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    Benzodiazepine Related Sedative/Hypnotics

    DEA CLASS

    Rx, schedule IV

    DESCRIPTION

    Non-benzodiazepine hypnotic.
    Used for insomnia to aide in sleep initiation; some products may be used for middle-of-the night awakenings.
    Available in immediate and extended release formulations; rapid onset and short half-life reduces 'hangover' effects; does not cause early-AM awakening.

    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. In residents meeting the criteria for treatment, the dose of zolpidem should not exceed 5 mg/day PO, 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. A taper is considered clinically contraindicated if the continued use of the medication is in accordance with relevant current standards of practice or the resident's target symptoms returned or worsened with the most recent tapering attempt within the facility, and the physician has documented the reason(s) that a dose reduction would likely impair the resident's function or cause psychiatric instability by exacerbating an underlying medical or psychiatric disorder.

    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, the dose of zolpidem should not exceed 5 mg/day PO, 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. A taper is considered clinically contraindicated if the continued use of the medication is in accordance with relevant current standards of practice or the resident's target symptoms returned or worsened with the most recent tapering attempt within the facility, and the physician has documented the reason(s) that a dose reduction would likely impair the resident's function or cause psychiatric instability by exacerbating an underlying medical or psychiatric disorder.

    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. In residents meeting the criteria for treatment, the dose of zolpidem should not exceed 5 mg/day PO, 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. A taper is considered clinically contraindicated if the continued use of the medication is in accordance with relevant current standards of practice or the resident's target symptoms returned or worsened with the most recent tapering attempt within the facility, and the physician has documented the reason(s) that a dose reduction would likely impair the resident's function or cause psychiatric instability by exacerbating an underlying medical or psychiatric disorder.

    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. In residents meeting the criteria for treatment, the dose of extended-release zolpidem should not exceed 6.25 mg/day PO, 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. A taper is considered clinically contraindicated if the continued use of the medication is in accordance with relevant current standards of practice or the resident's target symptoms returned or worsened with the most recent tapering attempt within the facility, and the physician has documented the reason(s) that a dose reduction would likely impair the resident's function or cause psychiatric instability by exacerbating an underlying medical or psychiatric disorder.

    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. 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. A taper is considered clinically contraindicated if the continued use of the medication is in accordance with relevant current standards of practice or the resident's target symptoms returned or worsened with the most recent tapering attempt within the facility, and the physician has documented the reason(s) that a dose reduction would likely impair the resident's function or cause psychiatric instability by exacerbating an underlying medical or psychiatric disorder.

    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

    Although some patients have shown improvement during zolpidem treatment, the drug cannot be considered generally beneficial due to lack of well-controlled studies with statistical power and apparent unpredictability of response. Use of zolpidem 5—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. Clinical improvements typically occur within 1 hour of administration, with a duration of effect lasting 3 to 4 hours. In one small placebo-controlled trial of 15 patients with MCS or VS of various etiologies, each patient received one blinded dose of 10 mg of zolpidem or placebo in a cross-over fashion. 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. The remaining 14 patients were considered non-responders. In one case series, 3 patients with permanent vegetative state due to traumatic brain injury or anoxia responded to daily administration of zolpidem 10 mg/day. Maximal arousal occurred about 1 hour after drug administration, with a duration of about 4 hours. No long-term side effects were noted after 3—6 years of daily use. Other case reports involving patients with anoxic brain injury have documented various improvements in functioning and communication after administration of 5—10 mg of zolpidem. In one case of a post-traumatic MCS patient, zolpidem administration resulted in either no change or a temporary decline in status according to objective test measures.

    Children and Adolescents 4 to 17 years of age

    There are very limited data in children; further study would be required to indicate any possible efficacy and to determine safety. In one placebo-controlled trial (n=3), three children (age range: 4—17 years) in a persistent vegetative state due to hypoxic or traumatic brain injury were randomly administered a daily dose of zolpidem 0.14—0.2 mg/kg PO or placebo 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

    Due to decreased hepatic clearance, lower doses are recommended, followed by close clinical monitoring of the patient's tolerance and response to therapy.
    Immediate-release tablets (i.e., Ambien): 5 mg/day PO as needed.
    Lingual spray (i.e., Zolpimist): 5 mg/day PO as needed.
    Orally disintegrating tablets (i.e., Tovalt ODT): 5 mg/day PO as needed.
    Extended-release tablets (i.e., Ambien CR): 6.25 mg/day PO as needed.
    Sublingual tablets (i.e. Edluar): 5 mg/day SL as needed.
    Sublingual tablets (i.e., Intermezzo): 1.75 mg SL once per night as needed.

    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 between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Ambien CR:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Edluar:
    - Protect from light
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Intermezzo:
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 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

    General Information

    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.

    Driving or operating machinery, ethanol ingestion, females

    Zolpidem has a rapid onset of action and products indicated for insomnia due to difficulty with sleep initiation should only be administered immediately prior to retiring and with at least 7 to 8 hours remaining before the planned time of waking, and 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. 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 prior to retiring. Patients receiving the extended-release formulation should be cautioned against engaging in hazardous activities (e.g., driving) or other activities requiring complete mental alertness the 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. 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 the morning after therapy. Alterations in CNS functioning caused by zolpidem may lead to falls and subsequent severe injuries. Use of zolpidem 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 for difficulty with sleep initiation (e.g., Ambien, Zolpimist, Edluar) are taken with less than a full night of sleep remaining (7—8 hours), if products for difficulty returning to sleep after middle-of-the-night awakenings (e.g., Intermezzo) are taken with less than 4 hours of bedtime remaining, if a higher than the recommended dose is taken, if zolpidem is co-administered with other CNS depressants or drugs that increase the blood levels of zolpidem, or during use of extended-release formulations (i.e., Ambien CR). Therefore, healthcare providers should caution all patients receiving zolpidem products about the risks of residual next-morning effects which may impair the ability to perform tasks requiring mental alertness, such as driving, even if the patient feels fully awake. Sedative-hypnotic medications can cause complex sleep-related behaviors such as sleep-driving, a state of driving after ingestion of a sedative-hypnotic while not fully awake and having no memory of the event. Other sleep-related behaviors may include making phone calls, sexual activity, or preparing and eating food while asleep or not fully awake, generally with amnesia of the event. The exact incidences among various sedative products are unknown; however patients should be informed of the risks prior to receiving any medication from this class. Anterograde amnesia may be particularly evident at zolpidem doses above 10 mg/day. Due to the risk to the patient and the general public, discontinuation of zolpidem should be strongly considered for patients who report a sleep-driving episode or other potentially harmful sleep-related complex behaviors. Concurrent alcohol use, or use of other CNS-depressant medications, increases the risk for complex sleep-related behaviors and other additive effects. Patients taking zolpidem should avoid ethanol ingestion, such as alcoholic beverages and other alcohol-containing products. Lower initial dosages of zolpidem should be considered in patients taking other CNS-depressant therapies concurrently.

    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 post-marketing 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.

    Depression, mental status changes, suicidal ideation

    Zolpidem, like all CNS depressants, should be used cautiously in patients with symptoms of depression. These patients may experience suicidal ideation and be more likely to intentionally overdose on medications. In addition, worsening of depression may occur during zolpidem administration. Suicidal thoughts and actions, including completed suicides, have been reported in association with the use of sedative/hypnotics. Zolpidem should be prescribed in the smallest quantity consistent with good patient management to reduce the risk of overdose. Sedative-hypnotic medications such as zolpidem can cause complex sleep-related behaviors (CSRB) which involve engaging in activities while asleep or not fully awake, generally with amnesia of the event. Para-suicidal amnestic behavior has been reported rarely with zolpidem use, in patients with no pre-existing or prior diagnosis of depression, but with concurrent alcohol use, which increases the risk for complex sleep-related behaviors or mental status changes. While these are relatively infrequent with zolpidem, any emergence of changes in thinking, moods or behavior should be evaluated. Sleep disturbances may indicate an underlying physical or psychiatric problem. The failure of insomnia to remit after 7—10 days of zolpidem treatment may indicate the presence of a primary medical or psychiatric illness; therefore, evaluation for a potential co-morbid diagnosis is recommended at that time.

    Geriatric

    Debilitated and/or geriatric patients may be more sensitive to the effects of zolpidem. In 3-week controlled trials, the adverse event profile of zolpidem extended-release was similar in elderly and younger adult populations. However, the impairment of cognitive and motor function may be more marked in the elderly and a lower initial dosage is recommended together with close monitoring. During studies evaluating sleep after discontinuation of zolpidem, elderly 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. 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. According to the Beers Criteria, zolpidem is considered a potentially inappropriate medication (PIM) in geriatric patients and use should be avoided; benzodiazepine-receptor agonists such as zolpidem may produce similar adverse effects as benzodiazepines in older adults, such as falls, fractures, and delirium. There are increased emergency department visits, hospitalizations, and motor vehicle crashes, as well as minimal improvement in sleep latency and duration in older adults. The Beers expert panel also recommends avoiding zolpidem in geriatric patients with dementia or cognitive impairment due to the potential for drug-induced adverse CNS effects, or those with delirium or at high risk of delirium since new-onset or worsening delirium may occur. In addition, the Beers expert panel recommends avoiding zolpidem in elderly patients with a history of falls or fractures, unless safer alternatives are not available, since zolpidem can produce ataxia, impaired psychomotor function, syncope, and additional falls; if zolpidem must be used, consider reducing 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 the use of sedative/hypnotics in residents of long-term care facilities. The OBRA guidelines provide criteria for use and dosage requirements for sedative/hypnotic medications including zolpidem.

    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 disease should receive a lower initial dosage to avoid adverse CNS reactions (see Dosage).

    Labor, obstetric delivery, pregnancy

    All formulations of zolpidem are classified as FDA pregnancy category C. One case report has documented the presence of zolpidem in human umbilical cord blood. Cases of severe neonatal respiratory depressive effects have been reported when zolpidem was used at the end of pregnancy, particularly when used with other CNS depressants. Babies born to mothers taking sedative/hypnotics may suffer withdrawal symptoms and possible neonatal flaccidity. Animal studies have shown no evidence of teratogenicity from zolpidem administration with any dosage form; however, maternal sedation and less weight gain have occurred in some studies. The no effect dose for fetal or maternal effects is roughly 4—5 times the maximal recommended human dose (MRHD) based on mg/m2. There are no adequate and well-controlled studies in pregnant women, and animal study outcomes are not always predictive of human response. Therefore, zolpidem should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Zolpidem has no established use during labor or obstetric delivery.

    Breast-feeding

    According to the manufacturer, zolpidem is excreted in human milk in small amounts, and caution should be used when the drug is administered to a nursing woman. Results from a study of 5 lactating women on postpartum days 3 or 4 suggest that small amounts of zolpidem are excreted into breast milk after a single maternal dosage of 20 mg, a dose that exceeds the usual recommended maximum of 10 mg/day. Three hours after drug administration, the mean milk to maternal plasma concentration ratio was 0.13 (range, 0.11—0.18). The amount of zolpidem measured in breast milk samples taken 3 hours after the dose represented 0.004—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 effects of zolpidem exposure on the breast-feeding infant have not been evaluated; however, the American Academy of Pediatrics has considered zolpidem usually compatible with lactation based on the available data. 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 also not been evaluated. Lactating women should avoid breast-feeding their infants at times of peak drug concentrations, and observe the infant for any indications of adverse events, like sedation, increased crying, poor feeding, or irritability. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children

    The safety and efficacy of zolpidem in children has not been established. Results of a controlled 8-week study for the treatment of insomnia in 201 children aged 6—17 years with attention-deficit hyperactivity disorder (ADHD) indicated that zolpidem was not effective compared to placebo. Ten patients discontinued treatment due to an adverse effect. Treatment-emergent adverse effects included dizziness, headache, and hallucinations.

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

    Post-market 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. It should be noted that cases of severe neonatal respiratory depression have been reported when zolpidem was used at the end of pregnancy, particularly when used with other CNS depressants.

    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
    suicidal ideation / Delayed / Incidence not known
    laryngeal edema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    hallucinations / Early / 0-7.4
    memory impairment / Delayed / 1.0-3.0
    amnesia / 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
    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
    impaired cognition / Early / 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
    tetany / Early / 0-0.1
    hot flashes / Early / 0-0.1
    tolerance / Delayed / 0-0.1
    confusion / Early / 1.0
    euphoria / Early / 1.0
    ataxia / Delayed / 1.0
    sleep-related behaviors / Early / Incidence not known
    respiratory depression / Rapid / Incidence not known
    erythema / Early / Incidence not known
    oral ulceration / 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 / 3.0-19.0
    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 (unspecified) / Early / 1.0-2.0
    arthralgia / Delayed / 0-2.0
    muscle cramps / Delayed / 2.0-2.0
    agitation / Early / 0.1-1.0
    nightmares / 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
    tremor / Early / 0.1-1.0
    emotional lability / Early / 0.1-1.0
    paresthesias / Delayed / 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
    yawning / Early / 0-0.1
    libido decrease / Delayed / 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: 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 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 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: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate to strong CYP3A4 inducers, such as barbiturates (e.g., phenobarbital, primidone). 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. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Due to cumulative CNS depressant effects, a reduction in dose of the CNS depressant or zolpidem may be needed. A dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended in patients receiving concomitant CNS depressants. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended.
    Acetaminophen; Butalbital; Caffeine: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate to strong CYP3A4 inducers, such as barbiturates (e.g., phenobarbital, primidone). 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. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Due to cumulative CNS depressant effects, a reduction in dose of the CNS depressant or zolpidem may be needed. A dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended in patients receiving concomitant CNS depressants. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended. 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 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 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: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate to strong CYP3A4 inducers, such as barbiturates (e.g., phenobarbital, primidone). 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. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Due to cumulative CNS depressant effects, a reduction in dose of the CNS depressant or zolpidem may be needed. A dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended in patients receiving concomitant CNS depressants. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended. Concomitant use of zolpidem can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. 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. A reduced dosage of codeine and/or zolpidem may be recommended. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Monitor patients for sedation and respiratory depression. 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 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 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: Concomitant use of zolpidem can potentiate the effects of dihydrocodeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. 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. A reduced dosage of dihydrocodeine and/or zolpidem may be recommended. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Monitor patients for sedation and respiratory depression. 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 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 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: 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. 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 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 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: 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. 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 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 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: 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: 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: 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: Concomitant use of zolpidem can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. 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. A reduced dosage of codeine and/or zolpidem may be recommended. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Monitor patients for sedation and respiratory depression.
    Acetaminophen; Dextromethorphan; Doxylamine: 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: 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: Concomitant use of hydrocodone with zolpidem may lead to hypotension, profound sedation, coma, respiratory depression and death. 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. 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.
    Acetaminophen; Oxycodone: 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: 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: 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: Extreme caution is needed in using tramadol at the same time as zolpidem. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and ethanol or other CNS depressants like tramadol than with zolpidem alone. In addition, tramadol use increases the risk of CNS depression and respiratory depression when used with other agents that are CNS depressants. A reduced dose of tramadol is recommended when used with another CNS depressant. 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: 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: 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: Concomitant use of alfentanil with zolpidem can potentiate the effects of alfentanil on respiration, CNS depression, sedation, and hypotension. Both the magnitude and duration of CNS and cardiovascular effects may be enhanced. Postoperative respiratory depression associated with alfentanil may also be augmented. 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. 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.
    Alprazolam: 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: 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: 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: 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. 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: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate to strong CYP3A4 inducers, such as barbiturates (e.g., phenobarbital, primidone). 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. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Due to cumulative CNS depressant effects, a reduction in dose of the CNS depressant or zolpidem may be needed. A dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended in patients receiving concomitant CNS depressants. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended.
    Amoxapine: CNS depressants should be combined cautiously with amoxapine because they could cause additive depressant effects and possible respiratory depression or hypotension.
    Amoxicillin; Clarithromycin; Lansoprazole: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as clarithromycin, 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.
    Amoxicillin; Clarithromycin; Omeprazole: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as clarithromycin, 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.
    Amprenavir: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, 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.
    Apomorphine: 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: 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: Use caution if zolpidem and aprepitant, fosaprepitant are used concurrently and monitor for an increase in zolpidem-related adverse effects for several days after administration of a multi-day aprepitant regimen. 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: 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: 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: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate to strong CYP3A4 inducers, such as barbiturates (e.g., phenobarbital, primidone). 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. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Due to cumulative CNS depressant effects, a reduction in dose of the CNS depressant or zolpidem may be needed. A dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended in patients receiving concomitant CNS depressants. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended. 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 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 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: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate to strong CYP3A4 inducers, such as barbiturates (e.g., phenobarbital, primidone). 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. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Due to cumulative CNS depressant effects, a reduction in dose of the CNS depressant or zolpidem may be needed. A dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended in patients receiving concomitant CNS depressants. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended. Concomitant use of zolpidem can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. 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. A reduced dosage of codeine and/or zolpidem may be recommended. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Monitor patients for sedation and respiratory depression. 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 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 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: Concomitant use of zolpidem can potentiate the effects of dihydrocodeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. 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. A reduced dosage of dihydrocodeine and/or zolpidem may be recommended. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Monitor patients for sedation and respiratory depression. 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 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 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: Carisoprodol can cause additive CNS depression if used concomitantly with other CNS depressants.
    Aspirin, ASA; Carisoprodol; Codeine: Carisoprodol can cause additive CNS depression if used concomitantly with other CNS depressants. Concomitant use of zolpidem can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. 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. A reduced dosage of codeine and/or zolpidem may be recommended. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Monitor patients for sedation and respiratory depression.
    Aspirin, ASA; Oxycodone: 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: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, 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.
    Atazanavir; Cobicistat: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, 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. It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of cobicistat, 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.
    Atropine; Difenoxin: 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: 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: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate to strong CYP3A4 inducers, such as barbiturates (e.g., phenobarbital, primidone). 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. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Due to cumulative CNS depressant effects, a reduction in dose of the CNS depressant or zolpidem may be needed. A dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended in patients receiving concomitant CNS depressants. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended. Scopolamine may cause dizziness and drowsiness. Concurrent use of scopolamine and CNS depressants can adversely increase the risk of CNS depression.
    atypical antipsychotic: 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: An enhanced CNS depressant effect may occur when azelastine is combined with CNS depressants including anxiolytics, sedatives, and hypnotics.
    Azelastine; Fluticasone: An enhanced CNS depressant effect may occur when azelastine is combined with CNS depressants including anxiolytics, sedatives, and hypnotics.
    Baclofen: 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: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate to strong CYP3A4 inducers, such as barbiturates (e.g., phenobarbital, primidone). 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. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Due to cumulative CNS depressant effects, a reduction in dose of the CNS depressant or zolpidem may be needed. A dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended in patients receiving concomitant CNS depressants. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate to strong CYP3A4 inducers, such as barbiturates (e.g., phenobarbital, primidone). 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. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Due to cumulative CNS depressant effects, a reduction in dose of the CNS depressant or zolpidem may be needed. A dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended in patients receiving concomitant CNS depressants. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended.
    Belladonna; Opium: Concomitant use of zolpidem and opium can potentiate the effects of opium, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. 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. 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.
    Benzodiazepines: 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: CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase the sedative effects of benztropine.
    Bexarotene: 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: 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: 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: 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: 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: 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: 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: 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: Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. 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: 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: Concomitant use of hydrocodone with zolpidem may lead to hypotension, profound sedation, coma, respiratory depression and death. 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. 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. 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: Concomitant use of hydrocodone with zolpidem may lead to hypotension, profound sedation, coma, respiratory depression and death. 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. 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. 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: 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: 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: 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: 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: 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: The combination of buspirone and other CNS depressants can increase the risk for sedation.
    Butabarbital: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate to strong CYP3A4 inducers, such as barbiturates (e.g., phenobarbital, primidone). 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. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Due to cumulative CNS depressant effects, a reduction in dose of the CNS depressant or zolpidem may be needed. A dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended in patients receiving concomitant CNS depressants. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended.
    Butorphanol: 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: 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 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 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 product prior to going to bed as these products may pharmacodynamically antagonize the sedative effects of zolpidem.
    Caffeine; Ergotamine: 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 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 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.
    Capsaicin; Metaxalone: 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: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate to strong CYP3A4 inducers, such as carbamazepine. 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: Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. 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: Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. 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: Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. 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: 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: 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: 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: Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. 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: 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: Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. 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: 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: 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: 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: Concomitant use of hydrocodone with zolpidem may lead to hypotension, profound sedation, coma, respiratory depression and death. 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. 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. 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: Concomitant use of hydrocodone with zolpidem may lead to hypotension, profound sedation, coma, respiratory depression and death. 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. 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. 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: 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: 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: 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: Carisoprodol can cause additive CNS depression if used concomitantly with other CNS depressants.
    Cetirizine: Additive drowsiness may occur if cetirizine/levocetirizine is administered with other drugs that depress the CNS, including anxiolytics, sedatives and hypnotics.
    Cetirizine; Pseudoephedrine: Additive drowsiness may occur if cetirizine/levocetirizine is administered with other drugs that depress the CNS, including anxiolytics, sedatives and hypnotics.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: 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: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as chloramphenicol, 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.
    Chlorcyclizine: 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: 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: 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.
    Chloroquine: Chloroquine inhibits CYP2D6 and may theoretically increase concentrations of other drugs metabolized by this enzyme including zolpidem.
    Chlorpheniramine: 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: Concomitant use of zolpidem can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. 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. A reduced dosage of codeine and/or zolpidem may be recommended. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Monitor patients for sedation and respiratory depression. 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: 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: 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: Concomitant use of zolpidem can potentiate the effects of dihydrocodeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. 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. A reduced dosage of dihydrocodeine and/or zolpidem may be recommended. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Monitor patients for sedation and respiratory depression. 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: Concomitant use of zolpidem can potentiate the effects of dihydrocodeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. 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. A reduced dosage of dihydrocodeine and/or zolpidem may be recommended. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Monitor patients for sedation and respiratory depression. 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: Concomitant use of hydrocodone with zolpidem may lead to hypotension, profound sedation, coma, respiratory depression and death. 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. 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. 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: Concomitant use of hydrocodone with zolpidem may lead to hypotension, profound sedation, coma, respiratory depression and death. 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. 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. 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: Concomitant use of hydrocodone with zolpidem may lead to hypotension, profound sedation, coma, respiratory depression and death. 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. 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. 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: Concomitant use of hydrocodone with zolpidem may lead to hypotension, profound sedation, coma, respiratory depression and death. 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. 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. 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: 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: 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.
    Cinacalcet: Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, including zolpidem.
    Ciprofloxacin: Zolpidem is primarily metabolized by CYP3A4, and to a lesser extent by other isoenzymes including CYP1A2. Ciprofloxacin (a strong inhibitor of CYP1A2 and a moderate inhibitor of CYP3A4) is likely to inhibit the metabolic pathways of zolpidem, potentially leading to an increase in zolpidem exposure.
    Citalopram: 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: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as clarithromycin, 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.
    Clemastine: 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: 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: 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: 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: 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: 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: It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of cobicistat, 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.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of cobicistat, 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.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of cobicistat, 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.
    Codeine: Concomitant use of zolpidem can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. 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. A reduced dosage of codeine and/or zolpidem may be recommended. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Monitor patients for sedation and respiratory depression.
    Codeine; Guaifenesin: Concomitant use of zolpidem can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. 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. A reduced dosage of codeine and/or zolpidem may be recommended. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Monitor patients for sedation and respiratory depression.
    Codeine; Phenylephrine; Promethazine: Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics. Concomitant use of zolpidem can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. 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. A reduced dosage of codeine and/or zolpidem may be recommended. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Monitor patients for sedation and respiratory depression.
    Codeine; Promethazine: Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics. Concomitant use of zolpidem can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. 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. A reduced dosage of codeine and/or zolpidem may be recommended. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Monitor patients for sedation and respiratory depression.
    COMT inhibitors: 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: Concurrent use of conivaptan, a potent CYP3A4 inhibitor, with CYP3A4 substrates, such as zolpidem, should be avoided. Co-administration of conivaptan with some CYP3A substrates has resulted in mean increases of 2 to 3 times the baseline AUC values of these substrates. According to the manufacturer of conivaptan, treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. If co-administration cannot be avoided, consider using a lower dose of zolpidem to minimize the potential for adverse CNS effects. There is evidence of an increase in pharmacodynamic effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4.
    Crizotinib: It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of crizotinib, 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.
    Cyclizine: 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: 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: 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: 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.
    Dalfopristin; Quinupristin: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as dalfopristin; quinupristin, 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.
    Danazol: 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: 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: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, 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.
    Darunavir; Cobicistat: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, 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. It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of cobicistat, 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.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, 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.
    Dasatinib: Dasatinib is a time-dependent, weak inhibitor of CYP3A4. Therefore, caution is warranted when drugs that are metabolized by this enzyme, including zolpidem, are administered concurrently with dasatinib as increased adverse reactions may occur.
    Deferasirox: 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: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as delavirdine, 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.
    Desipramine: 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: 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.
    Dexamethasone: 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: 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: 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: Co-administration of dexmedetomidine with anxiolytics, sedatives, and hypnotics is likely to lead to an enhancement of CNS depression.
    Dextromethorphan; Diphenhydramine; Phenylephrine: 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.
    Dextromethorphan; Promethazine: Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics.
    Diazepam: 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: Dicyclomine can cause drowsiness, so it should be used cautiously in patients receiving CNS depressants like anxiolytics, sedatives, and hypnotics.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: Concomitant use of zolpidem can potentiate the effects of dihydrocodeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. 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. A reduced dosage of dihydrocodeine and/or zolpidem may be recommended. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Monitor patients for sedation and respiratory depression.
    Diltiazem: 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: 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: 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: Concomitant use of hydrocodone with zolpidem may lead to hypotension, profound sedation, coma, respiratory depression and death. 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. 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. 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: 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: 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: 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: 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: 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, THC: 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: 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: 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: 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.
    Efavirenz: 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: 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.
    Elbasvir; Grazoprevir: 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.
    Enflurane: 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: 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: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as enzalutamide. 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.
    Erythromycin: 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: 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: 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.
    Eslicarbazepine: 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: 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: Alcohol is associated with CNS depression. The combined use of alcohol and CNS depressants can lead to additive CNS depression, which could be dangerous in tasks requiring mental alertness and fatal in overdose. Alcohol taken with other CNS depressants can lead to additive respiratory depression, hypotension, profound sedation, or coma. Consider the patient's use of alcohol or illicit drugs when prescribing CNS depressant medications. In many cases, the patient should receive a lower dose of the CNS depressant initially if the patient is not likely to be compliant with avoiding alcohol.
    Ethotoin: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of potent CYP3A4 inducers, such as hydantoins. 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: 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: 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: 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.
    Fentanyl: Concomitant use of fentanyl with zolpidem may cause respiratory depression, hypotension, and profound sedation. A coma could result in some circumstances. 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. If concurrent use is desired, significantly reduce the dose of fentanyl and/or zolpidem. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Blood pressure and respiration monitoring to ensure the absence of hypotension and respiratory depression, respectively may be desirable
    Fluconazole: 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: Flumazenil, a benzodiazepine antagonist, can reverse the sedative/hypnotic effects of zolpidem. Flumazenil and zolpidem are pharmacological opposites, and should not be used together.
    Fluoxetine: 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, atlhough there was no evidence of an additive effect in psychomotor performance.
    Fluoxetine; Olanzapine: 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. 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, atlhough there was no evidence of an additive effect in psychomotor performance.
    Flurazepam: 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: 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: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, 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.
    Fosphenytoin: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of potent CYP3A4 inducers, such as hydantoins. 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: 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.
    Gabapentin: 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: 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: 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: Concomitant use of hydrocodone with zolpidem may lead to hypotension, profound sedation, coma, respiratory depression and death. 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. 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.
    Guaifenesin; Hydrocodone; Pseudoephedrine: Concomitant use of hydrocodone with zolpidem may lead to hypotension, profound sedation, coma, respiratory depression and death. 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. 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.
    Guarana: Caffeine, an active constituent of guarana, is a CNS stimulant associated with heightened attentiveness and insomnia, and is used to treat or prevent drowsiness or fatigue; patients taking benzodiazepines or zolpidem for insomnia should not use guarana-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine or zolpidem.
    Haloperidol: Haloperidol can potentiate the actions of other CNS depressants such as anxiolytics, sedatives, and hypnotics, and they should be used cautiously in combination.
    Halothane: 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: Concomitant use of hydrocodone with zolpidem may lead to hypotension, profound sedation, coma, respiratory depression and death. 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. 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.
    Hydantoins: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of potent CYP3A4 inducers, such as hydantoins. 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: Concomitant use of hydrocodone with zolpidem may lead to hypotension, profound sedation, coma, respiratory depression and death. 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. 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.
    Hydrocodone; Ibuprofen: Concomitant use of hydrocodone with zolpidem may lead to hypotension, profound sedation, coma, respiratory depression and death. 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. 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.
    Hydrocodone; Phenylephrine: Concomitant use of hydrocodone with zolpidem may lead to hypotension, profound sedation, coma, respiratory depression and death. 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. 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.
    Hydrocodone; Potassium Guaiacolsulfonate: Concomitant use of hydrocodone with zolpidem may lead to hypotension, profound sedation, coma, respiratory depression and death. 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. 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.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: Concomitant use of hydrocodone with zolpidem may lead to hypotension, profound sedation, coma, respiratory depression and death. 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. 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.
    Hydrocodone; Pseudoephedrine: Concomitant use of hydrocodone with zolpidem may lead to hypotension, profound sedation, coma, respiratory depression and death. 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. 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.
    Hydromorphone: Concomitant use of hydromorphone with zolpidem can potentiate the effects of hydromorphone and may lead to additive CNS or respiratory depression, 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 of hydromorphone 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. Consider the patient's use of alcohol or illicit drugs. If hydromorphone is used concurrently with a CNS depressant, a reduced dosage of hydromorphone and/or the CNS depressant is recommended; start with one-third to one-half of the estimated hydromorphone starting dose when using hydromorphone extended-release tablets. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Hydroxyzine: 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: 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: Avoid concurrent use of idelalisib, a strong CYP3A inhibitor, with CYP3A substrates such as zolpidem if possible. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when co-administered with idelalisib. If concurrent use cannot be avoided, closely monitor zolpidem tolerability and safety, 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 pharmacodynamic effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4.
    Iloperidone: 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, STI-571: 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: 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: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, 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.
    Isavuconazonium: 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: 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: 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: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as isoniazid, INH, 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.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of potent CYP3A4 inducers, such as rifampin. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of a significant decrease in systemic exposure 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. It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as isoniazid, INH, 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.
    Isoniazid, INH; Rifampin: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of potent CYP3A4 inducers, such as rifampin. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of a significant decrease in systemic exposure 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. It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as isoniazid, INH, 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.
    Itraconazole: Pharmacokinetic studies have shown that the systemic azole antifungals inhibit the metabolism and clearance of zolpidem. Itraconazole resulted in a 34% increase in zolpidem AUC. There were no pharmacodynamic effects of zolpidem observed on subjective drowsiness, postural sway, or psychomotor performance. 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.
    Ivacaftor: Use caution when administering ivacaftor and zolpidem concurrently. Ivacaftor is an inhibitor of CYP3A and zolpidem is primarily metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as zolpidem, can theoretically increase zolpidem exposure leading to increased or prolonged therapeutic effects and adverse events.
    Kava Kava, Piper methysticum: 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: 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: Pharmacokinetic studies have shown that the systemic azole antifungals inhibit the metabolism and clearance of zolpidem. Ketoconazole has been shown to increase the Cmax and AUC of zolpidem by 30% and 70%, respectively, and prolong the half-life by 30%. 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.
    Lanreotide: It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of lanreotide, 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.
    Levocetirizine: Additive drowsiness may occur if cetirizine/levocetirizine is administered with other drugs that depress the CNS, including anxiolytics, sedatives and hypnotics.
    Levomethadyl: 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: 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: 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: 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.
    Lopinavir; Ritonavir: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, 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.
    Lorazepam: 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: 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.
    Luliconazole: Theoretically, luliconazole may increase the side effects of zolpidem, which is a CYP3A4 substrate. Monitor patients for adverse effects of zolpidem, such as CNS effects. In vitro, therapeutic doses of luliconazole inhibit the activity of CYP3A4 and small systemic concentrations may be noted with topical application, particularly when applied to patients with moderate to severe tinea cruris. No in vivo drug interaction trials were conducted prior to the approval of luliconazole.
    Lumacaftor; Ivacaftor: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of potent CYP3A4 inducers, such as lumacaftor; ivacaftor. 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.
    Lumacaftor; Ivacaftor: Use caution when administering ivacaftor and zolpidem concurrently. Ivacaftor is an inhibitor of CYP3A and zolpidem is primarily metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as zolpidem, can theoretically increase zolpidem exposure leading to increased or prolonged therapeutic effects and adverse events.
    Lurasidone: 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: CNS depressants should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension.
    Meclizine: 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: 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: CNS depression can be increased when mepenzolate is combined with other CNS depressants such as any anxiolytics, sedatives, and hypnotics.
    Meperidine: Concomitant use of zolpidem and meperidine can potentiate the effects of meperidine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. 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. If these drugs are used together, reduce the dose of one or both drugs. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Meperidine; Promethazine: Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics. Concomitant use of zolpidem and meperidine can potentiate the effects of meperidine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. 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. If these drugs are used together, reduce the dose of one or both drugs. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
    Mephobarbital: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate to strong CYP3A4 inducers, such as barbiturates (e.g., phenobarbital, primidone). 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. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Due to cumulative CNS depressant effects, a reduction in dose of the CNS depressant or zolpidem may be needed. A dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended in patients receiving concomitant CNS depressants. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended.
    Metaxalone: 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: 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: Methocarbamol may cause additive CNS depression if used concomitantly with other CNS depressants. Dosage reduction of one or both agents may be necessary.
    Methohexital: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate to strong CYP3A4 inducers, such as barbiturates (e.g., phenobarbital, primidone). 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. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Due to cumulative CNS depressant effects, a reduction in dose of the CNS depressant or zolpidem may be needed. A dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended in patients receiving concomitant CNS depressants. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended.
    Methscopolamine: CNS depression can be increased when methscopolamine is combined with other CNS depressants such as any anxiolytics, sedatives, and hypnotics.
    Metoclopramide: Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.
    Metyrapone: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as metyrapone. 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.
    Midazolam: 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.
    Milnacipran: 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: 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: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of potent CYP3A4 inducers, such as mitotane. 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 initially when mitotane is given with zolpidem.
    Modafinil: 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: 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: 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: 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: 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: 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: 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: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as nefazodone, 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.
    Nelfinavir: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, 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.
    Netupitant; Palonosetron: 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: 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: 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: 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: 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: 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: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, 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.
    Oritavancin: 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: Additive CNS depressant effects may be seen with combination use of orphenadrine and anxiolytics, sedatives, and hypnotics.
    Osimertinib: Use caution if coadministration of osimertinib and zolpidem is necessary, due to the risk of decreased zolpidem exposure. Zolpidem is a minor (14%) CYP1A2 substrate, while osimertinib is a CYP1A2 inducer in vitro. Coadministration may decrease the efficacy of zolpidem.
    Oxazepam: 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.
    Oxcarbazepine: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as oxcarbazepine. 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.
    Oxybutynin: 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: 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: 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.
    Paliperidone: 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: Concurrent use of papaverine with potent CNS depressants such as anxiolytics, sedatives, or hypnotics could lead to enhanced sedation.
    Paroxetine: 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: 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: 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: 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: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate to strong CYP3A4 inducers, such as barbiturates (e.g., phenobarbital, primidone). 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. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Due to cumulative CNS depressant effects, a reduction in dose of the CNS depressant or zolpidem may be needed. A dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended in patients receiving concomitant CNS depressants. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended.
    Perampanel: 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: 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: 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: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate to strong CYP3A4 inducers, such as barbiturates (e.g., phenobarbital, primidone). 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. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Due to cumulative CNS depressant effects, a reduction in dose of the CNS depressant or zolpidem may be needed. A dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended in patients receiving concomitant CNS depressants. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended.
    Phenothiazines: 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: 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.
    Phenylephrine; Promethazine: Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics.
    Phenytoin: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of potent CYP3A4 inducers, such as hydantoins. 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.
    Pimavanserin: 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.
    Pimozide: 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: Pharmacokinetic studies have shown that the systemic azole antifungals inhibit the metabolism and clearance of zolpidem. Voriconazole increased peak plasma concentrations of zolpidem by 1.23-fold and the AUC by 1.48-fold in healthy volunteers; however, the effect of voriconazole on the clinical effects of zolpidem were not clear. Findings similar to other azole antifungals should be expected with posaconazole, a potent CYP3A4 inhibitor. 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.
    Pramipexole: 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: 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: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate to strong CYP3A4 inducers, such as barbiturates (e.g., phenobarbital, primidone). 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. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Due to cumulative CNS depressant effects, a reduction in dose of the CNS depressant or zolpidem may be needed. A dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended in patients receiving concomitant CNS depressants. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended.
    Promethazine: Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics.
    Propofol: 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: 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: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, 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.
    Protriptyline: 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: 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: 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: 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: 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: 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: 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: Concomitant use of remifentanil with zolpidem can potentiate the effects of remifentanil on respiration, CNS depression, sedation, and hypotension. Both the magnitude and duration of CNS and cardiovascular effects may be enhanced. Postoperative respiratory depression associated with remifentanil may also be augmented. 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. 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.
    Rifabutin: 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: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of potent CYP3A4 inducers, such as rifampin. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of a significant decrease in systemic exposure 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: 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: 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: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, 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.
    Ropinirole: 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: 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.
    Rufinamide: 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.
    Saquinavir: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, 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.
    Scopolamine: Scopolamine may cause dizziness and drowsiness. Concurrent use of scopolamine and CNS depressants can adversely increase the risk of CNS depression.
    Secobarbital: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate to strong CYP3A4 inducers, such as barbiturates (e.g., phenobarbital, primidone). 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. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Due to cumulative CNS depressant effects, a reduction in dose of the CNS depressant or zolpidem may be needed. A dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended in patients receiving concomitant CNS depressants. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended.
    Sedating H1-blockers: 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, Transdermal: 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.
    Selegiline: 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: 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: 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: 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: 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: Until further information becomes available, it is advisable to individualize each patient's regimen according to response and tolerability. 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.
    Streptogramins: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as dalfopristin; quinupristin, 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.
    Sufentanil: Concomitant use of sufentanil with zolpidem can potentiate the effects of sufentanil on respiration, CNS depression, sedation, and hypotension. 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. Both the magnitude and duration of CNS and cardiovascular effects may be enhanced. Postoperative respiratory depression associated with sufentanil may also be augmented. 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.
    Suvorexant: 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.
    Tamoxifen: It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of tamoxifen, 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.
    Tapentadol: Additive CNS depressive effects are expected if tapentadol is used in conjunction with other CNS depressants including anxiolytics, sedatives, and hypnotics. Severe hypotension, profound sedation, coma, or respiratory depression may occur. Prior to concurrent use of tapentadol 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. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with tapentadol, a reduced dosage of tapentadol and/or the CNS depressant is recommended. If the extended-release tapentadol tablets are used concurrently with a CNS depressant, it is recommended to use an initial tapentadol dose of 50 mg PO every 12 hours. Monitor patients for sedation and respiratory depression.
    Telaprevir: 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: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as telithromycin, 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.
    Temazepam: 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: 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: 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: Avoid the concomitant use of thalidomide with anxiolytics, sedatives, and hypnotics due to the potential for additive sedative effects.
    Thiopental: It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate to strong CYP3A4 inducers, such as barbiturates (e.g., phenobarbital, primidone). 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. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Due to cumulative CNS depressant effects, a reduction in dose of the CNS depressant or zolpidem may be needed. A dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended in patients receiving concomitant CNS depressants. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended.
    Thiothixene: 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: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, 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.
    Tizanidine: 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: 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: 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: Extreme caution is needed in using tramadol at the same time as zolpidem. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and ethanol or other CNS depressants like tramadol than with zolpidem alone. In addition, tramadol use increases the risk of CNS depression and respiratory depression when used with other agents that are CNS depressants. A reduced dose of tramadol is recommended when used with another CNS depressant. 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: 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: 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: 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: 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: 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: CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase the sedative effects of trihexyphenidyl.
    Trimethobenzamide: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: Pharmacokinetic studies have shown that systemic azole antifungals inhibit the metabolism and clearance of zolpidem. In one study of healthy volunteers, voriconazole increased peak plasma concentrations of zolpidem by 1.23-fold and the AUC by 1.48-fold; however, the effect of voriconazole on the pharmacodynamics of zolpidem were not clear. 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.
    Ziconotide: CNS depressant medications may increase drowsiness, dizziness, and confusion that are associated with ziconotide.
    Ziprasidone: 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

    All formulations of zolpidem are classified as FDA pregnancy category C. One case report has documented the presence of zolpidem in human umbilical cord blood. Cases of severe neonatal respiratory depressive effects have been reported when zolpidem was used at the end of pregnancy, particularly when used with other CNS depressants. Babies born to mothers taking sedative/hypnotics may suffer withdrawal symptoms and possible neonatal flaccidity. Animal studies have shown no evidence of teratogenicity from zolpidem administration with any dosage form; however, maternal sedation and less weight gain have occurred in some studies. The no effect dose for fetal or maternal effects is roughly 4—5 times the maximal recommended human dose (MRHD) based on mg/m2. There are no adequate and well-controlled studies in pregnant women, and animal study outcomes are not always predictive of human response. Therefore, zolpidem should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Zolpidem has no established use during labor or obstetric delivery.

    MECHANISM OF ACTION

    Mechanism of Action: Subunit modulation of the GABA-A receptor chloride channel macromolecular complex is thought to be responsible for sedative, anti-convulsant, anxiolytic, and myorelaxant drug properties. The main site of modulatory drug action is located within the GABA-A receptor complex on the alpha-subunit, which is known as the benzodiazepine (BZ) or omega receptor. At least three subtypes of the omega-receptor have been identified within the CNS.Although zolpidem is chemically unrelated to the benzodiazepines or barbiturates, it interacts with the GABA-benzodiazepine receptor complex and does share some pharmacologic characteristics of the benzodiazepines. In contrast to the benzodiazepines, which non-selectively interact with all three known omega-receptor subtypes; zolpidem preferentially binds to the omega-1 receptor, which is found primarily on the Lamina IV of the sensorimotor cortical regions, the substantia nigra, the cerebellum molecular layer, olfactory bulb, ventral thalamic complex, pons, inferior colliculus, and the globus pallidus. While not absolute, the relative selectivity of zolpidem for the type 1 omega-receptor subtype may explain its lack of anxiolytic, muscle relaxant, and anticonvulsant effects at normally prescribed hypnotic dosages.Sleep studies in animals and humans indicate that zolpidem normally preserves deep sleep (stages 3 and 4) relative to placebo and that any minor changes in REM sleep that occur inconsistently. After zolpidem dosages of >= 10 mg, decreases in next morning recall may occur of information presented during the times of peak medication effect (i.e., 90 minutes post-dose). Anterograde amnesia is more likely to occur following dosages of > 10 mg. Following discontinuation of zolpidem therapy after continuous administration for <= 28 days, rebound insomnia is rare. As with the benzodiazepines, flumazenil, a benzodiazepine antagonist, can antagonize the sedative actions of zolpidem.

    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.