higher than the recommended dose is taken, or if zolpidem is co-administered with other CNS depressants or drugs that increase the blood levels of zolpidem. A full night of sleep (7 to 8 hours) is recommended to minimize the risk of next-day impairment.

    Adult Males

    Initially, 5 to 10 mg sublingually immediately before bedtime and with at least 7 to 8 hours remaining before the planned time of awakening; 5 mg PO at bedtime provides sufficient efficacy for many men, and this lower dosage should be considered. The 5 mg dose is recommended for debilitated adults. Use the lowest effective dose. Avoid co-use with other sedative-hypnotics, including other zolpidem products. During concurrent use of a CNS depressant, dosage adjustments of zolpidem and the CNS depressant may be necessary because of the potential for additive effects. Max: 10 mg/day if needed; however, the higher dose is more likely to cause next-day impairment. Administer as a single dose and do not re-administer during the same night. The risk for next-morning impairment is higher if zolpidem is taken with less than a full night of sleep remaining (7 to 8 hours), if a higher than the recommended dose is taken, or if zolpidem is co-administered with other CNS depressants or drugs that increase the blood levels of zolpidem. A full night of sleep (7 to 8 hours) is recommended to minimize the risk of next-day impairment, including effects on driving and performing other tasks requiring complete mental alertness.

    Geriatric Adults

    5 mg sublingually immediately before bedtime and with at least 7 to 8 hours remaining before the planned time of awakening. Use the lowest effective dose. Geriatric patients and debilitated adults may be particularly sensitive to the effects of the drug. Avoid co-use with other sedative-hypnotics, including other zolpidem products. During concurrent use of a CNS depressant, dosage adjustments of zolpidem and the CNS depressant may be necessary because of the potential for additive effects. Administer as a single dose and do not be re-administer during the same night. The risk for next-morning impairment is higher if zolpidem is taken with less than a full night of sleep remaining (7 to 8 hours), if a higher than the recommended dose is taken, or if zolpidem is co-administered with other CNS depressants or drugs that increase the blood levels of zolpidem. A full night of sleep (7 to 8 hours) is recommended to minimize the risk of next-day impairment, including effects on driving and performing other tasks requiring complete mental alertness. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of sedative/hypnotics in long-term care facility (LTCF) residents. In residents meeting the criteria for treatment, Max: 5 mg/day PO in residents meeting the criteria for treatment, except when documentation is provided showing that higher doses are necessary to maintain or improve the resident's functional status. 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.

    Lingual spray dosage (oral spray; e.g., Zolpimist)
    Adult Females

    Initially, 5 mg PO (1 spray in mouth over the tonque) immediately before bedtime and with at least 7 to 8 hours remaining before the planned time of awakening; this is also the recommended dose for debilitated adults. Avoid co-use with other sedative-hypnotics, including other zolpidem products. During concurrent use of a CNS depressant, dosage adjustments of zolpidem and the CNS depressant may be necessary because of the potential for additive effects. Max: 10 mg/day if needed; however, the higher dose is more likely to cause next-day impairment. Use the lowest effective dose. Administer as a single dose and do not re-administer during the same night. The risk for next-morning impairment is higher if zolpidem is taken with less than a full night of sleep remaining (7 to 8 hours), if a higher than the recommended dose is taken, or if zolpidem is co-administered with other CNS depressants or drugs that increase the blood levels of zolpidem. A full night of sleep (7 to 8 hours) is recommended to minimize the risk of next-day impairment.

    Adult Males

    Initially, 5 to 10 mg PO (1 to 2 sprays in mouth over the tongue) immediately before bedtime and with at least 7 to 8 hours remaining before the planned time of awakening; 5 mg (1 spray) at bedtime provides sufficient efficacy for many men, and this lower dosage should be considered. The 5 mg dose is recommended for debilitated adults. Use the lowest effective dose. Avoid co-use with other sedative-hypnotics, including other zolpidem products. During concurrent use of a CNS depressant, dosage adjustments of zolpidem and the CNS depressant may be necessary because of the potential for additive effects. Max: 10 mg/day if needed; however, the higher dose is more likely to cause next-day impairment. Administer as a single dose and do not re-administer during the same night. The risk for next-morning impairment is higher if zolpidem is taken with less than a full night of sleep remaining (7 to 8 hours), if a higher than the recommended dose is taken, or if zolpidem is co-administered with other CNS depressants or drugs that increase the blood levels of zolpidem. A full night of sleep (7 to 8 hours) is recommended to minimize the risk of next-day impairment, including effects on driving and performing other tasks requiring complete mental alertness.

    Geriatric Adults

    5 mg PO (1 spray into mouth and over the tongue) immediately before bedtime and with at least 7 to 8 hours remaining before the planned time of awakening. Use the lowest effective dose. Geriatric patients and debilitated adults may be particularly sensitive to the effects of the drug. Avoid co-use with other sedative-hypnotics, including other zolpidem products. During concurrent use of a CNS depressant, dosage adjustments of zolpidem and the CNS depressant may be necessary because of the potential for additive effects. Administer as a single dose and do not be re-administer during the same night. The risk for next-morning impairment is higher if zolpidem is taken with less than a full night of sleep remaining (7 to 8 hours), if a higher than the recommended dose is taken, or if zolpidem is co-administered with other CNS depressants or drugs that increase the blood levels of zolpidem. A full night of sleep (7 to 8 hours) is recommended to minimize the risk of next-day impairment, including effects on driving and performing other tasks requiring complete mental alertness. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of sedative/hypnotics in long-term care facility (LTCF) residents. Max: 5 mg/day PO in residents meeting criteria for treatment, except when documentation is provided showing that higher doses are necessary to maintain or improve the resident's functional status. 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.

    For insomnia characterized by difficulties with sleep onset and/or sleep maintenance.
    Oral dosage (extended-release tablets; e.g., Ambien CR)
    Adult Females

    Initially, 6.25 mg PO immediately before bedtime and with at least 7 to 8 hours remaining before the planned time of awakening. Max: 12.5 mg/day PO at bedtime if needed; however, the higher dose is more likely to cause next-day impairment. The recommended dose for debilitated adults is 6.25 mg immediately before bedtime; these patients may be particularly sensitive to the effects of the drug. Avoid co-use with other sedative-hypnotics, including other zolpidem products. During concurrent use of a CNS depressant, dosage adjustments of zolpidem and the CNS depressant may be necessary because of the potential for additive effects. Zolpidem should be taken as a single dose and should not be re-administered during the same night. The risk for next-morning impairment is higher if zolpidem is taken with less than a full night of sleep remaining (7 to 8 hours), if a higher than the recommended dose is taken, or if zolpidem is co-administered with other CNS depressants or drugs that increase the blood levels of zolpidem. A full night of sleep (7 to 8 hours) is recommended to minimize the risk of next-day impairment, including effects on driving and performing other tasks requiring complete mental alertness.

    Adult Males

    Initially, 6.25 to 12.5 mg PO immediately before bedtime and with at least 7 to 8 hours remaining before the planned time of awakening. A dose of 6.25 mg PO before bedtime provides sufficient efficacy for many men, and this lower dosage should be considered. Max: 12.5 mg/day PO at bedtime if needed; however, the higher dose is more likely to cause next-day impairment. The recommended dose for debilitated adults is 6.25 mg immediately before bedtime; these patients may be particularly sensitive to the effects of the drug. Avoid co-use with other sedative-hypnotics, including other zolpidem products. During concurrent use of a CNS depressant, dosage adjustments of zolpidem and the CNS depressant may be necessary because of the potential for additive effects. Zolpidem should be taken as a single dose and should not be re-administered during the same night. The risk for next-morning impairment is higher if zolpidem is taken with less than a full night of sleep remaining (7 to 8 hours), if a higher than the recommended dose is taken, or if zolpidem is co-administered with other CNS depressants or drugs that increase the blood levels of zolpidem. A full night of sleep (7 to 8 hours) is recommended to minimize the risk of next-day impairment, including effects on driving and performing other tasks requiring complete mental alertness.

    Geriatric Adults

    6.25 mg PO immediately before bedtime and with at least 7 to 8 hours remaining before the planned time of awakening. Geriatric patients and debilitated adults may be particularly sensitive to the effects of the drug. Avoid co-use with other sedative-hypnotics, including other zolpidem products. During concurrent use of a CNS depressant, dosage adjustments of zolpidem and the CNS depressant may be necessary because of the potential for additive effects. Zolpidem should be taken as a single dose and should not be re-administered during the same night. The risk for next-morning impairment is higher if zolpidem is taken with less than a full night of sleep remaining (7 to 8 hours), if a higher than the recommended dose is taken, or if zolpidem is co-administered with other CNS depressants or drugs that increase the blood levels of zolpidem. Patients should be cautioned regarding the risk of residual next-morning effects, and warned against engaging in hazardous activities, such as driving or other activities requiring complete mental alertness, the day after use until the patient is aware of how zolpidem affect them. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of sedative/hypnotics in long-term care facility (LTCF) residents. Max: 6.25 mg/day PO in residents meeting criteria for treatment, except when documentation is provided showing that higher doses are necessary to maintain or improve the resident's functional status. 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.

    For middle-of-the night awakening that is followed by difficulty returning to sleep.
    Sublingual dosage (sublingual tablets; Intermezzo ONLY)
    Adult Females

    1.75 mg sublingually taken once per night if needed for a middle-of-the night awakening followed by difficulty returning to sleep. The 1.75 mg dose is also recommended for patients receiving a concomitant CNS depressant. Avoid co-use with other sedative-hypnotics, including other zolpidem products at bedtime or in the middle of the night. Use only if the patient has at least 4 hours of bedtime remaining before the planned time of waking. The risk for next-morning impairment is higher if Intermezzo is taken with less than 4 hours of bedtime remaining, if a higher than the recommended dose is taken, or during co-administration with other CNS depressants or drugs that increase the blood levels of zolpidem. Patients should be cautioned regarding the risk of residual next-morning effects, and instructed to wait for at least 4 hours after dosing and until they feel fully awake before driving or engaging in other activities requiring full mental alertness.

    Adult Males

    3.5 mg sublingually taken once per night if needed for a middle-of-the night awakening followed by difficulty returning to sleep. Use only if the patient has at least 4 hours of bedtime remaining before the planned time of waking. A lower dose of 1.75 mg sublingually is recommended for males patients taking other CNS depressants. Avoid co-use with other sedative-hypnotics, including other zolpidem products, at bedtime or in the middle of the night. The risk for next-morning impairment is higher if Intermezzo is taken with less than 4 hours of bedtime remaining, if a higher than the recommended dose is taken, or during co-administration with other CNS depressants or drugs that increase the blood levels of zolpidem. Patients should be cautioned regarding the risk of residual next-morning effects, and instructed to wait for at least 4 hours after dosing and until they feel fully awake before driving or engaging in other activities requiring full mental alertness.

    Geriatric Adults

    1.75 mg sublingually taken once per night if needed for a middle-of-the night awakening followed by difficulty returning to sleep. Avoid co-use with other sedative-hypnotics, including other zolpidem products at bedtime or in the middle of the night. The 1.75 mg dose is also recommended for patients receiving a concomitant CNS depressant. Use only when there are at least 4 hours of bedtime remaining before the planned time of waking. The risk for next-morning impairment is higher if Intermezzo is taken with less than 4 hours of bedtime remaining, if a higher than the recommended dose is taken, or during co-administration with other CNS depressants or drugs that increase the blood levels of zolpidem. Patients should be cautioned regarding the risk of residual next-morning effects, and instructed to wait for at least 4 hours after dosing and until they feel fully awake before driving or engaging in other activities requiring full mental alertness. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of sedative/hypnotics in long-term care facility (LTCF) residents. Daily dose thresholds are not available for zolpidem use in middle-of-the night awakenings; use 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.

    For increasing awareness and responsiveness in patients with disorders of consciousness due to traumatic brain injury† (TBI†) or nontraumatic brain injury† (e.g., head trauma† or hypoxia, respectively).
    Oral dosage
    Adults

    Zolpidem cannot be considered generally beneficial due to lack of well-controlled studies with statistical power, and apparent unpredictability of response. Use of zolpidem 5 to 10 mg/day PO may result in temporary clinical improvement in certain patients with disorders of consciousness (e.g., minimally conscious state (MCS) or vegetative state (VS)) due to traumatic or nontraumatic brain injury (e.g., anoxic brain injury). Clinical improvements typically occur within 1 hour of administration, with a duration of 1 to 4 hours. No long-term adverse effects were noted in 3 patients receiving the drug for 3 to 6 years. In one small double-blind trial of 15 patients with MCS or VS of various etiologies receiving a single dose of zolpidem 10 mg and placebo in a cross-over design, one post-traumatic VS patient was considered a responder as determined by the Coma Recovery Scale-Revised (CRS-R). Within 30 minutes of drug administration, the responder began to show more spontaneous movement, exploratory eye movements, visual tracking, and command following. Re-challenge showed a less dramatic but superior response to placebo. An open-label study evaluated cerebral state monitoring (CSM) and single-photon emission computed tomography (SPECT) before and after a zolpidem 10 mg PO single dose in patients with VS who were categorized by the type of brain injury. Only patients with contrecoup contusion or space-occupying compression injuries had significant improvement in components of CSM and improved cerebral perfusion on SPECT. Eight patients with primary or secondary brain stem injury had worsening of a CSM component. In 23 neurologically disabled patients (18 fully conscious, 4 MRS, and 1 locked-in syndrome) receiving zolpidem 10 mg/day for 4 months or more, the mean improvement from baseline in the Tinetti Falls Efficacy Scale (TFES) was 11.3% and brain SPECT improved in 43% of patients. There was a significantly greater decrease in TFES in patients who had improved brain scans than in patients with no brain scan improvement.

    Children and Adolescents 4 to 17 years

    There are very limited data in pediatric patients. In one placebo-controlled trial (n = 3; pediatric patients 4 to 17 years in a persistent vegetative state due to hypoxic or traumatic brain injury) a daily dose of zolpidem 0.14 to 0.2 mg/kg PO or placebo was given for 4 days in a cross-over design with a wash-out of 10 days between treatments. Neither objective measures nor parental reports indicated increased arousal associated with zolpidem administration. Conversely, increased sedation was noted. PET scan results of regional perfusion during the zolpidem phase did not differ significantly from the placebo phase.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Immediate-release tablets (i.e., Ambien): 10 mg/day PO.
    Lingual spray (i.e., Zolpimist): 10 mg/day PO.
    Orally disintegrating tablets (i.e., Tovalt ODT): 10 mg/day PO.
    Extended-release tablets (i.e., Ambien CR): 12.5 mg/day PO.
    Sublingual tablets (i.e. Edluar): 10 mg/day SL.
    Sublingual tablets (i.e., Intermezzo): 1.75 mg SL once per night in women and 3.5 mg SL once per night in men.

    Geriatric

    Immediate-release tablets (i.e., Ambien): The recommended geriatric dose is 5 mg/day PO.
    Lingual spray (i.e., Zolpimist): The recommended geriatric dose is 5 mg/day PO.
    Extended-release tablets (i.e., Ambien CR): The recommended geriatric dose is 6.25 mg/day PO.
    Sublingual tablets (i.e. Edluar): The recommended geriatric dose is 5 mg/day SL.
    Sublingual tablets (i.e., Intermezzo): The recommended geriatric dose is 1.75 mg SL once per night as needed.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Immediate-release tablets (i.e., Ambien) or Lingual spray (i.e., Zolpimist):
    -mild to moderate hepatic impairment: 5 mg/day PO as needed.
    -severe hepatic impairment: Avoid use as it may contribute to encephalopathy.
     
    Extended-release tablets (i.e., Ambien CR):
    -mild to moderate hepatic impairment: 6.25 mg/day PO as needed.
    -severe hepatic impairment: Avoid use as it may contribute to encephalopathy.
     
    Sublingual tablets (i.e. Edluar):
    -mild to moderate hepatic impairment: 5 mg/day SL as needed.
    -severe hepatic impairment: Avoid use as it may contribute to encephalopathy.
     
    Sublingual tablets (i.e., Intermezzo):
    -mild to moderate hepatic impairment: 1.75 mg SL once per night as needed.
    -severe hepatic impairment: Avoid use as it may contribute to encephalopathy.

    Renal Impairment

    It appears that no dosage adjustments are needed. Although evidence to date does not indicate any need to use lower doses of zolpidem in patients with renal impairment or renal failure, as a general precaution these patients should be closely monitored clinically.
     
    Intermittent hemodialysis
    Zolpidem is not removed by hemodialysis. Based on limited study in end-stage renal disease patients on hemodialysis, it appears that no dosage accumulation occurs after 21 days of daily zolpidem administration. However, the manufacturers recommend close clinical monitoring of response to treatment as a general precaution.

    ADMINISTRATION

     
    A MedGuide that provides information about proper use and risks of sedative-hypnotics should be dispensed with each new prescription and refill.

    Oral Administration

    Food can decrease both the rate and extent of GI absorption; instruct patients to take zolpidem on an empty stomach to facilitate the onset of sleep.
    Formulations used for insomnia characterized by difficulty with sleep initiation (i.e., Ambien, Ambien CR, Zolpimist, Edluar): Administer immediately before retiring.
    Formulations used for insomnia characterized by difficulty returning to sleep after a middle-of-the night awakening (i.e., Intermezzo): Administer only if there are at least 4 hours of bedtime remaining before the planned time of waking.

    Oral Solid Formulations

    Immediate-release tablet (Ambien): Swallow with a drink of water. For optimal effect, do not administer with or immediately after a meal.
    Extended-release tablet (Ambien CR): Zolpidem tablets should not be chewed, broken, or crushed; they should be swallowed whole with a drink of water.
    Sublingual tablet (Edluar): The tablet should be placed under the tongue where it can disintegrate; it should not be swallowed. Do not take with water.
    Sublingual tablet (Intermezzo): The sublingual tablet should be placed under the tongue where it can disintegrate; it should not be swallowed whole. For optimal effect, do not administer with or immediately after a meal. The foil blister containing the tablet should be removed from exterior pouch just prior to dosing. The manufacturer recommends leaving the empty pouch where it can be seen throughout the night as a reminder that a dose has been taken. This product should be used for middle-of-the night awakenings only when there is at least 4 hours of bedtime left before the planned time of waking. A Dosing Time Chart and a Dosing Time Tool are provided with the product as aides to the patient in determining the latest time during the night the product may be taken. Refer to patient Instructions for Use included with package labeling for full instructions.
    Orally disintegrating tablet (Tovalt ODT): NOTE: This product is discontinued in the US. May be given with or without water. Place tablet in mouth where it can disintegrate and then be swallowed. Tablets should not be chewed, broken, or split.

    Other Oral Formulations

    Lingual spray (Zolpimist): Zolpidem may be given with or without water. Oral pump must be primed (5 pump depressions) prior to first use and re-primed (1 pump depression) if not used for 14 or more days. Spray dose directly into open mouth over the tongue. Do not inhale spray. Each spray provides 5 mg in 100 microliters. Immediately repeat a second spray if the prescribed dose is 10 mg. Replace child-resistant cover after each use; store upright. There are 60 metered actuations in each container after the 5 initial priming actuations. NOTE: Refer to Patient Instructions for Use included with package labeling for full instructions.

    STORAGE

    Ambien:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Ambien CR:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Edluar:
    - Protect from light
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Intermezzo:
    - Do not store outside the pouch provided
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Zolpimist:
    - Avoid temperatures above 86 degrees F
    - Do not freeze
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store upright

    CONTRAINDICATIONS / PRECAUTIONS

    Angioedema

    Zolpidem should be avoided in those with a hypersensitivity to zolpidem or any ingredient in the product. Reactions including anaphylaxis or angioedema may occur with sedative-hypnotics, and may become evident as early as the initial dose. Patients should be instructed on the appropriate action in the event of an allergic reaction. Treatment with zolpidem should not be reinitiated in patients who experience angioedema after administration of the drug.

    Behavioral changes, depression, suicidal ideation

    Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia or sleep disorders with zolpidem should be initiated only after a careful evaluation of the patient. The failure of the sleep disturbance 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 thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative/hypnotic drugs, including zolpidem. Because some adverse effects of zolpidem appear to be dose-related, it is important to use the lowest possible effective dose. A variety of abnormal thinking and behavioral changes have been reported to occur in association with the use of sedative/hypnotics, including zolpidem. Some of these changes included decreased inhibition (e.g., aggressiveness and extroversion that seemed out of character), bizarre behavior, agitation and depersonalization. Visual and auditory hallucinations have been reported. Amnesia and other neuropsychiatric symptoms may occur unpredictably. In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (suicidal ideation, including completed suicides), has been reported in association with the use of sedative/hypnotics. Intentional overdosage is more common in patients with depression; therefore, the least amount of drug that is feasible should be prescribed for the patient at any one time. The emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.

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

    Sedative-hypnotics can cause complex sleep-related behaviors such as phone calls, sexual activity, preparing and eating food, or sleep driving while not fully awake and in some cases having no memory of the event. These behaviors appear to be more frequent with nonbenzodiazepine benzodiazepine-receptor agonists (NBRAs), such as zolpidem, than other sedative-hypnotics. Although rare, serious injuries or death have occurred; therefore, zolpidem and other NBRAs are contraindicated in patients with a history of drug-induced complex sleep-related behaviors. Patients should be informed of the risks before receiving any medication from this class, including instructions to discontinue the medication if they experience a sleep-related episode and to contact their healthcare provider immediately. Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of NBRAs to the FDA MedWatch Safety Information and Adverse Event Reporting Program.[64083] Because zolpidem has a rapid onset of action and causes CNS depressant activity, zolpidem products indicated for insomnia due to difficulty with sleep initiation should only be administered immediately before retiring and with at least 7 to 8 hours remaining before the planned time of waking. Zolpidem products indicated for difficulty returning to sleep after middle-of-the-night awakenings should only be taken while the patient is in bed and has at least 4 hours of bedtime remaining before the planned time of waking. Vehicle drivers and machine operators should be warned that hypnotics, such as zolpidem, have a possible risk of adverse reactions including drowsiness, prolonged reaction time, dizziness, sleepiness, blurred/double vision, reduced alertness and impaired driving, even the day after use. Patients should be instructed to avoid driving or operating machinery or performing other tasks requiring mental alertness for at least 8 hours after taking immediate-release formulations, and patients receiving the extended-release formulation should be alerted about the potential impact on such activities the full day after use. Patients receiving zolpidem for middle-of-the-night awakenings should wait for at least 4 hours after dosing and until they feel fully awake before driving or engaging in other activities requiring full mental alertness. Because zolpidem can cause drowsiness and a decreased level of consciousness, there is a higher risk of falls, particularly in the elderly, with the potential for subsequent severe injuries. Zolpidem use has been associated with severe injuries such as hip fractures and intracranial hemorrhage. Due to gender differences in the elimination of zolpidem, a lower initial dose is recommended in adult females (women). Plasma levels of zolpidem in some patients, particularly women, may be high enough the morning after use to impair activities requiring mental alertness, such as driving. The risk for next-morning impairment is higher if zolpidem products are taken without adherence to the proper hours for sleep recommended following use or if a higher than the recommended dose is taken. Risks for impairment are also increased during coadministration with other CNS depressants with zolpidem or with use of drugs that increase the blood levels of zolpidem. Concurrent alcohol or CNS depressant use increases the risk for CNS depression, impairment, complex sleep-related behaviors, and other additive effects. Patients taking zolpidem should avoid ethanol ingestion. Lower initial dosages of zolpidem should be considered in patients taking other CNS-depressant therapies. Anterograde amnesia may be particularly evident at zolpidem doses above 10 mg/day.[46915] [31451] [44125] [57789] [52842] [60089] [60090]

    Abrupt discontinuation, alcoholism, substance abuse

    Immediate-release zolpidem is recommended for use in the short-term treatment of insomnia. No such recommendation exists in the package labeling for extended-release zolpidem, although cautious use is prudent when prescribing any hypnotic. Problems associated with abrupt discontinuation of hypnotic drugs are more likely to occur following chronic therapy. There is no reliable data documenting the occurrence of withdrawal symptoms following discontinuation of zolpidem, but evidence of fatigue, nausea/vomiting, flushing, lightheadedness, inconsolable crying, stomach cramps, panic attack, nervousness, and abdominal discomfort may constitute a withdrawal syndrome. Rare postmarketing reports of abuse, dependence, and withdrawal have been received. Withdrawal of some hypnotics also precipitates a rebound insomnia. If therapy is continued for more than 2 weeks the possibility of a withdrawal syndrome should be considered and abrupt discontinuation of therapy avoided. The possibility of physical and psychological dependence to zolpidem requires close monitoring. Zolpidem should be used cautiously in patients with a history of alcoholism or substance abuse.

    Encephalopathy, hepatic disease

    Zolpidem should be administered cautiously to patients with hepatic disease because the elimination half-life of the drug can be prolonged, with possible resultant toxicity. Patients with hepatic insufficiency do not clear zolpidem as rapidly as patients with normal hepatic function. Patients with mild to moderate hepatic disease (e.g., Child Pugh class A or B) should receive a lower initial dosage (i.e., 5 mg/day). Avoid zolpidem use in patients with severe hepatic impairment (e.g., Child Pugh class C) since the drug may contribute to encephalopathy. Gamma-aminobutyric acid (GABA) agonists, such as zolpidem, have been associated with the development of hepatic encephalopathy in patients with hepatic insufficiency.

    Chronic obstructive pulmonary disease (COPD), myasthenia gravis, pulmonary disease, respiratory depression, sleep apnea

    Postmarketing reports indicate that respiratory insufficiency or oxygen desaturation may occur in some patients treated with zolpidem, mostly in patients with pre-existing pulmonary disease. Zolpidem should be used with caution in patients with pre-existing respiratory depression, such as severe chronic obstructive pulmonary disease (COPD), sleep apnea, or myasthenia gravis to avoid the risk of depressing ventilatory function.

    Labor, neonates, obstetric delivery, pregnancy

    Available data from observational studies, birth registries, and case reports on the use of zolpidem during human pregnancy have not reported a clear association with the drug and major birth defects. Zolpidem crosses the placenta and may produce respiratory depression and sedation in neonates with in utero exposure during the later stages of pregnancy; there are a limited number of exposed neonatal cases of moderate to severe respiratory depression requiring aspiration, artificial ventilation, or intratracheal intubation. The majority of neonates recovered within hours to a few weeks after birth once treated. Neonatal flaccidity has also been reported in infants born to mothers who have received sedatives during pregnancy. Newborns who have been exposed to zolpidem during pregnancy and labor should be monitored for signs of sedation and respiratory depression and managed accordingly. Withdrawal symptoms may also be possible during the postnatal period. Zolpidem has no established use during labor or obstetric delivery.

    Breast-feeding

    The developmental and health benefits of breast-feeding should be assessed along with the mother's clinical need for zolpidem and potential adverse effects on the breastfed infant from zolpidem or any underlying maternal condition. Zolpidem is excreted into breast milk, and there are reports of excess sedation in babies exposed to zolpidem through breast milk; therefore, it is recommended to monitor the breast-fed infant for excess sedation, hypotonia, and respiratory depression. Alternatively, a lactating woman may consider interrupting breast-feeding and pumping and discarding breast milk during treatment and for 23 hours (about 5 half-lives) after zolpidem administration to minimize infant drug exposure. In one small study of lactating women (n = 5) who received a single 20 mg dose of zolpidem on postpartum day 3 or 4, the mean milk to maternal plasma concentration ratio was 0.13 (range, 0.11 to 0.18) three hours after drug administration. The amount of zolpidem measured in the breast milk samples represented 0.004% to 0.019% of the maternal administered dose. No detectable zolpidem was measured in subsequent milk samples taken at 13 and 16 hours after the dose. Breast-feeding was discontinued for 24 hours after drug administration; therefore, infant exposure was not assessed. The transfer of zaleplon, an alternative sedative, into breast milk has also been assessed; however, the effects of zaleplon exposure on the breast-feeding infant have not been formally evaluated.[31451] [40336] [44125] [45971] [46915] [57789]

    Children, infants

    The safety and efficacy of zolpidem in pediatric patients have not been established and the drug cannot be recommended for use in children, adolescents or infants. Studies of zolpidem in pediatric patients have not suggested efficacy of the drug over placebo, and, adverse events were frequent. Results of a controlled 8-week study for the treatment of insomnia in 201 children aged 6 to 17 years with attention-deficit hyperactivity disorder (ADHD) indicated that zolpidem was not effective compared to placebo. One or more adverse events was experienced in 62.5% of pediatric patients treated with zolpidem (dizziness [23.5%], headaches [23.5%], and hallucinations [7.4%]).

    Geriatric

    Debilitated and/or geriatric patients are more sensitive to the effects of zolpidem. The impairment of cognitive and motor function may be more marked in the elderly and a lower initial dosage of zolpidem is recommended with close monitoring. Because zolpidem can cause drowsiness and a decreased level of consciousness, there is a higher risk of falls, particularly in the elderly, with the potential for subsequent severe injuries. Elderly patients who receive greater than 5 mg/day of zolpidem immediate-release or greater than 6.25 mg/day of zolpidem extended-release may especially be at risk for falls or mental status changes. When zolpidem is discontinued, there may be a period of rebound insomnia if higher doses are used. During studies evaluating sleep after zolpidem was discontinued, geriatric patients reported impaired sleep on the first post-treatment night after using doses above 5 mg/day. No objective evidence of rebound insomnia was observed at recommended doses.[46915] [31451] [44125] [57789] [52842] [60089] [60090] According to the Beers Criteria, zolpidem is considered a potentially inappropriate medication (PIM) in geriatric patients and use should be avoided. Nonbenzodiazepine, benzodiazepine-receptor agonists (NBRAs) such as zolpidem may produce adverse effects similar to benzodiazepines such as falls, fractures, and delirium in older adults. There are increased emergency department visits, hospitalizations, and motor vehicle crashes, as well as minimal improvement in sleep latency and duration in older adults with the use of NBRAs. Avoid NBRA use in geriatric patients with dementia/cognitive impairment (adverse CNS effects) or delirium/high risk of delirium (new-onset or worsening delirium). Avoid use of an NBRA in elderly patients with a history of falls or fractures, unless safer alternatives are not available since NBRAs can produce ataxia, impaired psychomotor function, syncope, and additional falls. If an NBRA must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to the OBRA guidelines, evaluate factors that potentially cause insomnia 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. Non-pharmacologic interventions and maximized treatment of underlying conditions (if applicable) are expected to be addressed. Precede or accompany the initiation of a sleep induction or maintenance medication with other interventions to improve sleep. Use all sleep medications per 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 another comorbid condition until symptoms improve or the underlying cause can be identified and effectively treated. OBRA provides dosing guidance for most sedatives, including zolpidem. 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 per the OBRA guidelines.

    ADVERSE REACTIONS

    Severe

    visual impairment / Early / 0-3.0
    pulmonary embolism / Delayed / 0-0.1
    ventricular tachycardia / Early / 0-0.1
    pulmonary edema / Early / 0-0.1
    myocardial infarction / Delayed / 0-0.1
    arrhythmia exacerbation / Early / 0-0.1
    anaphylactic shock / Rapid / 0-0.1
    angioedema / Rapid / 0-0.1
    GI obstruction / Delayed / 0-0.1
    bronchospasm / Rapid / 0-0.1
    renal failure (unspecified) / Delayed / 0-0.1
    azotemia / Delayed / 0-0.1
    thrombosis / Delayed / 0-0.1
    bone fractures / Delayed / Incidence not known
    intracranial bleeding / Delayed / Incidence not known
    suicidal ideation / Delayed / Incidence not known
    laryngeal edema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    hepatic encephalopathy / Delayed / Incidence not known

    Moderate

    hallucinations / Early / 0-7.4
    amnesia / Delayed / 1.0-3.0
    memory impairment / Delayed / 1.0-3.0
    depression / Delayed / 1.0-2.0
    palpitations / Early / 2.0-2.0
    constipation / Delayed / 0.1-2.0
    blurred vision / Early / 2.0-2.0
    conjunctival hyperemia / Early / 2.0-2.0
    impaired cognition / Early / 0.1-1.0
    hypertension / Early / 0.1-1.0
    chest pain (unspecified) / Early / 0.1-1.0
    orthostatic hypotension / Delayed / 0.1-1.0
    sinus tachycardia / Rapid / 0.1-1.0
    edema / Delayed / 0.1-1.0
    dysphagia / Delayed / 0.1-1.0
    dyspnea / Early / 0.1-1.0
    vaginitis / Delayed / 0.1-1.0
    dysuria / Early / 0-1.0
    cystitis / Delayed / 0.1-1.0
    urinary incontinence / Early / 0.1-1.0
    hyperglycemia / Delayed / 0.1-1.0
    elevated hepatic enzymes / Delayed / 0-1.0
    dysarthria / Delayed / 0.1-1.0
    migraine / Early / 0.1-1.0
    hypotension / Rapid / 0-0.1
    angina / Early / 0-0.1
    phlebitis / Rapid / 0-0.1
    furunculosis / Delayed / 0-0.1
    bullous rash / Early / 0-0.1
    gastritis / Delayed / 0-0.1
    hemorrhoids / Delayed / 0-0.1
    myasthenia / Delayed / 0-0.1
    conjunctivitis / Delayed / 0-0.1
    photopsia / Delayed / 0-0.1
    hypoxia / Early / 0-0.1
    urinary retention / Early / 0-0.1
    impotence (erectile dysfunction) / Delayed / 0-0.1
    gout / Delayed / 0-0.1
    hyperlipidemia / Delayed / 0-0.1
    hypercholesterolemia / Delayed / 0-0.1
    hyperbilirubinemia / Delayed / 0-0.1
    anemia / Delayed / 0-0.1
    lymphadenopathy / Delayed / 0-0.1
    leukopenia / Delayed / 0-0.1
    hot flashes / Early / 0-0.1
    tetany / Early / 0-0.1
    tolerance / Delayed / 0-0.1
    confusion / Early / 1.0
    euphoria / Early / 1.0
    ataxia / Delayed / 1.0
    complex sleep-related behaviors / Early / Incidence not known
    respiratory depression / Rapid / Incidence not known
    erythema / Early / Incidence not known
    oral ulceration / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    withdrawal / Early / Incidence not known
    psychological dependence / Delayed / Incidence not known
    physiological dependence / Delayed / Incidence not known

    Mild

    dizziness / Early / 1.0-23.5
    headache / Early / 0-19.0
    drowsiness / Early / 0-8.0
    nausea / Early / 1.0-7.0
    malaise / Early / 3.0-6.0
    back pain / Delayed / 3.0-4.0
    myalgia / Early / 0-4.0
    sinusitis / Delayed / 4.0-4.0
    fatigue / Early / 1.0-3.0
    lethargy / Early / 3.0-3.0
    anxiety / Delayed / 0.1-3.0
    xerostomia / Early / 3.0-3.0
    diarrhea / Early / 1.0-3.0
    influenza / Delayed / 1.0-3.0
    psychomotor impairment / Early / 2.0-3.0
    rash / Early / 1.0-2.0
    arthralgia / Delayed / 0-2.0
    muscle cramps / Delayed / 2.0-2.0
    abnormal dreams / Early / 0.1-1.0
    nightmares / Early / 0.1-1.0
    agitation / Early / 0.1-1.0
    syncope / Early / 0.1-1.0
    pallor / Early / 0.1-1.0
    hyperhidrosis / Delayed / 0.1-1.0
    pruritus / Rapid / 0.1-1.0
    urticaria / Rapid / 0-1.0
    anorexia / Delayed / 0.1-1.0
    vomiting / Early / 0.1-1.0
    dysgeusia / Early / 0.1-1.0
    gastroesophageal reflux / Delayed / 1.0-1.0
    flatulence / Early / 0.1-1.0
    infection / Delayed / 0.1-1.0
    fever / Early / 0.1-1.0
    pharyngitis / Delayed / 0.1-1.0
    tinnitus / Delayed / 0.1-1.0
    ocular irritation / Rapid / 0.1-1.0
    ocular pain / Early / 0.1-1.0
    rhinitis / Early / 0.1-1.0
    cough / Delayed / 0.1-1.0
    menorrhagia / Delayed / 1.0-1.0
    vaginal irritation / Early / 1.0-1.0
    hypoesthesia / Delayed / 0.1-1.0
    paresthesias / Delayed / 0.1-1.0
    emotional lability / Early / 0.1-1.0
    tremor / Early / 0.1-1.0
    flushing / Rapid / 0-0.1
    photosensitivity / Delayed / 0-0.1
    acne vulgaris / Delayed / 0-0.1
    hypersalivation / Early / 0-0.1
    eructation / Early / 0-0.1
    dental caries / Delayed / 0-0.1
    tenesmus / Delayed / 0-0.1
    weight loss / Delayed / 0-0.1
    restless legs syndrome (RLS) / Delayed / 0-0.1
    chills / Rapid / 0-0.1
    lacrimation / Early / 0-0.1
    epistaxis / Delayed / 0-0.1
    laryngitis / Delayed / 0-0.1
    mastalgia / Delayed / 0-0.1
    nocturia / Early / 0-0.1
    increased urinary frequency / Early / 0-0.1
    polyuria / Early / 0-0.1
    purpura / Delayed / 0-0.1
    libido decrease / Delayed / 0-0.1
    yawning / Early / 0-0.1
    appetite stimulation / Delayed / 0-0.1
    hiccups / Early / 1.0
    dyspepsia / Early / 1.0
    asthenia / Delayed / 1.0
    diplopia / Early / 1.0
    vertigo / Early / 1.0
    insomnia / Early / 1.0
    somnambulism / Early / Incidence not known
    abdominal pain / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages within the hours 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. However, in healthy subjects (without insomnia) in a pharmacokinetic study, coadministration of caffeine at a dosage of 150 to 300 mg with zolpidem did not counteract the sedative effects of a single 10 mg dose of zolpidem.
    Acetaminophen; Butalbital: (Major) Concurrent use of zolpidem with barbiturates should be avoided if possible due to additive CNS depression. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended. Dosage reduction may be required for co-use in some patients. For example, a dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended when used with another CNS depressant. Barbiturates are CYP3A4 enzyme inducers and may cause decreased plasma concentrations of zolpidem; in some patients efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during coadministration of a potent CYP3A4 inducer.
    Acetaminophen; Butalbital; Caffeine: (Major) Concurrent use of zolpidem with barbiturates should be avoided if possible due to additive CNS depression. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended. Dosage reduction may be required for co-use in some patients. For example, a dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended when used with another CNS depressant. Barbiturates are CYP3A4 enzyme inducers and may cause decreased plasma concentrations of zolpidem; in some patients efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during coadministration of a potent CYP3A4 inducer. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages within the hours 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. However, in healthy subjects (without insomnia) in a pharmacokinetic study, coadministration of caffeine at a dosage of 150 to 300 mg with zolpidem did not counteract the sedative effects of a single 10 mg dose of zolpidem.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. (Major) Concurrent use of zolpidem with barbiturates should be avoided if possible due to additive CNS depression. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended. Dosage reduction may be required for co-use in some patients. For example, a dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended when used with another CNS depressant. Barbiturates are CYP3A4 enzyme inducers and may cause decreased plasma concentrations of zolpidem; in some patients efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during coadministration of a potent CYP3A4 inducer. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages within the hours 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. However, in healthy subjects (without insomnia) in a pharmacokinetic study, coadministration of caffeine at a dosage of 150 to 300 mg with zolpidem did not counteract the sedative effects of a single 10 mg dose of zolpidem.
    Acetaminophen; Caffeine: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages within the hours 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. However, in healthy subjects (without insomnia) in a pharmacokinetic study, coadministration of caffeine at a dosage of 150 to 300 mg with zolpidem did not counteract the sedative effects of a single 10 mg dose of zolpidem.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages within the hours 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. However, in healthy subjects (without insomnia) in a pharmacokinetic study, coadministration of caffeine at a dosage of 150 to 300 mg with zolpidem did not counteract the sedative effects of a single 10 mg dose of zolpidem.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages within the hours 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. However, in healthy subjects (without insomnia) in a pharmacokinetic study, coadministration of caffeine at a dosage of 150 to 300 mg with zolpidem did not counteract the sedative effects of a single 10 mg dose of zolpidem.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages within the hours 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. However, in healthy subjects (without insomnia) in a pharmacokinetic study, coadministration of caffeine at a dosage of 150 to 300 mg with zolpidem did not counteract the sedative effects of a single 10 mg dose of zolpidem.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Acetaminophen; Codeine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Acetaminophen; Diphenhydramine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Acetaminophen; Hydrocodone: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Acetaminophen; Oxycodone: (Major) Concomitant use of oxycodone with zolpidem may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If zolpidem is used concurrently with oxycodone, a reduced dosage of oxycodone and/or zolpidem is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Monitor for sedation and respiratory depression.
    Acetaminophen; Pentazocine: (Moderate) Concomitant use of pentazocine with zolpidem can potentiate respiratory depression, CNS depression, and sedation. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone. Pentazocine should be used cautiously in any patient receiving zolpidem. If concurrent use is necessary, a dose reduction of one or both medications may be required. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Acetaminophen; Propoxyphene: (Moderate) Concomitant use of CNS depressants can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses.
    Acetaminophen; Tramadol: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. A dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended in patients receiving concomitant CNS depressants.
    Acrivastine; Pseudoephedrine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Aldesleukin, IL-2: (Moderate) Aldesleukin, IL-2 may affect CNS function significantly. Therefore, psychotropic pharmacodynamic interactions could occur following concomitant administration of drugs with significant CNS activity. Use with caution.
    Alfentanil: (Moderate) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Alprazolam: (Moderate) Concomitant administration of benzodiazepines with zolpidem can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Concurrent use of zolpidem with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Amiodarone: (Moderate) It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of amiodarone, a moderate CYP3A4 inhibitor, since CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism. There is evidence of an increase in pharmacodynamic effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4, such as azole antifungals.
    Amitriptyline: (Moderate) Zolpidem appears to interact with tricyclic antidepressants and may cause decreased alertness. Zolpidem reduced peak serum concentrations of imipramine by 20%, but other pharmacokinetic parameters were not affected. In rare case reports, zolpidem has caused visual hallucinations or loss of alertness when these drugs (e.g., imipramine, desipramine) were administered concurrently. Interactions with other tricyclic antidepressants have not been studied, but additive drowsiness is also possible. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Amitriptyline; Chlordiazepoxide: (Moderate) Concomitant administration of benzodiazepines with zolpidem can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Concurrent use of zolpidem with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone. (Moderate) Zolpidem appears to interact with tricyclic antidepressants and may cause decreased alertness. Zolpidem reduced peak serum concentrations of imipramine by 20%, but other pharmacokinetic parameters were not affected. In rare case reports, zolpidem has caused visual hallucinations or loss of alertness when these drugs (e.g., imipramine, desipramine) were administered concurrently. Interactions with other tricyclic antidepressants have not been studied, but additive drowsiness is also possible. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Amobarbital: (Major) Concurrent use of zolpidem with barbiturates should be avoided if possible due to additive CNS depression. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended. Dosage reduction may be required for co-use in some patients. For example, a dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended when used with another CNS depressant. Barbiturates are CYP3A4 enzyme inducers and may cause decreased plasma concentrations of zolpidem; in some patients efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during coadministration of a potent CYP3A4 inducer.
    Amoxapine: (Moderate) CNS depressants should be combined cautiously with amoxapine because they could cause additive depressant effects and possible respiratory depression or hypotension.
    Amoxicillin; Clarithromycin; Lansoprazole: (Moderate) Consider decreasing the dose of zolpidem if coadministration with clarithromycin is necessary. Zolpidem is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Consider decreasing the dose of zolpidem if coadministration with clarithromycin is necessary. Zolpidem is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Amprenavir: (Moderate) Consider decreasing the dose of zolpidem if coadministration with protease inhibitors is necessary. Zolpidem is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Apalutamide: (Major) Coadministration of zolpidem with apalutamide is not recommended due to decreased plasma concentrations of zolpidem. Zolpidem is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased zolpidem exposure by 73% and significantly reduced the pharmacodynamic effects of zolpidem.
    Apomorphine: (Moderate) Apomorphine causes significant somnolence. Concomitant administration of apomorphine and CNS depressants could result in additive depressant effects. A reduction in the dose of one or both drugs should be considered to minimize additive sedative effects. In addition, the risk of next-day psychomotor impairment is increased during co-administration of eszopiclone and other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    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 zolpidem and a multi-day regimen of oral aprepitant are used concurrently and monitor for an increase in zolpidem-related adverse effects for several days after administration. Zolpidem 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 zolpidem. 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.
    Aripiprazole: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zolpidem. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Asenapine: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zolpidem. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Concurrent use of zolpidem with barbiturates should be avoided if possible due to additive CNS depression. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended. Dosage reduction may be required for co-use in some patients. For example, a dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended when used with another CNS depressant. Barbiturates are CYP3A4 enzyme inducers and may cause decreased plasma concentrations of zolpidem; in some patients efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during coadministration of a potent CYP3A4 inducer. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages within the hours 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. However, in healthy subjects (without insomnia) in a pharmacokinetic study, coadministration of caffeine at a dosage of 150 to 300 mg with zolpidem did not counteract the sedative effects of a single 10 mg dose of zolpidem.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. (Major) Concurrent use of zolpidem with barbiturates should be avoided if possible due to additive CNS depression. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended. Dosage reduction may be required for co-use in some patients. For example, a dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended when used with another CNS depressant. Barbiturates are CYP3A4 enzyme inducers and may cause decreased plasma concentrations of zolpidem; in some patients efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during coadministration of a potent CYP3A4 inducer. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages within the hours 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. However, in healthy subjects (without insomnia) in a pharmacokinetic study, coadministration of caffeine at a dosage of 150 to 300 mg with zolpidem did not counteract the sedative effects of a single 10 mg dose of zolpidem.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages within the hours 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. However, in healthy subjects (without insomnia) in a pharmacokinetic study, coadministration of caffeine at a dosage of 150 to 300 mg with zolpidem did not counteract the sedative effects of a single 10 mg dose of zolpidem.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Additive CNS depressant effects may be seen with combination use of orphenadrine and anxiolytics, sedatives, and hypnotics. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages within the hours 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. However, in healthy subjects (without insomnia) in a pharmacokinetic study, coadministration of caffeine at a dosage of 150 to 300 mg with zolpidem did not counteract the sedative effects of a single 10 mg dose of zolpidem.
    Aspirin, ASA; Carisoprodol: (Moderate) Carisoprodol can cause additive CNS depression if used concomitantly with other CNS depressants.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. (Moderate) Carisoprodol can cause additive CNS depression if used concomitantly with other CNS depressants.
    Aspirin, ASA; Oxycodone: (Major) Concomitant use of oxycodone with zolpidem may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If zolpidem is used concurrently with oxycodone, a reduced dosage of oxycodone and/or zolpidem is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Monitor for sedation and respiratory depression.
    Atazanavir: (Moderate) Consider decreasing the dose of zolpidem if coadministration with protease inhibitors is necessary. Zolpidem is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Atazanavir; Cobicistat: (Moderate) Consider decreasing the dose of zolpidem if coadministration with cobicistat is necessary. Zolpidem is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%. (Moderate) Consider decreasing the dose of zolpidem if coadministration with protease inhibitors is necessary. Zolpidem is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with anxiolytics, sedatives, and hypnotics can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Diphenoxylate: (Moderate) Concurrent administration of diphenoxylate/difenoxin with anxiolytics, sedatives, and hypnotics can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Concurrent use of zolpidem with barbiturates should be avoided if possible due to additive CNS depression. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended. Dosage reduction may be required for co-use in some patients. For example, a dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended when used with another CNS depressant. Barbiturates are CYP3A4 enzyme inducers and may cause decreased plasma concentrations of zolpidem; in some patients efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during coadministration of a potent CYP3A4 inducer. (Moderate) Scopolamine may cause dizziness and drowsiness. Concurrent use of scopolamine and CNS depressants can adversely increase the risk of CNS depression.
    atypical antipsychotic: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zolpidem. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Azelastine: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with CNS depressants including anxiolytics, sedatives, and hypnotics.
    Azelastine; Fluticasone: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with CNS depressants including anxiolytics, sedatives, and hypnotics.
    Baclofen: (Moderate) Concurrent use of baclofen and CNS depressants such as certain sedatives or hypnotics can cause additive CNS depression. A reduction in the dose of these medications may be considered to minimize additive sedative effects, if they occur. With hypnotic medications, the risk of next-day psychomotor impairment is increased during co-administration of other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Barbiturates: (Major) Concurrent use of zolpidem with barbiturates should be avoided if possible due to additive CNS depression. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended. Dosage reduction may be required for co-use in some patients. For example, a dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended when used with another CNS depressant. Barbiturates are CYP3A4 enzyme inducers and may cause decreased plasma concentrations of zolpidem; in some patients efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during coadministration of a potent CYP3A4 inducer.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Concurrent use of zolpidem with barbiturates should be avoided if possible due to additive CNS depression. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended. Dosage reduction may be required for co-use in some patients. For example, a dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended when used with another CNS depressant. Barbiturates are CYP3A4 enzyme inducers and may cause decreased plasma concentrations of zolpidem; in some patients efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during coadministration of a potent CYP3A4 inducer.
    Belladonna; Opium: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opioid agonists with zolpidem may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with zolpidem 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. If benzhydrocodone is initiated in a patient taking zolpidem, reduce initial dosage and titrate to clinical response. If zolpidem is initiated a patient taking an opioid agonist, use a lower initial dose of zolpidem and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Benzodiazepines: (Moderate) Concomitant administration of benzodiazepines with zolpidem can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Concurrent use of zolpidem with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Benztropine: (Moderate) CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase the sedative effects of benztropine.
    Bexarotene: (Moderate) It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as bexarotene. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer.
    Boceprevir: (Major) It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as boceprevir, and consider using a lower dose of zolpidem to minimize the potential for adverse CNS effects. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4, such as azole antifungals.
    Bosentan: (Moderate) It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as bosentan. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer.
    Brexpiprazole: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zolpidem. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Brimonidine: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of anxiolytics, sedatives, and hypnotics.
    Brimonidine; Brinzolamide: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of anxiolytics, sedatives, and hypnotics.
    Brimonidine; Timolol: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of anxiolytics, sedatives, and hypnotics.
    Brompheniramine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Brompheniramine; Pseudoephedrine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Buprenorphine: (Moderate) If concurrent use of zolpidem and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Concurrent use of zolpidem with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended. Sedation, coma, or respiratory depression may occur during co-administration. 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 zolpidem and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Concurrent use of zolpidem with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended. Sedation, coma, or respiratory depression may occur during co-administration. 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.
    Bupropion: (Moderate) Rare cases of hallucinations have occurred when zolpidem was administered concurrently with bupropion. Dosage reductions in zolpidem may be needed if bupropion is used concurrently.
    Bupropion; Naltrexone: (Moderate) Rare cases of hallucinations have occurred when zolpidem was administered concurrently with bupropion. Dosage reductions in zolpidem may be needed if bupropion is used concurrently.
    Buspirone: (Moderate) The combination of buspirone and other CNS depressants can increase the risk for sedation.
    Butabarbital: (Major) Concurrent use of zolpidem with barbiturates should be avoided if possible due to additive CNS depression. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended. Dosage reduction may be required for co-use in some patients. For example, a dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended when used with another CNS depressant. Barbiturates are CYP3A4 enzyme inducers and may cause decreased plasma concentrations of zolpidem; in some patients efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during coadministration of a potent CYP3A4 inducer.
    Butorphanol: (Moderate) Concomitant use of butorphanol with other CNS depressants can potentiate the effects of butorphanol on respiratory depression, CNS depression (e.g., dizziness, impaired mental function), and sedation. Butorphanol should be used cautiously in any patient receiving these agents, which may include zolpidem. A dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended in patients receiving concomitant CNS depressants. A reduction in dose of the CNS depressant may also be needed. Concurrent use Intermezzo with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended.
    Caffeine: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages within the hours 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. However, in healthy subjects (without insomnia) in a pharmacokinetic study, coadministration of caffeine at a dosage of 150 to 300 mg with zolpidem did not counteract the sedative effects of a single 10 mg dose of zolpidem.
    Caffeine; Ergotamine: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages within the hours 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. However, in healthy subjects (without insomnia) in a pharmacokinetic study, coadministration of caffeine at a dosage of 150 to 300 mg with zolpidem did not counteract the sedative effects of a single 10 mg dose of zolpidem.
    Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration. CNS depressants can potentiate the effects of cannabidiol.
    Capsaicin; Metaxalone: (Moderate) Concomitant administration of metaxalone with other CNS depressants, such as certain sedatives and hypnotics, can potentiate the sedative effects of either agent. A reduction in the dose of these medications may be considered to minimize additive sedative effects, if they occur. With hypnotic medications, the risk of next-day psychomotor impairment is increased during co-administration of other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Carbamazepine: (Major) Concurrent use of zolpidem with potent CYP3A4 inducers, such as carbamazepine, should be avoided if possible because decreased plasma concentrations of zolpidem are possible and efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamics effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer.
    Carbetapentane; Chlorpheniramine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Carbetapentane; Pseudoephedrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Carbidopa; Levodopa; Entacapone: (Moderate) COMT inhibitors such as entacapone and tolcapone should be given cautiously with other agents that cause CNS depression, including zolpidem, due to the possibility of additive sedation. Sleep-related behaviors, such as sleep-driving, are also more likely to occur during concurrent use of zolpidem and CNS depressants than with zolpidem alone. If concurrent use is necessary, monitor for additive side effects. A reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Carbinoxamine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Carbinoxamine; Phenylephrine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Carbinoxamine; Pseudoephedrine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Cariprazine: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zolpidem. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Carisoprodol: (Moderate) Carisoprodol can cause additive CNS depression if used concomitantly with other CNS depressants.
    Ceritinib: (Moderate) Consider decreasing the dose of zolpidem if coadministration with ceritinib is necessary. Zolpidem is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC of zolpidem by 34% to 70%.
    Cetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with zolpidem should generally be avoided. Concurrent use of zolpidem with other CNS depressants increases the risk for CNS depression and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). If concurrent use is necessary, patients should be instructed to contact their provider immediately if these symptoms or behaviors occur.
    Cetirizine; Pseudoephedrine: (Moderate) Concurrent use of cetirizine/levocetirizine with zolpidem should generally be avoided. Concurrent use of zolpidem with other CNS depressants increases the risk for CNS depression and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). If concurrent use is necessary, patients should be instructed to contact their provider immediately if these symptoms or behaviors occur.
    Chlophedianol; Dexbrompheniramine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Chloramphenicol: (Moderate) Consider decreasing the dose of zolpidem if coadministration with chloramphenicol is necessary. Zolpidem is a CYP3A4 substrate and chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Chlorcyclizine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Chlordiazepoxide: (Moderate) Concomitant administration of benzodiazepines with zolpidem can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Concurrent use of zolpidem with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Chlordiazepoxide; Clidinium: (Moderate) Concomitant administration of benzodiazepines with zolpidem can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Concurrent use of zolpidem with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Chlorpheniramine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Chlorpheniramine; Codeine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Chlorpheniramine; Dextromethorphan: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Chlorpheniramine; Hydrocodone: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Chlorpheniramine; Phenylephrine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Chlorpheniramine; Pseudoephedrine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Chlorzoxazone: (Moderate) Concurrent use of chlorzoxazone and CNS depressants such as certain sedatives or hypnotics can cause additive CNS depression. A reduction in the dose of these medications may be considered to minimize additive sedative effects, if they occur. With hypnotic medications, the risk of next-day psychomotor impairment is increased during co-administration of other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Ciprofloxacin: (Moderate) Avoid coadministration of zolpidem and ciprofloxacin as the combination may potentially lead to an increase in zolpidem exposure. Zolpidem is primarily metabolized by CYP3A4 and to a lesser extent by other isoenzymes, including CYP1A2. Ciprofloxacin is an inhibitor of both enzymes.
    Citalopram: (Moderate) Disorientation, delusions, or hallucinations have been reported rarely during co-administration of zolpidem and SSRIs (e.g., fluoxetine, sertraline, fluvoxamine). The duration of the visual hallucinations has ranged from 30 minutes to 7 hours. Data from a clinical study in which SSRI-treated patients were given immediate-release zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n = 95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction. The mechanism for the interaction is thought to be pharmacodynamic in nature; therefore, a similar reaction is possible with other SSRIs such as citalopram.
    Clarithromycin: (Moderate) Consider decreasing the dose of zolpidem if coadministration with clarithromycin is necessary. Zolpidem is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Clemastine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Clobazam: (Moderate) Concomitant administration of clobazam with other CNS depressant drugs including anxiolytics, sedatives, and hypnotics, can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent.
    Clomipramine: (Moderate) Zolpidem appears to interact with tricyclic antidepressants and may cause decreased alertness. Zolpidem reduced peak serum concentrations of imipramine by 20%, but other pharmacokinetic parameters were not affected. In rare case reports, zolpidem has caused visual hallucinations or loss of alertness when these drugs (e.g., imipramine, desipramine) were administered concurrently. Interactions with other tricyclic antidepressants have not been studied, but additive drowsiness is also possible. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Clonazepam: (Moderate) Concomitant administration of benzodiazepines with zolpidem can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Concurrent use of zolpidem with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Clorazepate: (Moderate) Concomitant administration of benzodiazepines with zolpidem can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Concurrent use of zolpidem with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Clozapine: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zolpidem. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Cobicistat: (Moderate) Consider decreasing the dose of zolpidem if coadministration with cobicistat is necessary. Zolpidem is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Codeine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Codeine; Guaifenesin: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Codeine; Promethazine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    COMT inhibitors: (Moderate) COMT inhibitors such as entacapone and tolcapone should be given cautiously with other agents that cause CNS depression, including zolpidem, due to the possibility of additive sedation. Sleep-related behaviors, such as sleep-driving, are also more likely to occur during concurrent use of zolpidem and CNS depressants than with zolpidem alone. If concurrent use is necessary, monitor for additive side effects. A reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Conivaptan: (Moderate) Consider decreasing the dose of zolpidem if coadministration with conivaptan is necessary. Zolpidem is a CYP3A4 substrate and conivaptan is a strong CYP3A4 inhibitor. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Cyclizine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    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.
    Cyproheptadine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Dabrafenib: (Moderate) It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as dabrafenib. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer.
    Danazol: (Moderate) It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of danazol, a moderate CYP3A4 inhibitor, since CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism. There is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4, such as azole antifungals.
    Dantrolene: (Moderate) Simultaneous use of dantrolene and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase CNS depression (e.g., drowsiness). A reduction in the dose of these medications may be considered to minimize additive sedative effects, if they occur. With hypnotic medications, the risk of next-day psychomotor impairment is increased during co-administration of other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Darunavir: (Moderate) Consider decreasing the dose of zolpidem if coadministration with protease inhibitors is necessary. Zolpidem is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Darunavir; Cobicistat: (Moderate) Consider decreasing the dose of zolpidem if coadministration with cobicistat is necessary. Zolpidem is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%. (Moderate) Consider decreasing the dose of zolpidem if coadministration with protease inhibitors is necessary. Zolpidem is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Consider decreasing the dose of zolpidem if coadministration with cobicistat is necessary. Zolpidem is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%. (Moderate) Consider decreasing the dose of zolpidem if coadministration with protease inhibitors is necessary. Zolpidem is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Consider decreasing the dose of zolpidem if coadministration with protease inhibitors is necessary. Zolpidem is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Deferasirox: (Moderate) It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as deferasirox. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer.
    Delavirdine: (Moderate) Consider decreasing the dose of zolpidem if coadministration with delavirdine is necessary. Zolpidem is a CYP3A4 substrate and delavirdine is a strong CYP3A4 inhibitor. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Desipramine: (Moderate) Zolpidem appears to interact with tricyclic antidepressants and may cause decreased alertness. Zolpidem reduced peak serum concentrations of imipramine by 20%, but other pharmacokinetic parameters were not affected. In rare case reports, zolpidem has caused visual hallucinations or loss of alertness when these drugs (e.g., imipramine, desipramine) were administered concurrently. Interactions with other tricyclic antidepressants have not been studied, but additive drowsiness is also possible. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Desvenlafaxine: (Moderate) Disorientation, delusions, or hallucinations have been reported rarely during co-administration of zolpidem and antidepressants. The duration of the visual hallucinations has ranged from 30 minutes to 7 hours. The interaction is thought to be pharmacodynamic in nature; therefore, a similar reaction is possible with dexvenlafaxine. Data from a clinical study in which SSRI-treated patients were given immediate-release zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n = 95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction.
    Deutetrabenazine: (Moderate) Advise patients that concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as zolpidem, may have additive effects and worsen drowsiness or sedation.
    Dexamethasone: (Moderate) It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as dexamethasone. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer.
    Dexchlorpheniramine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Dexmedetomidine: (Moderate) Co-administration of dexmedetomidine with anxiolytics, sedatives, and hypnotics is likely to lead to an enhancement of CNS depression.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Diazepam: (Moderate) Concomitant administration of benzodiazepines with zolpidem can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Concurrent use of zolpidem with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Dicyclomine: (Moderate) Dicyclomine can cause drowsiness, so it should be used cautiously in patients receiving CNS depressants like anxiolytics, sedatives, and hypnotics.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Diltiazem: (Moderate) It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of diltiazem, a moderate CYP3A4 inhibitor, since CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism. There is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4, such as azole antifungals.
    Dimenhydrinate: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Diphenhydramine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Diphenhydramine; Ibuprofen: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Diphenhydramine; Naproxen: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Diphenhydramine; Phenylephrine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Doxepin: (Moderate) Zolpidem appears to interact with tricyclic antidepressants and may cause decreased alertness. Zolpidem reduced peak serum concentrations of imipramine by 20%, but other pharmacokinetic parameters were not affected. In rare case reports, zolpidem has caused visual hallucinations or loss of alertness when these drugs (e.g., imipramine, desipramine) were administered concurrently. Interactions with other tricyclic antidepressants have not been studied, but additive drowsiness is also possible. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Doxylamine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Doxylamine; Pyridoxine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Dronabinol: (Moderate) Concomitant use of dronabinol with other CNS depressants can potentiate the effects of dronabinol on respiratory depression. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Dronedarone: (Moderate) It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of dronedarone, a moderate CYP3A4 inhibitor, since CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism. There is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4, such as azole antifungals.
    Droperidol: (Moderate) Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and ethanol or other CNS depressants like droperidol than with zolpidem alone. Other CNS depressant drugs may also have cumulative sedative effects when administered concurrently and they should be used cautiously with zolpidem. A dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended in patients receiving concomitant CNS depressants. A reduction in dose of droperidol may also be needed.
    Duloxetine: (Moderate) Disorientation, delusions, or hallucinations have been reported rarely during co-administration of zolpidem and antidepressants. The duration of the visual hallucinations has ranged from 30 minutes to 7 hours. The interaction is thought to be pharmacodynamic in nature; therefore, a similar reaction is possible with duloxetine. Data from a clinical study in which SSRI-treated patients were given immediate-release zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n = 95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction.
    Duvelisib: (Moderate) Monitor for an increase in zolpidem-related adverse reactions, including excess sedation, if coadministration with duvelisib is necessary. A dose reduction of zolpidem may be necessary. Zolpidem is a CYP3A4 substrate and duvelisib is a moderate CYP3A4 inhibitor. There is evidence of an increase in pharmacodynamic effects and systemic exposure of zolpidem during coadministration with some potent inhibitors of CYP3A4.
    Efavirenz: (Moderate) It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as efavirenz. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as efavirenz. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as efavirenz. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer.
    Elagolix: (Moderate) Monitor for reduced therapeutic response to zolpidem is coadministration with elagolix is necessary. Zolpidem exposure may be decreased. Zolpidem is a CYP3A4 substrate; elagolix is a weak to moderate CYP3A4 inducer.
    Elbasvir; Grazoprevir: (Moderate) The primary isoenzyme responsible for the metabolism of zolpidem is CYP3A4. The effect of weak CYP3A4 inhibitors, such as elbasvir; grazoprevir, on zolpidem exposure is not known. Until further information is available, it is advisable to monitor for zolpidem-related CNS effects when this combination is administered. There is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4, such as azole antifungals.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Consider decreasing the dose of zolpidem if coadministration with cobicistat is necessary. Zolpidem is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Consider decreasing the dose of zolpidem if coadministration with cobicistat is necessary. Zolpidem is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Enflurane: (Moderate) The effects of CNS depressant drugs, such as zolpidem, may increase when administered concurrently with general anesthetics. A temporary dose reduction of the CNS depressant should be considered following administration of general anesthetics. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Entacapone: (Moderate) COMT inhibitors such as entacapone and tolcapone should be given cautiously with other agents that cause CNS depression, including zolpidem, due to the possibility of additive sedation. Sleep-related behaviors, such as sleep-driving, are also more likely to occur during concurrent use of zolpidem and CNS depressants than with zolpidem alone. If concurrent use is necessary, monitor for additive side effects. A reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Enzalutamide: (Major) Coadministration of zolpidem with enzalutamide is not recommended due to decreased plasma concentrations of zolpidem. Zolpidem is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased zolpidem exposure by 73% and significantly reduced the pharmacodynamic effects of zolpidem.
    Erythromycin: (Moderate) It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of erythromycin, a moderate CYP3A4 inhibitor, since CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism. There is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4, such as azole antifungals.
    Erythromycin; Sulfisoxazole: (Moderate) It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of erythromycin, a moderate CYP3A4 inhibitor, since CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism. There is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4, such as azole antifungals.
    Escitalopram: (Moderate) Disorientation, delusions, or hallucinations have been reported rarely during co-administration of zolpidem and SSRIs (i.e., fluoxetine, sertraline, fluvoxamine). The duration of the visual hallucinations has ranged from 30 minutes to 7 hours. Data from a clinical study in which SSRI-treated patients were given immediate-release zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n = 95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction. The mechanism for the interaction is thought to be pharmacodynamic in nature; therefore, a similar reaction is possible with other SSRIs such as escitalopram.
    Esketamine: (Major) Use of zolpidem during treatment with esketamine may increase sedation and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Instruct patients to contact their provider immediately if these symptoms or behaviors occur and not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
    Eslicarbazepine: (Moderate) It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as eslicarbazepine. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamics effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer.
    Estazolam: (Moderate) Concomitant administration of benzodiazepines with zolpidem can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Concurrent use of zolpidem with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Ethanol: (Major) Advise patients not to use zolpidem if they drank alcohol that evening or before bed. An additive adverse effect on psychomotor performance between alcohol and zolpidem has been demonstrated. The risk of next-day psychomotor impairment, including impaired driving, is increased if zolpidem is taken with alcohol.
    Ethotoin: (Major) Concurrent use of zolpidem with potent CYP3A4 inducers, such as hydantoins, should be avoided if possible because decreased plasma concentrations of zolpidem are possible and efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer. An alternative hypnotic agent may be more prudent in patients taking CYP3A4 inducers.
    Etomidate: (Moderate) The effects of CNS depressant drugs, such as zolpidem, may increase when administered concurrently with general anesthetics. A temporary dose reduction of the CNS depressant should be considered following administration of general anesthetics. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Etravirine: (Moderate) It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as etravirine. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamics effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer.
    Ezogabine: (Moderate) Due to the CNS effects of ezogabine, an enhanced CNS depressant effect may occur when it is combined with other centrally-acting medications such as anxiolytics, sedatives, and hypnotics. Patients should be monitored for excessive somnolence during concurrent therapy with these agents.
    Fedratinib: (Moderate) Monitor for an increase in zolpidem-related adverse reactions, including excess sedation, if coadministration with fedratinib is necessary. A dose reduction of zolpidem may be necessary. Zolpidem is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. There is evidence of an increase in pharmacodynamic effects and systemic exposure of zolpidem during coadministration with some potent inhibitors of CYP3A4.
    Fentanyl: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Fluconazole: (Moderate) Pharmacokinetic studies have shown that the systemic azole antifungals inhibit the metabolism and clearance of zolpidem. Fluconazole may reduce zolpidem clearance, but to a lesser extent than azole antifungals. It is prudent to monitor the response to zolpidem during concurrent systemic azole antifungal use and adjust dosage as needed to minimize the potential for adverse CNS effects.
    Flumazenil: (Major) Flumazenil, a benzodiazepine antagonist, can reduce the sedative hypnotic effects of zolpidem. Flumazenil and zolpidem are pharmacological opposites and should not be used together therapeutically.
    Fluoxetine: (Moderate) Disorientation, delusions, or hallucinations have been reported rarely during co-administration of zolpidem and SSRIs including fluoxetine. The duration of the visual hallucinations ranged from 30 minutes to 7 hours. Data from a clinical study in which SSRI-treated patients were given immediate-release zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n = 95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction. The mechanism for the interaction is thought to be pharmacodynamic in nature. In one study evaluating the effect of zolpidem 10 mg plus fluoxetine 20 mg at steady-state, male volunteers did not demonstrate any clinically significant pharmacokinetic or pharmacodynamic interactions. When multiple doses of zolpidem and fluoxetine were given at steady-state in healthy females, an increase in the zolpidem half-life (17%) was observed, although there was no evidence of an additive effect in psychomotor performance.
    Fluoxetine; Olanzapine: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zolpidem. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone. (Moderate) Disorientation, delusions, or hallucinations have been reported rarely during co-administration of zolpidem and SSRIs including fluoxetine. The duration of the visual hallucinations ranged from 30 minutes to 7 hours. Data from a clinical study in which SSRI-treated patients were given immediate-release zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n = 95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction. The mechanism for the interaction is thought to be pharmacodynamic in nature. In one study evaluating the effect of zolpidem 10 mg plus fluoxetine 20 mg at steady-state, male volunteers did not demonstrate any clinically significant pharmacokinetic or pharmacodynamic interactions. When multiple doses of zolpidem and fluoxetine were given at steady-state in healthy females, an increase in the zolpidem half-life (17%) was observed, although there was no evidence of an additive effect in psychomotor performance.
    Flurazepam: (Moderate) Concomitant administration of benzodiazepines with zolpidem can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Concurrent use of zolpidem with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Fluvoxamine: (Moderate) It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of fluvoxamine, since the metabolism of zolpidem may be decreased by CYP3A4, CYP1A2, and CYP2C9 inhibition of fluvoxamine. There is evidence of an increase in pharmacodynamic effects and systemic exposure of zolpidem when the drug is co-administered with some potent inhibitors of CYP3A4, such as azole antifungals. In addition, disorientation, delusions, or hallucinations have been reported rarely during co-administration of zolpidem and SSRIs including fluvoxamine. The duration of the visual hallucinations has ranged from 30 minutes to 7 hours. Data from a clinical study in which SSRI-treated patients were given immediate-release zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n = 95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction. In one case report, an elderly female patient experienced visual hallucinations and amnesia of the events three days after an increase in fluvoxamine dose to 50 mg three times daily after stabilization on zolpidem 10 mg/night. and fluvoxamine 50 mg twice daily. The mechanism for the interaction is unknown but may be pharmacodynamic in nature and/or related to increased zolpidem exposure from fluvoxamine inhibition of CYP3A4.
    Fosamprenavir: (Moderate) Consider decreasing the dose of zolpidem if coadministration with protease inhibitors is necessary. Zolpidem is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Fosphenytoin: (Major) Concurrent use of zolpidem with potent CYP3A4 inducers, such as hydantoins, should be avoided if possible because decreased plasma concentrations of zolpidem are possible and efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer. An alternative hypnotic agent may be more prudent in patients taking CYP3A4 inducers.
    Fospropofol: (Moderate) The effects of CNS depressant drugs, such as zolpidem, may increase when administered concurrently with general anesthetics. A temporary dose reduction of the CNS depressant should be considered following administration of general anesthetics. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Fostamatinib: (Moderate) Monitor for zolpidem toxicities that may require zolpidem dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a CYP3A4 substrate may increase the concentration of the CYP3A4 substrate. The active metabolite of fostamatinib, R406, is a CYP3A4 inhibitor; zolpidem is a substrate for CYP3A4. Coadministration of fostamatinib with a sensitive CYP3A4 substrate increased the substrate AUC by 64% and Cmax by 113%.
    Gabapentin: (Moderate) Coadministration of gabapentin with anxiolytics, sedatives, and hypnotics may increase CNS depressive effects such as drowsiness and dizziness. Use caution when administering gabapentin with CNS depressants. Patients should limit activity until they are aware of how coadministration affects them.
    General anesthetics: (Moderate) The effects of CNS depressant drugs, such as zolpidem, may increase when administered concurrently with general anesthetics. A temporary dose reduction of the CNS depressant should be considered following administration of general anesthetics. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Green Tea: (Minor) In healthy subjects in a pharmacokinetic study, coadministration of caffeine at a dosage of 150 to 300 mg with zolpidem did not counteract the sedative effects of a single 10 mg dose of zolpidem. In general, patients taking medications for insomnia should not use caffeine-containing products including medications, dietary supplements such as guarana, and beverages (e.g., coffee, green tea, other teas, or colas) prior to going to bed as these products may pharmacodynamically antagonize the sedative effects of zolpidem.
    Guaifenesin; Hydrocodone: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Haloperidol: (Moderate) Haloperidol can potentiate the actions of other CNS depressants such as anxiolytics, sedatives, and hypnotics, and they should be used cautiously in combination.
    Halothane: (Moderate) The effects of CNS depressant drugs, such as zolpidem, may increase when administered concurrently with general anesthetics. A temporary dose reduction of the CNS depressant should be considered following administration of general anesthetics. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Homatropine; Hydrocodone: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Hydantoins: (Major) Concurrent use of zolpidem with potent CYP3A4 inducers, such as hydantoins, should be avoided if possible because decreased plasma concentrations of zolpidem are possible and efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer. An alternative hypnotic agent may be more prudent in patients taking CYP3A4 inducers.
    Hydrocodone: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Hydrocodone; Ibuprofen: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zolpidem. Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Hydromorphone: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Hydroxyzine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Ibuprofen; Oxycodone: (Major) Concomitant use of oxycodone with zolpidem may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If zolpidem is used concurrently with oxycodone, a reduced dosage of oxycodone and/or zolpidem is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Monitor for sedation and respiratory depression.
    Idelalisib: (Moderate) Consider decreasing the dose of zolpidem if coadministration with idelalisib is necessary. Zolpidem is a CYP3A4 substrate and idelalisib is a strong CYP3A4 inhibitor. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Iloperidone: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zolpidem. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Imatinib: (Major) It is advisable to closely monitor zolpidem tolerability and safety during co-administration of CYP3A4 inhibitors, such as imatinib, STI-571, and consider using a lower dose of zolpidem to minimize the potential for adverse CNS effects. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4, such as azole antifungals.
    Imipramine: (Moderate) Zolpidem appears to interact with tricyclic antidepressants and may cause decreased alertness. Zolpidem reduced peak serum concentrations of imipramine by 20%, but other pharmacokinetic parameters were not affected. In rare case reports, zolpidem has caused visual hallucinations or loss of alertness when these drugs (e.g., imipramine, desipramine) were administered concurrently. Interactions with other tricyclic antidepressants have not been studied, but additive drowsiness is also possible. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Indinavir: (Moderate) Consider decreasing the dose of zolpidem if coadministration with protease inhibitors is necessary. Zolpidem is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Isavuconazonium: (Moderate) It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of isavuconazonium, a moderate CYP3A4 inhibitor, since CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism. There is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4, such as azole antifungals.
    Isocarboxazid: (Moderate) The manufacturers of MAOIs contraindicate the use of MAOIs with some CNS depressant drugs due to additive CNS depressant effects. If combination therapy is necessary, use caution; warn patients to avoid driving or performing other hazardous activities until they know how the combination affects them. A dose reduction of one or both medications may be required.
    Isoflurane: (Moderate) The effects of CNS depressant drugs, such as zolpidem, may increase when administered concurrently with general anesthetics. A temporary dose reduction of the CNS depressant should be considered following administration of general anesthetics. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Concurrent use of zolpidem with potent CYP3A4 inducers, such as rifampin, is not recommended. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of a significant decrease in systemic exposure and pharmacodynamic effects of zolpidem during co-administration of rifampin. During one small drug interaction study of healthy females, a single 10 mg dose of zolpidem co-administered with rifampin at steady state levels resulted in a 73%, 58%, and 36% decrease in the AUC, Cmax, and half-life, respectively, of zolpidem; this decrease in exposure resulted in significant reductions in the pharmacodynamic effects of zolpidem.
    Isoniazid, INH; Rifampin: (Major) Concurrent use of zolpidem with potent CYP3A4 inducers, such as rifampin, is not recommended. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of a significant decrease in systemic exposure and pharmacodynamic effects of zolpidem during co-administration of rifampin. During one small drug interaction study of healthy females, a single 10 mg dose of zolpidem co-administered with rifampin at steady state levels resulted in a 73%, 58%, and 36% decrease in the AUC, Cmax, and half-life, respectively, of zolpidem; this decrease in exposure resulted in significant reductions in the pharmacodynamic effects of zolpidem.
    Itraconazole: (Moderate) Consider decreasing the dose of zolpidem if coadministration with itraconazole is necessary. Zolpidem is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration with itraconazole increased the AUC of zolpidem by 34%.
    Kava Kava, Piper methysticum: (Major) Any substance that acts on the CNS, such as zolpidem, may interact with kava kava, Piper methysticum. These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action. The possibility of pharmacodynamic interactions at normal prescription dosages of zolpidem signals the need for patients to avoid concomitant administration of dietary supplements promoted for sleep and relaxation. Additionally, CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism and CYP3A4 inhibition by kava may theoretically increase systemic zolpidem exposure.
    Ketamine: (Moderate) The effects of CNS depressant drugs, such as zolpidem, may increase when administered concurrently with general anesthetics. A temporary dose reduction of the CNS depressant should be considered following administration of general anesthetics. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Ketoconazole: (Moderate) Consider decreasing the dose of zolpidem if coadministration with ketoconazole is necessary. Zolpidem is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the AUC of zolpidem by 70%.
    Lefamulin: (Moderate) Monitor for an increase in zolpidem-related adverse reactions, including excess sedation, if coadministration with oral lefamulin is necessary. A dose reduction of zolpidem may be necessary. Zolpidem is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. There is evidence of an increase in pharmacodynamic effects and systemic exposure of zolpidem during coadministration with some potent inhibitors of CYP3A4.
    Letermovir: (Moderate) Plasma concentrations and pharmacodynamic effect of zolpidem could be increased when administered concurrently with letermovir. Closely monitor for adverse events and consider zolpidem dose reductions if appropriate in patients also receiving cyclosporine because the magnitude of the interaction may increase. Zolpidem is primarily metabolized by CYP3A4. Letermovir is a moderate inhibitor of CYP3A4; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent use with a strong CYP3A4 inhibitor increased the zolpidem Cmax and AUC by 30% and 70%, respectively. In addition, concurrent use prolonged zolpidem half-life by 30% and increased the pharmacodynamic effects of zolpidem.
    Levocetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with zolpidem should generally be avoided. Concurrent use of zolpidem with other CNS depressants increases the risk for CNS depression and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). If concurrent use is necessary, patients should be instructed to contact their provider immediately if these symptoms or behaviors occur.
    Levomethadyl: (Moderate) Concomitant use of CNS depressants can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses.
    Levomilnacipran: (Moderate) Disorientation, delusions, or hallucinations have been reported rarely during co-administration of zolpidem and some SNRI antidepressants. The duration of the visual hallucinations has ranged from 30 minutes to 7 hours. The interaction is thought to be pharmacodynamic in nature; therefore, a similar reaction is possible with levomilnacipran. Data from a clinical study in which SSRI-treated patients were given immediate-release zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n = 95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction.
    Levorphanol: (Major) Concomitant use of levorphanol with other CNS depressants such as zolpidem can potentiate the effects of levorphanol on respiration, blood pressure, and alertness. Severe hypotension, respiratory depression, profound sedation, or coma may occur. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. When concomitant treatment is necessary, reduce the dose of 1 or both drugs. The initial dose of levorphanol should be reduced by approximately 50% or more when levorphanol is used with another drug that may depress respiration. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    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 additive sedation during coadministration of lofexidine and anxiolytics, sedatives, and hypnotics. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
    Lopinavir; Ritonavir: (Moderate) Consider decreasing the dose of zolpidem if coadministration with protease inhibitors is necessary. Zolpidem is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Lorazepam: (Moderate) Concomitant administration of benzodiazepines with zolpidem can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Concurrent use of zolpidem with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Loxapine: (Moderate) CNS depressant drugs, including loxapine, may have cumulative effects when administered concurrently and they should be used cautiously with zolpidem. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Lumacaftor; Ivacaftor: (Major) Concurrent use of zolpidem with potent CYP3A4 inducers, such as lumacaftor; ivacaftor, should be avoided if possible because decreased plasma concentrations of zolpidem are possible and efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer.
    Lurasidone: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zolpidem. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Maprotiline: (Moderate) CNS depressants should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension.
    Meclizine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Melatonin: (Major) Pharmacodynamic interactions often occur when sedative agents are used together. Avoid combining melatonin with zolpidem. In a clinical trial, there was clear evidence for a transitory pharmacodynamic interaction between melatonin and zolpidem one hour following co-dosing. Concomitant administration resulted in increased impairment of attention, memory and coordination compared to zolpidem 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 reporting unusual sleep-related behaviors likely should discontinue melatonin use.
    Mepenzolate: (Moderate) CNS depression can be increased when mepenzolate is combined with other CNS depressants such as any anxiolytics, sedatives, and hypnotics.
    Meperidine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Meperidine; Promethazine: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Mephobarbital: (Major) Concurrent use of zolpidem with barbiturates should be avoided if possible due to additive CNS depression. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended. Dosage reduction may be required for co-use in some patients. For example, a dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended when used with another CNS depressant. Barbiturates are CYP3A4 enzyme inducers and may cause decreased plasma concentrations of zolpidem; in some patients efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during coadministration of a potent CYP3A4 inducer.
    Metaxalone: (Moderate) Concomitant administration of metaxalone with other CNS depressants, such as certain sedatives and hypnotics, can potentiate the sedative effects of either agent. A reduction in the dose of these medications may be considered to minimize additive sedative effects, if they occur. With hypnotic medications, the risk of next-day psychomotor impairment is increased during co-administration of other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Methadone: (Major) Concomitant use of methadone with zolpidem can lead to additive respiratory depression, hypotension, profound sedation, or coma. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; in opioid-naive adults, use an initial methadone dose of 2.5 mg every 12 hours. Also consider a using a lower dose of zolpidem. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Monitor patients for sedation and respiratory depression.
    Methocarbamol: (Moderate) Methocarbamol may cause additive CNS depression if used concomitantly with other CNS depressants. Dosage reduction of one or both agents may be necessary.
    Methohexital: (Major) Concurrent use of zolpidem with barbiturates should be avoided if possible due to additive CNS depression. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended. Dosage reduction may be required for co-use in some patients. For example, a dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended when used with another CNS depressant. Barbiturates are CYP3A4 enzyme inducers and may cause decreased plasma concentrations of zolpidem; in some patients efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during coadministration of a potent CYP3A4 inducer.
    Methscopolamine: (Moderate) CNS depression can be increased when methscopolamine is combined with other CNS depressants such as any anxiolytics, sedatives, and hypnotics.
    Metoclopramide: (Minor) Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.
    Metyrapone: (Moderate) Metyrapone may cause dizziness and/or drowsiness. Other drugs that may also cause drowsiness, such as zolpidem, should be used with caution. Additive drowsiness and/or dizziness is possible.
    Midazolam: (Moderate) Concomitant administration of benzodiazepines with zolpidem can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Concurrent use of zolpidem with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Mifepristone: (Moderate) Consider decreasing the dose of zolpidem if coadministration with chronic mifepristone therapy is necessary. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown. Zolpidem is a CYP3A4 substrate and mifepristone is a strong CYP3A4 inhibitor. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Milnacipran: (Moderate) Disorientation, delusions, or hallucinations have been reported rarely during co-administration of zolpidem and some SNRI-type antidepressants. The duration of the visual hallucinations has ranged from 30 minutes to 7 hours. The interaction is thought to be pharmacodynamic in nature; therefore, a similar reaction is possible with levomilnacipran or milnacipran. Data from a clinical study in which SSRI-treated patients were given immediate-release zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n = 95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction.
    Mirtazapine: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including benzodiazepines.
    Mitotane: (Major) Concurrent use of zolpidem with potent CYP3A4 inducers, such as mitotane, should be avoided if possible because decreased plasma concentrations of zolpidem are possible and efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamics effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur when mitotane is given with zolpidem.
    Modafinil: (Moderate) It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as modafinil. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamics effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer.
    Molindone: (Moderate) Additive CNS-depressant effects may occur with zolpidem and molindone. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Monoamine oxidase inhibitors: (Moderate) The manufacturers of MAOIs contraindicate the use of MAOIs with some CNS depressant drugs due to additive CNS depressant effects. If combination therapy is necessary, use caution; warn patients to avoid driving or performing other hazardous activities until they know how the combination affects them. A dose reduction of one or both medications may be required.
    Morphine: (Moderate) Concomitant use of morphine with zolpidem can potentiate the effects of morphine on respiration, blood pressure, and alertness. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If zolpidem is used concurrently with morphine, a reduced dosage of morphine and/or zolpidem is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Monitor patients for sedation and respiratory depression.
    Morphine; Naltrexone: (Moderate) Concomitant use of morphine with zolpidem can potentiate the effects of morphine on respiration, blood pressure, and alertness. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If zolpidem is used concurrently with morphine, a reduced dosage of morphine and/or zolpidem is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Monitor patients for sedation and respiratory depression.
    Nabilone: (Moderate) Concomitant use of nabilone with other CNS depressants can potentiate the effects of nabilone on respiratory depression. Sleep-related behaviors, such as sleep-driving, are also more likely to occur during concurrent use of zolpidem and ethanol or other CNS depressants than with zolpidem alone. A reduction in the dose, should be considered to minimize additive sedative effects; for Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Nalbuphine: (Moderate) Concomitant use of nalbuphine with other CNS depressants, such as zolpidem, can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Concurrent use of zolpidem with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended.
    Nefazodone: (Moderate) Consider decreasing the dose of zolpidem if coadministration with nefazodone is necessary. Zolpidem is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Nelfinavir: (Moderate) Consider decreasing the dose of zolpidem if coadministration with protease inhibitors is necessary. Zolpidem is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Netupitant, Fosnetupitant; Palonosetron: (Moderate) It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of netupitant, a moderate CYP3A4 inhibitor, since CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism. There is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4, such as azole antifungals.
    Nevirapine: (Moderate) It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as nevirapine. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamics effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer.
    Nilotinib: (Moderate) It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of nilotinib, a moderate CYP3A4 inhibitor, since CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism. There is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem when the drug is co-administered with some potent inhibitors of CYP3A4, such as azole antifungals. Concurrent administration of nilotinib and midazolam, a CYP3A4 substrate, increased midazolam exposure by 30%.
    Nortriptyline: (Moderate) Zolpidem appears to interact with tricyclic antidepressants and may cause decreased alertness. Zolpidem reduced peak serum concentrations of imipramine by 20%, but other pharmacokinetic parameters were not affected. In rare case reports, zolpidem has caused visual hallucinations or loss of alertness when these drugs (e.g., imipramine, desipramine) were administered concurrently. Interactions with other tricyclic antidepressants have not been studied, but additive drowsiness is also possible. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Octreotide: (Moderate) It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of octreotide, a moderate CYP3A4 inhibitor, since CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism. There is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4, such as azole antifungals.
    Olanzapine: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zolpidem. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Consider decreasing the dose of zolpidem if coadministration with protease inhibitors is necessary. Zolpidem is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Oritavancin: (Moderate) Zolpidem is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of zolpidem may be reduced if these drugs are administered concurrently.
    Orphenadrine: (Moderate) Additive CNS depressant effects may be seen with combination use of orphenadrine and anxiolytics, sedatives, and hypnotics.
    Oxazepam: (Moderate) Concomitant administration of benzodiazepines with zolpidem can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Concurrent use of zolpidem with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Oxybutynin: (Moderate) Oxybutynin causes CNS-depressant effects including somnolence and drowsiness; concurrent use with other CNS-depressant drugs, including anxiolytics, sedatives, and hypnotics, can increase the total sedative effects of oxybutynin.
    Oxycodone: (Major) Concomitant use of oxycodone with zolpidem may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If zolpidem is used concurrently with oxycodone, a reduced dosage of oxycodone and/or zolpidem is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Monitor for sedation and respiratory depression.
    Oxymorphone: (Major) Concomitant use of oxymorphone with zolpidem may produce additive CNS depressant effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If zolpidem is used concurrently with oxymorphone, a reduced dosage of oxymorphone (1/3 to 1/2 of the usual dose) and/or zolpidem is recommended. If the extended-release oxymorphone tablets are used concurrently with a CNS depressant, it is recommended to use an initial oxymorphone ER dosage of 5 mg PO every 12 hours. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Monitor for sedation or respiratory depression.
    Palbociclib: (Moderate) Monitor for an increase in sedation and other zolpidem-related adverse reactions if coadministration with palbociclib is necessary. Zolpidem is a CYP3A4 substrate and palbociclib is a weak, time-dependent CYP3A4 inhibitor.
    Paliperidone: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zolpidem. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Papaverine: (Moderate) Papaverine is a benzylisoquinoline alkaloid of opium and may have synergistic effects with potent CNS depressants such as anxiolytics, sedatives, and hypnotics, which could lead to enhanced sedation.
    Paroxetine: (Moderate) Disorientation, delusions, or hallucinations have been reported rarely during co-administration of zolpidem and SSRIs (e.g., fluoxetine, sertraline, fluvoxamine). The duration of the visual hallucinations has ranged from 30 minutes to 7 hours. Data from a clinical study in which SSRI-treated patients were given immediate-release zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n = 95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction. The mechanism for the interaction is thought to be pharmacodynamic in nature; therefore, a similar reaction is possible with other SSRIs such as paroxetine.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and zolpidem, a CYP3A4 substrate, may cause an increase in systemic concentrations of zolpidem. Use caution when administering these drugs concomitantly.
    Pentazocine: (Moderate) Concomitant use of pentazocine with zolpidem can potentiate respiratory depression, CNS depression, and sedation. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone. Pentazocine should be used cautiously in any patient receiving zolpidem. If concurrent use is necessary, a dose reduction of one or both medications may be required. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Pentazocine; Naloxone: (Moderate) Concomitant use of pentazocine with zolpidem can potentiate respiratory depression, CNS depression, and sedation. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone. Pentazocine should be used cautiously in any patient receiving zolpidem. If concurrent use is necessary, a dose reduction of one or both medications may be required. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Pentobarbital: (Major) Concurrent use of zolpidem with barbiturates should be avoided if possible due to additive CNS depression. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended. Dosage reduction may be required for co-use in some patients. For example, a dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended when used with another CNS depressant. Barbiturates are CYP3A4 enzyme inducers and may cause decreased plasma concentrations of zolpidem; in some patients efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during coadministration of a potent CYP3A4 inducer.
    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 zolpidem.
    Perphenazine; Amitriptyline: (Moderate) Zolpidem appears to interact with tricyclic antidepressants and may cause decreased alertness. Zolpidem reduced peak serum concentrations of imipramine by 20%, but other pharmacokinetic parameters were not affected. In rare case reports, zolpidem has caused visual hallucinations or loss of alertness when these drugs (e.g., imipramine, desipramine) were administered concurrently. Interactions with other tricyclic antidepressants have not been studied, but additive drowsiness is also possible. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Phenelzine: (Moderate) The manufacturers of MAOIs contraindicate the use of MAOIs with some CNS depressant drugs due to additive CNS depressant effects. If combination therapy is necessary, use caution; warn patients to avoid driving or performing other hazardous activities until they know how the combination affects them. A dose reduction of one or both medications may be required.
    Phenobarbital: (Major) Concurrent use of zolpidem with barbiturates should be avoided if possible due to additive CNS depression. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended. Dosage reduction may be required for co-use in some patients. For example, a dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended when used with another CNS depressant. Barbiturates are CYP3A4 enzyme inducers and may cause decreased plasma concentrations of zolpidem; in some patients efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during coadministration of a potent CYP3A4 inducer.
    Phenothiazines: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered with other CNS depressant drugs and they should be used cautiously with anxiolytic, sedative, and hypnotics. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of hypnotics and other CNS depressants than with use of a hypnotic alone.
    Phentermine; Topiramate: (Major) Although not specifically studied, coadministration of CNS depressant drugs (e.g., anxiolytics, sedatives, and hypnotics) 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.
    Phenytoin: (Major) Concurrent use of zolpidem with potent CYP3A4 inducers, such as hydantoins, should be avoided if possible because decreased plasma concentrations of zolpidem are possible and efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer. An alternative hypnotic agent may be more prudent in patients taking CYP3A4 inducers.
    Pimozide: (Moderate) Additive CNS-depressant effects may occur when the antipsychotic pimozide is combined with zolpidem. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Posaconazole: (Moderate) Consider decreasing the dose of zolpidem if coadministration with posaconazole is necessary. Zolpidem is a CYP3A4 substrate and posaconazole is a strong CYP3A4 inhibitor. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Pramipexole: (Moderate) Other CNS depressant drugs, such as pramipexole, may have cumulative effects when administered concurrently with zolpidem and they should be used cautiously with zolpidem. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Concurrent use of zolpidem with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended.
    Pregabalin: (Moderate) Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and ethanol or other CNS depressants, like pregabalin, than with zolpidem alone. Pregabalin may also have cumulative sedative effects when administered concurrently and should be used cautiously with zolpidem. A reduction in dose of the CNS depressant may be needed in some cases. A dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended in patients receiving concomitant CNS depressants. A reduction in dose of the CNS depressant may also be needed.
    Primidone: (Major) Concurrent use of zolpidem with barbiturates should be avoided if possible due to additive CNS depression. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended. Dosage reduction may be required for co-use in some patients. For example, a dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended when used with another CNS depressant. Barbiturates are CYP3A4 enzyme inducers and may cause decreased plasma concentrations of zolpidem; in some patients efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during coadministration of a potent CYP3A4 inducer.
    Propofol: (Moderate) The effects of CNS depressant drugs, such as zolpidem, may increase when administered concurrently with general anesthetics. A temporary dose reduction of the CNS depressant should be considered following administration of general anesthetics. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Propoxyphene: (Moderate) Concomitant use of CNS depressants can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses.
    Protease inhibitors: (Moderate) Consider decreasing the dose of zolpidem if coadministration with protease inhibitors is necessary. Zolpidem is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Protriptyline: (Moderate) Zolpidem appears to interact with tricyclic antidepressants and may cause decreased alertness. Zolpidem reduced peak serum concentrations of imipramine by 20%, but other pharmacokinetic parameters were not affected. In rare case reports, zolpidem has caused visual hallucinations or loss of alertness when these drugs (e.g., imipramine, desipramine) were administered concurrently. Interactions with other tricyclic antidepressants have not been studied, but additive drowsiness is also possible. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Quazepam: (Moderate) Concomitant administration of benzodiazepines with zolpidem can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Concurrent use of zolpidem with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Quetiapine: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zolpidem. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Quinine: (Moderate) It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of quinine, a moderate CYP3A4 inhibitor, since CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism. There is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4, such as azole antifungals.
    Ramelteon: (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.
    Ranolazine: (Moderate) In vitro studies indicate that ranolazine and its O-demethylated metabolite are inhibitors of CYP3A isoenzymes. In theory, ranolazine may inhibit zolpidem CYP3A4 metabolism, potentially leading to increased zolpidem plasma concentrations. Although not studied, excessive sedation and possible respiratory depression may occur.
    Rasagiline: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including buprenorphine, butorphanol, dronabinol, THC, nabilone, nalbuphine, and anxiolytics, sedatives, and hypnotics. 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: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Ribociclib: (Moderate) Monitor for an increase in sedation and other zolpidem-related adverse reactions if coadministration with ribociclib is necessary. Zolpidem is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased zolpidem exposure by 34% to 70%
    Ribociclib; Letrozole: (Moderate) Monitor for an increase in sedation and other zolpidem-related adverse reactions if coadministration with ribociclib is necessary. Zolpidem is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased zolpidem exposure by 34% to 70%
    Rifabutin: (Moderate) It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as rifabutin. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer.
    Rifampin: (Major) Concurrent use of zolpidem with potent CYP3A4 inducers, such as rifampin, is not recommended. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of a significant decrease in systemic exposure and pharmacodynamic effects of zolpidem during co-administration of rifampin. During one small drug interaction study of healthy females, a single 10 mg dose of zolpidem co-administered with rifampin at steady state levels resulted in a 73%, 58%, and 36% decrease in the AUC, Cmax, and half-life, respectively, of zolpidem; this decrease in exposure resulted in significant reductions in the pharmacodynamic effects of zolpidem.
    Rifapentine: (Moderate) It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as rifapentine. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer.
    Risperidone: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zolpidem. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Ritonavir: (Moderate) Consider decreasing the dose of zolpidem if coadministration with protease inhibitors is necessary. Zolpidem is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Ropinirole: (Moderate) Concomitant use of ropinirole with other CNS depressants, such as zolpidem, can potentiate the sedation effects of ropinirole. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Rotigotine: (Moderate) A reduction in the dose of anxiolytics, sedatives, hypnotics and concomitantly administered dopamine agonists with sedative properties (e.g., ropinirole, pramipexole, rotigotine, apomorphine) should be considered to minimize additive sedative effects. In addition, the risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Rucaparib: (Moderate) Monitor for an increase in sedation and other zolpidem-related adverse reactions if coadministration with rucaparib is necessary. Zolpidem is a CYP3A4 and CYP1A2 substrate. Rucaparib is a moderate CYP1A2 inhibitor as well as a weak inhibitor of CYP3A4.
    Rufinamide: (Minor) Rufinamide is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as zolpidem, may occur during concurrent use with rufinamide.
    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 anxiolytics, sedatives, and hypnotics.
    Saquinavir: (Moderate) Consider decreasing the dose of zolpidem if coadministration with protease inhibitors is necessary. Zolpidem is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Scopolamine: (Moderate) Scopolamine may cause dizziness and drowsiness. Concurrent use of scopolamine and CNS depressants can adversely increase the risk of CNS depression.
    Secobarbital: (Major) Concurrent use of zolpidem with barbiturates should be avoided if possible due to additive CNS depression. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended. Dosage reduction may be required for co-use in some patients. For example, a dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended when used with another CNS depressant. Barbiturates are CYP3A4 enzyme inducers and may cause decreased plasma concentrations of zolpidem; in some patients efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during coadministration of a potent CYP3A4 inducer.
    Sedating H1-blockers: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Selegiline: (Moderate) The manufacturers of MAOIs contraindicate the use of MAOIs with some CNS depressant drugs due to additive CNS depressant effects. If combination therapy is necessary, use caution; warn patients to avoid driving or performing other hazardous activities until they know how the combination affects them. A dose reduction of one or both medications may be required.
    Sertraline: (Moderate) Disorientation, delusions, or hallucinations have been reported rarely during co-administration of zolpidem and SSRIs including sertraline. The duration of the visual hallucinations ranged from 30 minutes to 7 hours. Data from a clinical study in which SSRI-treated patients were given immediate-release zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n = 95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction. The mechanism for the interaction is thought to be pharmacodynamic in nature. In one study with sertraline, inhibition of zolpidem metabolism occurred when sertraline was chronically coadministered; zolpidem Cmax was significantly higher (43%) and Tmax was significantly decreased (53%).
    Sevoflurane: (Moderate) The effects of CNS depressant drugs, such as zolpidem, may increase when administered concurrently with general anesthetics. A temporary dose reduction of the CNS depressant should be considered following administration of general anesthetics. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Simeprevir: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of zolpidem, which is a CYP3A4 substrate. Monitor patients for adverse effects of zolpidem.
    Sodium Oxybate: (Severe) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    St. John's Wort, Hypericum perforatum: (Major) Concurrent use of zolpidem with potent CYP3A4 inducers, such as St. John's Wort, is not recommended because decreased plasma concentrations of zolpidem are possible and efficacy may be decreased. In one small controlled pharmacokinetic trial evaluating the effects of co-administration of zolpidem and St. John's wort, Hypericum perforatum, 14 healthy male subjects received a single 10 mg dose of zolpidem followed by St. John's wort (300 mg three times per day) for 14 days. The last dose of St. John's wort was administered with a second single dose of zolpidem. Compared to zolpidem alone, the combination resulted in the following overall changes in the pharmacokinetic parameters of zolpidem: the mean AUC was 30% lower, the Cmax was 33.7% lower, and the oral clearance was 8.2% higher. There was a small increase in zolpidem AUC in three patients. No significant differences were observed in the half-life or Tmax of zolpidem.
    Sufentanil: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Suvorexant: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. Use cautiously with any anxiolytics; use with other sedatives and hypnotics should generally be avoided due to duplication of treatments.
    Tapentadol: (Major) Concomitant use of opioid agonists with other CNS depressants may cause excessive sedation and somnolence. Limit the use of opioid pain medications with anotehr CNS depressant 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.
    Telaprevir: (Moderate) Clinical monitoring is advised when administering zolpidem with telaprevir due to the potential for decreased zolpidem efficacy. The dose of zolpidem should be titrated to achieve desired clinical response. If zolpidem dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment.
    Telithromycin: (Moderate) Consider decreasing the dose of zolpidem if coadministration with telithromycin is necessary. Zolpidem is a CYP3A4 substrate and telithromycin is a strong CYP3A4 inhibitor. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Temazepam: (Moderate) Concomitant administration of benzodiazepines with zolpidem can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Concurrent use of zolpidem with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Terbinafine: (Moderate) In vitro studies have shown systemic terbinafine to inhibit hepatic isoenzyme CYP2D6, and thus may inhibit the clearance of drugs metabolized by this isoenzyme, such as zolpidem.
    Tetrabenazine: (Moderate) Concurrent use of tetrabenazine and drugs that can cause CNS depression, such as anxiolytics, sedatives, and hypnotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Thalidomide: (Major) The use of anxiolytics, sedatives, or hypnotics concomitantly with thalidomide may cause an additive sedative effect and should be avoided. Thalidomide frequently causes drowsiness and somnolence. Dose reductions may be required. Patients should be instructed to avoid situations where drowsiness may be a problem and not to take other medications that may cause drowsiness without adequate medical advice. Advise patients as to the possible impairment of mental and/or physical abilities required for the performance of hazardous tasks, such as driving a car or operating other complex or dangerous machinery.
    Thiopental: (Major) Concurrent use of zolpidem with barbiturates should be avoided if possible due to additive CNS depression. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended. Dosage reduction may be required for co-use in some patients. For example, a dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended when used with another CNS depressant. Barbiturates are CYP3A4 enzyme inducers and may cause decreased plasma concentrations of zolpidem; in some patients efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during coadministration of a potent CYP3A4 inducer.
    Thiothixene: (Moderate) Zolpidem and thiothixene may have cumulative effects on CNS depression when administered concurrently and they should be used together with caution. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Tipranavir: (Moderate) Consider decreasing the dose of zolpidem if coadministration with protease inhibitors is necessary. Zolpidem is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Tizanidine: (Moderate) Concurrent use of tizanidine and CNS depressants such as certain sedatives or hypnotics can cause additive CNS depression. A reduction in the dose of these medications may be considered to minimize additive sedative effects, if they occur. With hypnotic medications, the risk of next-day psychomotor impairment is increased during co-administration of other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Tolcapone: (Moderate) COMT inhibitors such as entacapone and tolcapone should be given cautiously with other agents that cause CNS depression, including zolpidem, due to the possibility of additive sedation. Sleep-related behaviors, such as sleep-driving, are also more likely to occur during concurrent use of zolpidem and CNS depressants than with zolpidem alone. If concurrent use is necessary, monitor for additive side effects. A reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Topiramate: (Major) Although not specifically studied, coadministration of CNS depressant drugs (e.g., anxiolytics, sedatives, and hypnotics) 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: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. A dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended in patients receiving concomitant CNS depressants.
    Trandolapril; Verapamil: (Moderate) It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of verapamil, a moderate CYP3A4 inhibitor, since CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism. There is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4, such as azole antifungals.
    Tranylcypromine: (Moderate) The manufacturers of MAOIs contraindicate the use of MAOIs with some CNS depressant drugs due to additive CNS depressant effects. If combination therapy is necessary, use caution; warn patients to avoid driving or performing other hazardous activities until they know how the combination affects them. A dose reduction of one or both medications may be required.
    Trazodone: (Moderate) Zolpidem should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Triazolam: (Moderate) Concomitant administration of benzodiazepines with zolpidem can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Concurrent use of zolpidem with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Tricyclic antidepressants: (Moderate) Zolpidem appears to interact with tricyclic antidepressants and may cause decreased alertness. Zolpidem reduced peak serum concentrations of imipramine by 20%, but other pharmacokinetic parameters were not affected. In rare case reports, zolpidem has caused visual hallucinations or loss of alertness when these drugs (e.g., imipramine, desipramine) were administered concurrently. Interactions with other tricyclic antidepressants have not been studied, but additive drowsiness is also possible. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Trihexyphenidyl: (Moderate) CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase the sedative effects of trihexyphenidyl.
    Trimethobenzamide: (Moderate) The concurrent use of trimethobenzamide with other medications that cause CNS depression, like anxiolytics, sedatives and hypnotics, may potentiate the effects of either trimethobenzamide or the anxiolytics, sedatives and hypnotics.
    Trimipramine: (Moderate) Zolpidem appears to interact with tricyclic antidepressants and may cause decreased alertness. Zolpidem reduced peak serum concentrations of imipramine by 20%, but other pharmacokinetic parameters were not affected. In rare case reports, zolpidem has caused visual hallucinations or loss of alertness when these drugs (e.g., imipramine, desipramine) were administered concurrently. Interactions with other tricyclic antidepressants have not been studied, but additive drowsiness is also possible. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Triprolidine: (Moderate) The CNS-depressant effects of zolpidem can be potentiated with concomitant administration of other drugs known to cause CNS depression, such as sedating H1-blockers. A dose reduction of either or both drugs should be considered to minimize additive sedative effects. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Valerian, Valeriana officinalis: (Major) Any substances that act on the CNS, including sedatives and hypnotics, may theoretically interact with valerian, Valeriana officinalis. 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. These interactions are probably pharmacodynamic in nature. There is a possibility of interaction with valerian at normal prescription dosages of sedatives and hypnotics. Patients who are taking barbiturates or other sedative/hypnotic drugs should avoid concomitant administration of valerian.
    Valproic Acid, Divalproex Sodium: (Moderate) A probable interaction between zolpidem and valproic acid resulted in somnambulism (sleep walking) in one case report. A 47 year old patient with a history of bipolar disorder was receiving citalopram (40 mg once daily) and zolpidem (5 mg at bedtime). Manic symptoms developed during treatment and he received valproic acid. Somnambulism developed 2 days after the valproic acid was initiated. The sleep walking stopped after the valproic acid was discontinued and with a rechallenge the symptoms reappeared. It is not known if this interaction is of a pharmacokinetic or pharmacodynamic nature. Somnambulism has also been reported as a rare side effect of zolpidem when used without interacting medications; however this patient did not experience sleep walking with zolpidem monotherapy or with valproic acid monotherapy.
    Vemurafenib: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as zolpidem, could be expected with concurrent use. Use caution, and monitor therapeutic effects of zolpidem when coadministered with vemurafenib.
    Venlafaxine: (Moderate) Disorientation, delusions, or hallucinations have been reported rarely during co-administration of zolpidem and antidepressants. The duration of the visual hallucinations has ranged from 30 minutes to 7 hours. The interaction is thought to be pharmacodynamic in nature; therefore, a similar reaction is possible with venlafaxine. Data from a clinical study in which SSRI-treated patients were given immediate-release zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n = 95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction.
    Verapamil: (Moderate) It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of verapamil, a moderate CYP3A4 inhibitor, since CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism. There is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4, such as azole antifungals.
    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 anxiolytics, sedatives, and hypnotics.
    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) Consider decreasing the dose of zolpidem if coadministration with voriconazole is necessary. Zolpidem is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
    Ziconotide: (Moderate) Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects such as anxiolytics, sedatives, and hypnotics. Coadministration of CNS depressants may increase drowsiness, dizziness, and confusion that are associated with ziconotide. Patients taking sedatives with ziconotide may be at higher risk of depressed levels of consciousness. If altered consciousness occurs, consideration of sedative cessation is warranted in addition to ziconotide discontinuation.
    Ziprasidone: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zolpidem. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.

    PREGNANCY AND LACTATION

    Pregnancy

    The developmental and health benefits of breast-feeding should be assessed along with the mother's clinical need for zolpidem and potential adverse effects on the breastfed infant from zolpidem or any underlying maternal condition. Zolpidem is excreted into breast milk, and there are reports of excess sedation in babies exposed to zolpidem through breast milk; therefore, it is recommended to monitor the breast-fed infant for excess sedation, hypotonia, and respiratory depression. Alternatively, a lactating woman may consider interrupting breast-feeding and pumping and discarding breast milk during treatment and for 23 hours (about 5 half-lives) after zolpidem administration to minimize infant drug exposure. In one small study of lactating women (n = 5) who received a single 20 mg dose of zolpidem on postpartum day 3 or 4, the mean milk to maternal plasma concentration ratio was 0.13 (range, 0.11 to 0.18) three hours after drug administration. The amount of zolpidem measured in the breast milk samples represented 0.004% to 0.019% of the maternal administered dose. No detectable zolpidem was measured in subsequent milk samples taken at 13 and 16 hours after the dose. Breast-feeding was discontinued for 24 hours after drug administration; therefore, infant exposure was not assessed. The transfer of zaleplon, an alternative sedative, into breast milk has also been assessed; however, the effects of zaleplon exposure on the breast-feeding infant have not been formally evaluated.[31451] [40336] [44125] [45971] [46915] [57789]

    MECHANISM OF ACTION

    Zolpidem is a gamma-aminobutyric acid-A (GABA-A) receptor positive modulator thought to exert its therapeutic effect in the treatment of insomnia through binding at the omega-1 subunit of the GABA-A receptor site. Binding at the omega-1 subunit increases the frequency of chloride channel opening, which results in the inhibition of neuronal exitation. Zolpidem is chemically unrelated to benzodiazepines, which non-selectively interact with omega-receptor subtypes at the GABA-A receptor site. Zolpidem binds to the omega-1 subunit with greater affinity than the omega-2 or omega-3 subunits and has no appreciable binding to omega-5, which may explain its lack of myorelaxant, anxiolytic, and anticonvulsant effects compared to benzodiazepines. Sleep studies in humans indicate that zolpidem normally preserves deep sleep (stages 3 and 4) and that changes in rapid eye movement (REM) sleep are minor and inconsistent. Anterograde amnesia appears to be more likely with dosages higher than 10 mg. In one study of zolpidem 10 mg or 20 mg, a significant decrease in next morning recall of information was observed during the times of peak medication effect (i.e., 90 minutes post-dose). Signs and symptoms of withdrawal may occur with rapid dose reduction or abrupt discontinuation. Flumazenil, a benzodiazepine antagonist and reversal agent, has been shown to reduce the sedative effects of zolpidem. Zolpidem has no appreciable binding affinity for dopaminergic (D2), serotonergic (5-HT2), adrenergic, histaminic, or muscarinic receptors.

    PHARMACOKINETICS

    Zolpidem is administered orally as an immediate-release tablet, controlled-release tablet, lingual spray, and sublingual tablet. It is about 92% bound to plasma protein. Hepatic metabolism through CYP isoenzymes produces inactive metabolites that are primarily excreted in the urine. Immediate-release zolpidem has not been shown to accumulate in studies ranging up to 2 weeks. The mean elimination half-life of the immediate-release tablets is roughly 2.6 hours in patients with normal hepatic and renal function. The half-life and plasma protein binding are similar between the extended-release and immediate-release tablet formulations. Similar to immediate-release, accumulation has not been shown to occur with the extended-release product. However, data show that the risk for next-morning impairment is higher for the extended-release than the immediate-release formulation. The mean half-life of zolpidem lingual spray (Zolpimist) is 2.7 hours for the 5 mg dose (range: 1.7 to 5 hours) and 3 hours for the 10 mg dose (range: 1.7 to 8.4 hours). The mean elimination half-life of the Edluar brand of the sublingual tablet is 2.85 hours (range: 1.57 to 6.73 hours) and 2.65 hours (range: 1.75 to 3.77 hours) after a single dose of 5 or 10 mg, respectively, in healthy adult volunteers. The elimination half-life of a single 3.5 mg dose of the Intermezzo brand of the sublingual tablet is about 2.5 hours (range: 1.4 to 3.6 hours). Blood concentrations above 50 ng/mL appear to be capable of impairing driving to a level that increases the risk of a motor vehicle accident.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A4, CYP2C9, CYP2D6, CYP2C19
    Based on in vitro data, approximately 61% of zolpidem is metabolized by CYP3A4, with minor metabolism pathways by CYP2C9 (22%), CYP1A2 (14%), CYP2D6 (less than 3%), and CYP2C19 (less than 3%). Although zolpidem has multiple pathways for metabolism, clinically significant interactions may be considered with concurrent use of potent CYP3A4 inhibitors and inducers based on in vivo interactions with azole antifungals and rifampin, respectively. The effect of drugs that inhibit or induce other CYP isoenzymes on the systemic exposure of zolpidem is unknown.

    Oral Route

    Immediate-release tablets (i.e., Ambien): Zolpidem is rapidly absorbed after oral administration. Peak medication effects of the immediate-release tablet occur within 90 minutes of a single oral dosage. In single-dose studies in subjects administered 5 mg and 10 mg zolpidem, the mean peak concentrations (Cmax) were 59 (range: 29—113) and 121 (range: 58—272) ng/ml, respectively, occurring at a mean time (Tmax) of 1.6 hours for both strengths. The presence of food reduces the amount of absorption and increases the time taken to achieve maximum concentration, delaying sleep onset. Therefore all formulations of zolpidem should be taken on an empty stomach versus after a meal.
    Extended-release tablets (i.e., Ambien CR): Extended-release zolpidem exhibits biphasic absorption characteristics through a coated two-layer tablet with rapid initial absorption from the GI tract through the first tablet layer similar to zolpidem immediate-release, followed by extended plasma concentrations beyond 3 hours after administration by release of drug through the second layer. Similar to the immediate-release dosage form, zolpidem extended-release should be taken on an empty stomach for faster absorption and sleep-onset. Data show that the risk for next-morning impairment is higher for the extended-release than the immediate-release formulation.
    Lingual spray (i.e., Zolpimist): Zolpidem lingual spray is rapidly absorbed from the oral mucosa and GI tract. The spray is bioequivalent to immediate release zolpidem tablets (Ambien). The mean time to peak plasma concentrations (Tmax) is approximately 0.9 hours. The mean Tmax is prolonged by 225% when the drug is administered after eating a standard high-fat meal; therefore, for faster sleep onset, zolpidem spray should not be administered with or immediately after a meal.
    Sublingual tablets (i.e., Edluar): Zolpidem sublingual tablets are bioequivalent to the immediate-release tablets with regard to Cmax and AUC. The mean peak plasma concentration occurs at a median time of 82 minutes (range: 30—180 minutes) after administration. When the drug is administered within 20 minutes after a high fat meal, the mean AUC and Cmax are decreased by 20% and 31%, respectively, compared to administration while fasting. The median Tmax is prolonged by 28%. Therefore, for faster sleep onset, zolpidem sublingual tablets should not be taken with or immediately after a meal.
    Sublingual tablets (i.e., Intermezzo): Zolpidem sublingual tablets disintegrate in the sublingual cavity after administration. The mean Tmax is about 35—75 minutes. The average Cmax and AUC are higher in women than men. Administration with food decreases the overall Cmax and AUC by 42% and 19% respectively, and increases the Tmax to nearly 3 hours. Therefore, administration with or immediately after a meal is not recommended.
    Orally disintegrating tablets (i.e., Tovalt ODT): NOTE: The orally disintegrating tablet (ODT) is discontinued in the US.Zolpidem orally disintegrating tablets are bioequivalent to the immediate-release tablets. The mean Cmax of the oral disintegrating tablets occurs in about 1.75 hours. The presence of food reduces the amount of absorption and increases the time taken to achieve maximum concentration, delaying sleep onset. Therefore zolpidem orally disintegrating tablets should be taken on an empty stomach versus after a meal.