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  • CLASSES

    Non-Benzodiazepine, Benzodiazepine Receptor Agonists (NBRA)s

    BOXED WARNING

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

    Sedative-hypnotics can cause complex sleep-related behaviors such as phone calls, sexual activity, preparing and eating food, or driving while not fully awake and in some cases having no memory of the event. These behaviors appear to be more frequent with nonbenzodiazepine benzodiazepine-receptor agonists (NBRAs), such as zaleplon, than other sedative-hypnotics and may occur with or without the concomitant use of alcohol or other CNS depressants. Although rare, serious injuries or death have occurred; therefore, zaleplon and other NBRAs are contraindicated in patients with a history of drug-induced complex sleep-related behaviors. Patients should be informed of the risks before receiving any medication from this class, including instructions to discontinue the medication if they experience a sleep-related episode and to contact their health care provider immediately. Health care professionals and patients are encouraged to report adverse events or side effects related to the use of NBRAs to the FDA MedWatch Safety Information and Adverse Event Reporting Program.[64083] Because zaleplon has a rapid onset of action and causes CNS depressant effects, the drug should only be administered immediately prior to going to bed or after the patient has gone to bed and has experienced difficulty falling asleep. Patients should be cautioned against driving or operating machinery or performing other tasks that require mental alertness or motor coordination after taking their dose. The risk of next-day psychomotor impairment, including impaired driving, is increased if zaleplon is taken with less than a full night of sleep remaining (7 to 8 hours); if the dose taken is greater than the recommended dose; or during coadministration with other CNS depressants, alcohol, or drugs that increase zaleplon drug concentrations. Because zaleplon can cause drowsiness and a decreased level of consciousness, there is a higher risk of falls, particularly in the elderly, with the potential for subsequent severe injuries. As with all sedative/hypnotics, patients should be warned that taking zaleplon while still up and about may result in short-term memory impairment, hallucinations, impaired coordination, dizziness, and lightheadedness. Dosage adjustment of zaleplon may be necessary during coadministration with other CNS depressants because of the potential for additive effects. Do not use zaleplon with other sedative-hypnotic agents, and ethanol ingestion should be avoided during use. Zaleplon potentiates alcohol-induced impairment. Amnesia and other neuropsychiatric symptoms may occur unpredictably.[29887]

    DEA CLASS

    Rx, schedule IV

    DESCRIPTION

    Short-acting non-benzodiazepine hypnotic.
    More rapid onset than zolpidem; short half-life reduces "hangover" effects; does not cause early-AM awakening; anticonvulsant, anxiolytic, and myorelaxant effects more likely with higher doses.
    Used for treatment of insomnia.

    COMMON BRAND NAMES

    Sonata

    HOW SUPPLIED

    Sonata/Zaleplon Oral Cap: 5mg, 10mg

    DOSAGE & INDICATIONS

    For the short-term (generally 7 to 10 days) treatment of insomnia.
    Oral dosage
    Adults

    10 mg PO at bedtime. May take either at bedtime or after an attempt to fall asleep without medication, provided at least 4 or more hours of sleep time remain. For certain debilitated, low weight patients, patients with hepatic insufficiency, or those on medications that reduce zaleplon clearance, use 5 mg PO initially. A 20 mg PO bedtime dose may be considered for the occasional patient who does not benefit from 10 mg at bedtime.

    Geriatric Adults

    5 mg PO at bedtime. Max: 10 mg/day, if necessary. Zaleplon may be taken either at bedtime or after an attempt to fall asleep without medication, provided at least 4 or more hours of sleep time remain. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of sedative/hypnotics in long-term care facility (LTCF) residents. Max: 5 mg/day PO in residents meeting the criteria for treatment, except when documentation is provided showing that higher doses are necessary to maintain or improve the resident's functional status. All sleep medications should be used in accordance with approved product labeling. If the sleep agent is used routinely and is beyond the manufacturer's recommendations for duration of use, the facility should attempt a quarterly taper unless clinically contraindicated as defined in the OBRA guidelines.

    MAXIMUM DOSAGE

    Adults

    20 mg/day PO at bedtime. Debilitated adult patients may require 10 mg/day PO.

    Geriatric

    10 mg/day PO at bedtime.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild to moderate hepatic impairment (e.g., Child Pugh A or B): Use an initial dose of 5 mg PO at bedtime for mild to moderate hepatic impairment due to reduced clearance.
    Severe hepatic impairment (i.e., Child Pugh C): Zaleplon is not recommended. Marked increases in maximal concentrations and exposure occur (up to 4-fold and 7-fold in compensated and decompensated cirrhotic patients, respectively).

    Renal Impairment

    No dosage adjustment is necessary in patients with mild to moderate renal impairment. Zaleplon has not been adequately studied in patients with severe renal impairment. Renal excretion of unchanged zaleplon accounts for less than 1% of the administered dose and zaleplon pharmacokinetics are not altered in patients with renal insufficiency.

    ADMINISTRATION

    Oral Administration

    Administer immediately before bedtime or after the patient has gone to bed and has experienced difficulty falling asleep, as long as at least 4 hours of sleep time remain.
    Administration with or immediately after a heavy, high-fat meal slows absorption and is expected to reduce effects on sleep latency.

    STORAGE

    Sonata:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    History of angioedema, salicylate hypersensitivity, tartrazine dye hypersensitivity

    Zaleplon is contraindicated in any patient with a known hypersensitivity or a history of angioedema to zaleplon or allergy to any of its excipients. Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including zaleplon. Some patients have had additional symptoms such as difficulty breathing, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with zaleplon should not be rechallenged with the drug. Some commercial preparations of zaleplon contain FD and C Yellow No. 5 (tartrazine) and should be used with caution in patients with tartrazine dye hypersensitivity, because allergic-type reactions may occur. Although the overall incidence of tartrazine sensitivity in the general population is low, it is frequently seen in patients with aspirin hypersensitivity (salicylate hypersensitivity).

    Behavioral changes, depression, suicidal ideation

    Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia with zaleplon should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative/hypnotic drugs, including zaleplon. Because some of the important adverse effects of zaleplon appear to be dose-related, it is important to use the lowest possible effective dose. A variety of abnormal thinking and behavioral changes have been reported to occur in association with the use of sedative/hypnotics. Some of these changes may be characterized by decreased inhibition (e.g., aggressiveness and extroversion that seem out of character). Other reported behavioral changes have included bizarre behavior, agitation, hallucinations, and depersonalization. Amnesia and other neuropsychiatric symptoms may occur unpredictably. In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (suicidal ideation, including completed suicides), has been reported in association with the use of sedative/hypnotics. Intentional overdosage is more common in patients with depression; therefore, the least amount of drug that is feasible should be prescribed for the patient at any one time. The emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.

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

    Sedative-hypnotics can cause complex sleep-related behaviors such as phone calls, sexual activity, preparing and eating food, or driving while not fully awake and in some cases having no memory of the event. These behaviors appear to be more frequent with nonbenzodiazepine benzodiazepine-receptor agonists (NBRAs), such as zaleplon, than other sedative-hypnotics and may occur with or without the concomitant use of alcohol or other CNS depressants. Although rare, serious injuries or death have occurred; therefore, zaleplon and other NBRAs are contraindicated in patients with a history of drug-induced complex sleep-related behaviors. Patients should be informed of the risks before receiving any medication from this class, including instructions to discontinue the medication if they experience a sleep-related episode and to contact their health care provider immediately. Health care professionals and patients are encouraged to report adverse events or side effects related to the use of NBRAs to the FDA MedWatch Safety Information and Adverse Event Reporting Program.[64083] Because zaleplon has a rapid onset of action and causes CNS depressant effects, the drug should only be administered immediately prior to going to bed or after the patient has gone to bed and has experienced difficulty falling asleep. Patients should be cautioned against driving or operating machinery or performing other tasks that require mental alertness or motor coordination after taking their dose. The risk of next-day psychomotor impairment, including impaired driving, is increased if zaleplon is taken with less than a full night of sleep remaining (7 to 8 hours); if the dose taken is greater than the recommended dose; or during coadministration with other CNS depressants, alcohol, or drugs that increase zaleplon drug concentrations. Because zaleplon can cause drowsiness and a decreased level of consciousness, there is a higher risk of falls, particularly in the elderly, with the potential for subsequent severe injuries. As with all sedative/hypnotics, patients should be warned that taking zaleplon while still up and about may result in short-term memory impairment, hallucinations, impaired coordination, dizziness, and lightheadedness. Dosage adjustment of zaleplon may be necessary during coadministration with other CNS depressants because of the potential for additive effects. Do not use zaleplon with other sedative-hypnotic agents, and ethanol ingestion should be avoided during use. Zaleplon potentiates alcohol-induced impairment. Amnesia and other neuropsychiatric symptoms may occur unpredictably.[29887]

    Hepatic disease

    Initial dosage reductions are required in patients with mild to moderate hepatic disease; use with caution. Zaleplon is extensively metabolized in the liver is not recommended for use in patients with severe hepatic impairment, as maximal concentrations and zaleplon exposure are significantly increased.

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

    Zaleplon use in patients with concomitant respiratory illness is limited. Although studies did not reveal respiratory depressant effects at hypnotic doses of zaleplon in normal subjects, caution should be exercised when zaleplon is administered to patients with chronic obstructive pulmonary disease (COPD), sleep apnea, or other respiratory insufficiency. Clinical trials of zaleplon 10 mg at bedtime to patients with COPD or sleep apnea did not reveal alterations in blood gases or apnea/hypopnea index, respectively. However, patients with respiratory insufficiency should be closely monitored for respiratory depression.

    Abrupt discontinuation, alcoholism, substance abuse

    Studies to assess the abuse potential of zaleplon in subjects with known histories of sedative drug abuse indicate that zaleplon has an abuse potential similar to benzodiazepine and benzodiazepine-like hypnotics. Because individuals with a history of alcoholism or addiction to or substance abuse of drugs or alcohol are at risk of habituation and dependence, they should be under careful surveillance when receiving zaleplon or any other hypnotic. Following rapid dose decrease or abrupt discontinuation of the use of sedative/hypnotics such as zaleplon, there have been reports of signs and symptoms similar to those associated with withdrawal from other CNS-depressant drugs.

    Geriatric

    Debilitated and geriatric patients may be more sensitive to the effects of zaleplon. The impairment of cognitive and motor function may be more marked in this patient group, and a lower initial dosage is recommended for the elderly adult. Because zaleplon can cause drowsiness and a decreased level of consciousness, the elderly are particularly at a higher risk of falls, with the potential for subsequent severe injuries. According to the Beers Criteria, zaleplon is considered a potentially inappropriate medication (PIM) in geriatric patients and use should be avoided. Nonbenzodiazepine, benzodiazepine-receptor agonists (NBRAs) such as zaleplon may produce adverse effects similar to benzodiazepines such as falls, fractures, and delirium in older adults. There are increased emergency department visits, hospitalizations, and motor vehicle crashes, as well as minimal improvement in sleep latency and duration in older adults with the use of NBRAs. Avoid NBRA use in geriatric patients with dementia/cognitive impairment (adverse CNS effects) or delirium/high risk of delirium (new-onset or worsening delirium). Avoid use of an NBRA in elderly patients with a history of falls or fractures, unless safer alternatives are not available since NBRAs can produce ataxia, impaired psychomotor function, syncope, and additional falls. If an NBRA must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to the OBRA guidelines, evaluate factors that potentially cause insomnia before initiating a sedative (e.g., sleep environment, inadequate physical activity, provision of care disruptions, caffeine or medications, pain, and discomfort, or other underlying conditions that cause insomnia). Most cases of insomnia are associated with other underlying conditions. Non-pharmacologic interventions and maximized treatment of underlying conditions (if applicable) are expected to be addressed. Precede or accompany the initiation of a sleep induction or maintenance medication with other interventions to improve sleep. Use all sleep medications per approved product labeling. The use of sedating medications for individuals with diagnosed sleep apnea requires careful assessment, documented clinical rationale, and close monitoring. Exceptions to the OBRA provisions include: single-dose sedative use for a dental or medical procedure or short-term sedative use during initiation of treatment for depression, pain, or another comorbid condition until symptoms improve or the underlying cause can be identified and effectively treated. OBRA provides dosing guidance for most sedatives, including zaleplon. When a drug is being used to induce sleep or treat a sleep disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity per the OBRA guidelines.

    Labor, obstetric delivery, pregnancy

    There are no studies of zaleplon use in pregnant women; therefore, the drug is not recommended during pregnancy. Animal studies have shown no evidence of teratogenicity. However, in one pre- and postnatal development study in rats, increased stillbirth and postnatal mortality, decreased growth, and decreased physical development were observed in the offspring of females treated during the latter part of gestation and throughout lactation. These adverse effects appeared to be the result of both in utero and lactational exposure to the drug. In a separate embryofetal development study in rats, pre- and postnatal growth of the offspring were reduced at a maternally administered dose of 100 mg/kg/day. Clinical signs of maternal toxicity also occurred, as well as decreased maternal body weight gain during gestation. No adverse effects on embryofetal development have been observed in rabbits. Zaleplon has no established use in labor and obstetric delivery.

    Breast-feeding

    Zaleplon is excreted in human breast milk, with the highest excreted amount occurring during feeding at approximately 1 hour after drug administration. Since the small amount of the drug from breast milk may result in potentially important concentrations in an infant and because the effects of zaleplon on a nursing infant are not known, the manufacturer recommends that zaleplon not be administered while breast-feeding. Based on peak breast milk concentrations from 5 women administered 10 mg of zaleplon, the estimated dose an infant would receive is 1.28 to 1.66 mcg or 0.013% to 0.017% of the maternal dose. This amount was considered to be clinically insignificant; however, the effects of zaleplon exposure on the breast-feeding infant have not been evaluated. Zolpidem, a similar agent, with similarly low excretion to breast milk, is a potential alternative. Lactating women should avoid breast-feeding at times of peak drug concentrations, and observe the infant for any indications of adverse events, like sedation, increased crying, poor feeding, or irritability.

    Children, infants

    Safe and effective use of zaleplon in infants, children, or adolescents under 18 years of age has not been established.

    ADVERSE REACTIONS

    Severe

    visual impairment / Early / 0-2.0
    bronchospasm / Rapid / 0.1-1.0
    GI obstruction / Delayed / 0-0.1
    peptic ulcer / Delayed / 0-0.1
    hearing loss / Delayed / 0-0.1
    retinal detachment / Delayed / 0-0.1
    ocular hemorrhage / Delayed / 0-0.1
    corneal erosion / Delayed / 0-0.1
    pleural effusion / Delayed / 0-0.1
    apnea / Delayed / 0-0.1
    cyanosis / Early / 0-0.1
    ventricular tachycardia / Early / 0-0.1
    bradycardia / Rapid / 0-0.1
    pulmonary embolism / Delayed / 0-0.1
    pericardial effusion / Delayed / 0-0.1
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    seizures / Delayed / Incidence not known

    Moderate

    amnesia / Delayed / 2.0-4.0
    hyperesthesia / Delayed / 0-2.0
    hyperacusis / Delayed / 1.0-2.0
    gastritis / Delayed / 0.1-1.0
    melena / Delayed / 0.1-1.0
    glossitis / Early / 0.1-1.0
    stomatitis / Delayed / 0.1-1.0
    oral ulceration / Delayed / 0.1-1.0
    esophagitis / Delayed / 0.1-1.0
    colitis / Delayed / 0-1.0
    edema / Delayed / 0.1-1.0
    euphoria / Early / 0.1-1.0
    hypotonia / Delayed / 0.1-1.0
    nystagmus / Delayed / 0.1-1.0
    hallucinations / Early / 0-1.0
    ataxia / Delayed / 0.1-1.0
    hypertonia / Delayed / 0-1.0
    confusion / Early / 0-1.0
    neuropathic pain / Delayed / 0.1-1.0
    photophobia / Early / 0.1-1.0
    atopic dermatitis / Delayed / 0.1-1.0
    contact dermatitis / Delayed / 0.1-1.0
    dyspnea / Early / 0.1-1.0
    myasthenia / Delayed / 0.1-1.0
    hematuria / Delayed / 0.1-1.0
    nephrolithiasis / Delayed / 0.1-1.0
    impotence (erectile dysfunction) / Delayed / 0.1-1.0
    urinary incontinence / Early / 0.1-1.0
    vaginitis / Delayed / 0.1-1.0
    cystitis / Delayed / 0.1-1.0
    dysuria / Early / 0.1-1.0
    hypercholesterolemia / Delayed / 0.1-1.0
    gout / Delayed / 0.1-1.0
    peripheral edema / Delayed / 0-1.0
    bundle-branch block / Early / 0.1-1.0
    angina / Early / 0.1-1.0
    peripheral vasodilation / Rapid / 0.1-1.0
    hypotension / Rapid / 0.1-1.0
    palpitations / Early / 0.1-1.0
    hypertension / Early / 0.1-1.0
    sinus tachycardia / Rapid / 0.1-1.0
    lymphadenopathy / Delayed / 0.1-1.0
    anemia / Delayed / 0.1-1.0
    cholelithiasis / Delayed / 0-0.1
    teeth grinding (bruxism) / Delayed / 0-0.1
    dysphagia / Delayed / 0-0.1
    elevated hepatic enzymes / Delayed / 0-0.1
    dysarthria / Delayed / 0-0.1
    myoclonia / Delayed / 0-0.1
    dystonic reaction / Delayed / 0-0.1
    trismus / Delayed / 0-0.1
    hyperreflexia / Delayed / 0-0.1
    hostility / Early / 0-0.1
    blepharitis / Early / 0-0.1
    cataracts / Delayed / 0-0.1
    psoriasis / Delayed / 0-0.1
    osteoporosis / Delayed / 0-0.1
    vaginal bleeding / Delayed / 0-0.1
    urinary retention / Early / 0-0.1
    proteinuria / Delayed / 0-0.1
    hypoglycemia / Early / 0-0.1
    hyperglycemia / Delayed / 0-0.1
    hyperuricemia / Delayed / 0-0.1
    hyperbilirubinemia / Delayed / 0-0.1
    orthostatic hypotension / Delayed / 0-0.1
    diabetes mellitus / Delayed / 0-0.1
    goiter / Delayed / 0-0.1
    hypothyroidism / Delayed / 0-0.1
    eosinophilia / Delayed / 0-0.1
    lymphocytosis / Delayed / 0-0.1
    constipation / Delayed / 1.0
    depression / Delayed / 1.0
    conjunctivitis / Delayed / 1.0
    chest pain (unspecified) / Early / 1.0
    impaired cognition / Early / Incidence not known
    memory impairment / Delayed / Incidence not known
    complex sleep-related behaviors / Early / Incidence not known
    respiratory depression / Rapid / Incidence not known
    physiological dependence / Delayed / Incidence not known

    Mild

    headache / Early / 30.0-42.0
    dizziness / Early / 7.0-9.0
    nausea / Early / 6.0-8.0
    asthenia / Delayed / 5.0-7.0
    abdominal pain / Early / 6.0-6.0
    drowsiness / Early / 5.0-6.0
    ocular pain / Early / 3.0-4.0
    dysmenorrhea / Delayed / 3.0-4.0
    paresthesias / Delayed / 3.0-3.0
    anorexia / Delayed / 0-2.0
    malaise / Early / 0-2.0
    tremor / Early / 2.0-2.0
    parosmia / Delayed / 0-2.0
    gingivitis / Delayed / 0.1-1.0
    tongue discoloration / Delayed / 0.1-1.0
    flatulence / Early / 0.1-1.0
    eructation / Early / 0.1-1.0
    appetite stimulation / Delayed / 0.1-1.0
    vertigo / Early / 0-1.0
    libido decrease / Delayed / 0.1-1.0
    emotional lability / Early / 0.1-1.0
    agitation / Early / 0.1-1.0
    hyperkinesis / Delayed / 0.1-1.0
    xerophthalmia / Early / 0.1-1.0
    tinnitus / Delayed / 0.1-1.0
    diplopia / Early / 0.1-1.0
    otalgia / Early / 0-1.0
    photosensitivity / Delayed / 0-1.0
    acne vulgaris / Delayed / 0.1-1.0
    urticaria / Rapid / 0.1-1.0
    maculopapular rash / Early / 0.1-1.0
    xerosis / Delayed / 0.1-1.0
    hyperhidrosis / Delayed / 0.1-1.0
    alopecia / Delayed / 0.1-1.0
    epistaxis / Delayed / 0-1.0
    laryngitis / Delayed / 0.1-1.0
    arthropathy / Delayed / 0.1-1.0
    menorrhagia / Delayed / 0.1-1.0
    increased urinary frequency / Early / 0.1-1.0
    mastalgia / Delayed / 0.1-1.0
    urinary urgency / Early / 0.1-1.0
    weight gain / Delayed / 0.1-1.0
    syncope / Early / 0.1-1.0
    ecchymosis / Delayed / 0.1-1.0
    cheilitis / Delayed / 0-0.1
    hypersalivation / Early / 0-0.1
    hyporeflexia / Delayed / 0-0.1
    ptosis / Delayed / 0-0.1
    psychomotor impairment / Early / 0-0.1
    somnambulism / Early / 0-0.1
    skin discoloration / Delayed / 0-0.1
    hiccups / Early / 0-0.1
    hyperventilation / Early / 0-0.1
    menstrual irregularity / Delayed / 0-0.1
    leukorrhea / Delayed / 0-0.1
    weight loss / Delayed / 0-0.1
    lactose intolerance / Early / 0-0.1
    leukocytosis / Delayed / 0-0.1
    purpura / Delayed / 0-0.1
    dyspepsia / Early / 1.0
    xerostomia / Early / 1.0
    back pain / Delayed / 1.0
    fever / Early / 1.0
    anxiety / Delayed / 1.0
    dysgeusia / Early / 1.0
    rash / Early / 1.0
    pruritus / Rapid / 1.0
    myalgia / Early / 1.0
    arthralgia / Delayed / 1.0
    nightmares / Early / Incidence not known
    abnormal dreams / Early / Incidence not known
    insomnia / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zaleplon should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Acetaminophen; Caffeine: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zaleplon should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zaleplon should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zaleplon should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zaleplon should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Acetaminophen; Chlorpheniramine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Acetaminophen; Codeine: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Major) Concomitant administration of zaleplon with CNS depressant drugs, including dichloralphenazone, can potentiate the CNS effects of either agent.
    Acetaminophen; Diphenhydramine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Acetaminophen; Hydrocodone: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Oxycodone: (Moderate) Concomitant use of oxycodone with zaleplon may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. 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 zaleplon is used concurrently with oxycodone, a reduced dosage of oxycodone and/or zaleplon is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression.
    Acetaminophen; Pamabrom; Pyrilamine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Acetaminophen; Pentazocine: (Moderate) Concomitant use of pentazocine with zaleplon can potentiate respiratory depression, CNS depression, and sedation. Pentazocine should be used cautiously in any patient receiving zaleplon. If concurrent use is necessary, a dose reduction of one or both medications may be required.
    Acetaminophen; Propoxyphene: (Moderate) Concomitant use of CNS depressants can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses.
    Acrivastine; Pseudoephedrine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Aldesleukin, IL-2: (Moderate) Aldesleukin, IL-2 may affect CNS function significantly. Therefore, psychotropic pharmacodynamic interactions could occur following concomitant administration of drugs with significant CNS activity. Use with caution.
    Alfentanil: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Alprazolam: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include benzodiazepines. If used together, a reduction in the dose of one or both drugs may be needed.
    Amitriptyline: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other tricyclic antidepressants. If used together, a reduction in the dose of one or both drugs may be needed.
    Amobarbital: (Major) Coadministration of zaleplon and barbiturates may result in additive CNS depression. Caution should be exercised during concomitant use of anxiolytics, sedatives, and hypnotics and any barbiturate. In addition, zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inducers, such as barbiturates, may increase the clearance of zaleplon. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Amoxapine: (Moderate) CNS depressants should be combined cautiously with amoxapine because they could cause additive depressant effects and possible respiratory depression or hypotension.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as clarithromycin, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Apalutamide: (Moderate) Monitor for decreased efficacy of zaleplon if coadministration with apalutamide is necessary. Zaleplon is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Although CYP3A4 is normally a minor metabolizing enzyme of zaleplon, coadministration with another strong CYP3A4 inducer reduced zaleplon exposure by approximately 80%. Coadministration with apalutamide could lead to ineffectiveness of zaleplon.
    Apomorphine: (Moderate) Apomorphine causes significant somnolence. Concomitant administration of apomorphine and CNS depressants could result in additive depressant effects. A reduction in the dose of one or both drugs should be considered to minimize additive sedative effects. In addition, the risk of next-day psychomotor impairment is increased during co-administration of eszopiclone and other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Apraclonidine: (Minor) No specific drug interactions were identified with systemic agents and apraclonidine during clinical trials. Theoretically, apraclonidine might potentiate the effects of CNS depressant drugs such as the anxiolytics, sedatives, and hypnotics, including barbiturates or benzodiazepines.
    Aripiprazole: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zaleplon. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of CNS depressants than with zaleplon alone. In premarketing studies, zaleplon potentiated the CNS effects of a phenothiazine antipsychotic for at least 2 to 4 hours. Other antipsychotics may also have additive CNS effects with zaleplon.
    Asenapine: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zaleplon. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of CNS depressants than with zaleplon alone. In premarketing studies, zaleplon potentiated the CNS effects of a phenothiazine antipsychotic for at least 2 to 4 hours. Other antipsychotics may also have additive CNS effects with zaleplon.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Coadministration of zaleplon and barbiturates may result in additive CNS depression. Caution should be exercised during concomitant use of anxiolytics, sedatives, and hypnotics and any barbiturate. In addition, zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inducers, such as barbiturates, may increase the clearance of zaleplon. Dosage adjustments should be made on an individual basis according to efficacy and tolerability. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zaleplon should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Coadministration of zaleplon and barbiturates may result in additive CNS depression. Caution should be exercised during concomitant use of anxiolytics, sedatives, and hypnotics and any barbiturate. In addition, zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inducers, such as barbiturates, may increase the clearance of zaleplon. Dosage adjustments should be made on an individual basis according to efficacy and tolerability. (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zaleplon should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Aspirin, ASA; Caffeine: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zaleplon should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zaleplon should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Additive CNS depressant effects may be seen with combination use of orphenadrine and anxiolytics, sedatives, and hypnotics. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zaleplon should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Aspirin, ASA; Carisoprodol: (Moderate) Carisoprodol can cause additive CNS depression if used concomitantly with other CNS depressants.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Carisoprodol can cause additive CNS depression if used concomitantly with other CNS depressants.
    Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of oxycodone with zaleplon may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. 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 zaleplon is used concurrently with oxycodone, a reduced dosage of oxycodone and/or zaleplon is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression.
    Atazanavir: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as atazanavir, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Atazanavir; Cobicistat: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as atazanavir, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability. (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as cobicistat, may decrease the clearance of zaleplon. Coadministration with a moderate CYP3A4 inhibitor increased zaleplon exposure by 20%. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with anxiolytics, sedatives, and hypnotics can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    atypical antipsychotic: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zaleplon. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of CNS depressants than with zaleplon alone. In premarketing studies, zaleplon potentiated the CNS effects of a phenothiazine antipsychotic for at least 2 to 4 hours. Other antipsychotics may also have additive CNS effects with zaleplon.
    Azelastine: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with CNS depressants including anxiolytics, sedatives, and hypnotics.
    Azelastine; Fluticasone: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with CNS depressants including anxiolytics, sedatives, and hypnotics.
    Baclofen: (Moderate) Concurrent use of baclofen and CNS depressants such as certain sedatives or hypnotics can cause additive CNS depression. A reduction in the dose of these medications may be considered to minimize additive sedative effects, if they occur. With hypnotic medications, the risk of next-day psychomotor impairment is increased during co-administration of other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Barbiturates: (Major) Coadministration of zaleplon and barbiturates may result in additive CNS depression. Caution should be exercised during concomitant use of anxiolytics, sedatives, and hypnotics and any barbiturate. In addition, zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inducers, such as barbiturates, may increase the clearance of zaleplon. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Coadministration of zaleplon and barbiturates may result in additive CNS depression. Caution should be exercised during concomitant use of anxiolytics, sedatives, and hypnotics and any barbiturate. In addition, zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inducers, such as barbiturates, may increase the clearance of zaleplon. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Belladonna; Opium: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opioid agonists with zaleplon may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If benzhydrocodone is initiated in a patient taking zaleplon, reduce initial dosage and titrate to clinical response. If zaleplon is initiated a patient taking an opioid agonist, use a lower initial dose of zaleplon and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Benzodiazepines: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include benzodiazepines. If used together, a reduction in the dose of one or both drugs may be needed.
    Benztropine: (Moderate) CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase the sedative effects of benztropine.
    Brexpiprazole: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zaleplon. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of CNS depressants than with zaleplon alone. In premarketing studies, zaleplon potentiated the CNS effects of a phenothiazine antipsychotic for at least 2 to 4 hours. Other antipsychotics may also have additive CNS effects with zaleplon.
    Brimonidine: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of anxiolytics, sedatives, and hypnotics.
    Brimonidine; Brinzolamide: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of anxiolytics, sedatives, and hypnotics.
    Brimonidine; Timolol: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of anxiolytics, sedatives, and hypnotics.
    Brompheniramine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Brompheniramine; Phenylephrine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Brompheniramine; Pseudoephedrine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Buprenorphine: (Moderate) If concurrent use of zaleplon and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Buprenorphine; Naloxone: (Moderate) If concurrent use of zaleplon and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Buspirone: (Major) The combination of buspirone and other CNS depressants can increase the risk for sedation.
    Butabarbital: (Major) Coadministration of zaleplon and barbiturates may result in additive CNS depression. Caution should be exercised during concomitant use of anxiolytics, sedatives, and hypnotics and any barbiturate. In addition, zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inducers, such as barbiturates, may increase the clearance of zaleplon. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Butalbital; Acetaminophen: (Major) Coadministration of zaleplon and barbiturates may result in additive CNS depression. Caution should be exercised during concomitant use of anxiolytics, sedatives, and hypnotics and any barbiturate. In addition, zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inducers, such as barbiturates, may increase the clearance of zaleplon. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Butalbital; Acetaminophen; Caffeine: (Major) Coadministration of zaleplon and barbiturates may result in additive CNS depression. Caution should be exercised during concomitant use of anxiolytics, sedatives, and hypnotics and any barbiturate. In addition, zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inducers, such as barbiturates, may increase the clearance of zaleplon. Dosage adjustments should be made on an individual basis according to efficacy and tolerability. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zaleplon 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.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Coadministration of zaleplon and barbiturates may result in additive CNS depression. Caution should be exercised during concomitant use of anxiolytics, sedatives, and hypnotics and any barbiturate. In addition, zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inducers, such as barbiturates, may increase the clearance of zaleplon. Dosage adjustments should be made on an individual basis according to efficacy and tolerability. (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zaleplon 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.
    Butorphanol: (Moderate) Concomitant use of butorphanol with other central nervous system (CNS) depressants, such as zaleplon, can potentiate the effects of butorphanol and may lead to additive CNS or respiratory depression. Prior to concurrent use of butorphanol 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. If these agents are used together, a reduced dosage of butorphanol and/or zaleplon may be necessary. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression.
    Caffeine: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zaleplon should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Caffeine; Sodium Benzoate: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zaleplon 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.
    Calcium, Magnesium, Potassium, Sodium Oxybates: (Contraindicated) 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.
    Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration. CNS depressants can potentiate the effects of cannabidiol.
    Capsaicin; Metaxalone: (Moderate) Concomitant administration of metaxalone with other CNS depressants, such as certain sedatives and hypnotics, can potentiate the sedative effects of either agent. A reduction in the dose of these medications may be considered to minimize additive sedative effects, if they occur. With hypnotic medications, the risk of next-day psychomotor impairment is increased during co-administration of other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Carbamazepine: (Moderate) Monitor for decreased efficacy of zaleplon if coadministration with carbamazepine is necessary. Zaleplon is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Although CYP3A4 is normally a minor metabolizing enzyme of zaleplon, coadministration with another strong CYP3A4 inducer reduced zaleplon exposure by approximately 80%. Coadministration with carbamazepine could lead to ineffectiveness of zaleplon.
    Carbetapentane; Chlorpheniramine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Carbetapentane; Pseudoephedrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Carbidopa; Levodopa; Entacapone: (Major) Additive CNS depressant effects are possible during concurrent use of COMT inhibitors and zaleplon. If concurrent use is necessary, monitor for additive side effects. A reduction in the dose of one or both drugs may be needed. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
    Carbinoxamine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Carbinoxamine; Phenylephrine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Carbinoxamine; Pseudoephedrine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Cariprazine: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zaleplon. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of CNS depressants than with zaleplon alone. In premarketing studies, zaleplon potentiated the CNS effects of a phenothiazine antipsychotic for at least 2 to 4 hours. Other antipsychotics may also have additive CNS effects with zaleplon.
    Carisoprodol: (Moderate) Carisoprodol can cause additive CNS depression if used concomitantly with other CNS depressants.
    Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and zaleplon. Concurrent use increases the risk for CNS depression and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Patients should be instructed to contact their provider immediately if these symptoms or behaviors occur.
    Ceritinib: (Moderate) Monitor for an increase in zaleplon-related adverse reactions if coadministration with ceritinib is necessary. Zaleplon is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Cetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with zaleplon should generally be avoided. Concurrent use of zaleplon with other CNS depressants increases the risk for CNS depression and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). If concurrent use is necessary, patients should be instructed to contact their provider immediately if these symptoms or behaviors occur.
    Cetirizine; Pseudoephedrine: (Moderate) Concurrent use of cetirizine/levocetirizine with zaleplon should generally be avoided. Concurrent use of zaleplon with other CNS depressants increases the risk for CNS depression and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). If concurrent use is necessary, patients should be instructed to contact their provider immediately if these symptoms or behaviors occur.
    Chlophedianol; Dexbrompheniramine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Chloramphenicol: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as chloramphenicol, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Chlorcyclizine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Chlordiazepoxide: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include benzodiazepines. If used together, a reduction in the dose of one or both drugs may be needed.
    Chlordiazepoxide; Amitriptyline: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include benzodiazepines. If used together, a reduction in the dose of one or both drugs may be needed. (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other tricyclic antidepressants. If used together, a reduction in the dose of one or both drugs may be needed.
    Chlordiazepoxide; Clidinium: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include benzodiazepines. If used together, a reduction in the dose of one or both drugs may be needed.
    Chlorpheniramine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Chlorpheniramine; Codeine: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Chlorpheniramine; Dextromethorphan: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Chlorpheniramine; Hydrocodone: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Chlorpheniramine; Phenylephrine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Chlorpheniramine; Pseudoephedrine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Chlorzoxazone: (Moderate) Concurrent use of chlorzoxazone and CNS depressants such as certain sedatives or hypnotics can cause additive CNS depression. A reduction in the dose of these medications may be considered to minimize additive sedative effects, if they occur. With hypnotic medications, the risk of next-day psychomotor impairment is increased during co-administration of other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Cimetidine: (Major) Reduce the initial dose of zaleplon to 5 mg in patients receiving concomitant cimetidine therapy. Coadministration of cimetidine resulted in an 85% increase in the Cmax and AUC of zaleplon in a drug interaction study. Cimetidine inhibits both aldehyde oxidase and CYP3A4, the primary and secondary enzymes, respectively, responsible for zaleplon metabolism.
    Clarithromycin: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as clarithromycin, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Clemastine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Clobazam: (Moderate) Concomitant administration of clobazam with other CNS depressant drugs including anxiolytics, sedatives, and hypnotics, can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent.
    Clomipramine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other tricyclic antidepressants. If used together, a reduction in the dose of one or both drugs may be needed.
    Clonazepam: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include benzodiazepines. If used together, a reduction in the dose of one or both drugs may be needed.
    Clorazepate: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include benzodiazepines. If used together, a reduction in the dose of one or both drugs may be needed.
    Clozapine: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zaleplon. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of CNS depressants than with zaleplon alone. In premarketing studies, zaleplon potentiated the CNS effects of a phenothiazine antipsychotic for at least 2 to 4 hours. Other antipsychotics may also have additive CNS effects with zaleplon.
    Cobicistat: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as cobicistat, may decrease the clearance of zaleplon. Coadministration with a moderate CYP3A4 inhibitor increased zaleplon exposure by 20%. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Codeine: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Codeine; Guaifenesin: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Codeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Codeine; Promethazine: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    COMT inhibitors: (Major) Additive CNS depressant effects are possible during concurrent use of COMT inhibitors and zaleplon. If concurrent use is necessary, monitor for additive side effects. A reduction in the dose of one or both drugs may be needed. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
    Cyclizine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Cyclobenzaprine: (Moderate) Cyclobenzaprine may cause additive CNS depression if used concomitantly with other CNS depressants, such as anxiolytics, sedatives, and hypnotics. Combination therapy can cause additive effects of sedation and dizziness, which can impair the patient's ability to undertake tasks requiring mental alertness. Dosage adjustments of either or both medications may be necessary.
    Cyproheptadine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Dantrolene: (Moderate) Simultaneous use of dantrolene and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase CNS depression (e.g., drowsiness). A reduction in the dose of these medications may be considered to minimize additive sedative effects, if they occur. With hypnotic medications, the risk of next-day psychomotor impairment is increased during co-administration of other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Darunavir: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as darunavir, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Darunavir; Cobicistat: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as cobicistat, may decrease the clearance of zaleplon. Coadministration with a moderate CYP3A4 inhibitor increased zaleplon exposure by 20%. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability. (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as darunavir, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as cobicistat, may decrease the clearance of zaleplon. Coadministration with a moderate CYP3A4 inhibitor increased zaleplon exposure by 20%. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability. (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as darunavir, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as ritonavir, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Delavirdine: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as delavirdine, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Desipramine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other tricyclic antidepressants. If used together, a reduction in the dose of one or both drugs may be needed.
    Deutetrabenazine: (Moderate) Advise patients that concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as zaleplon, may have additive effects and worsen drowsiness or sedation.
    Dexbrompheniramine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Dexbrompheniramine; Pseudoephedrine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Dexchlorpheniramine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Dexmedetomidine: (Moderate) Co-administration of dexmedetomidine with anxiolytics, sedatives, and hypnotics is likely to lead to an enhancement of CNS depression.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Diazepam: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include benzodiazepines. If used together, a reduction in the dose of one or both drugs may be needed.
    Dicyclomine: (Moderate) Dicyclomine can cause drowsiness, so it should be used cautiously in patients receiving CNS depressants like anxiolytics, sedatives, and hypnotics.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Dimenhydrinate: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Diphenhydramine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Diphenhydramine; Ibuprofen: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Diphenhydramine; Naproxen: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Diphenhydramine; Phenylephrine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Diphenoxylate; Atropine: (Moderate) Concurrent administration of diphenoxylate/difenoxin with anxiolytics, sedatives, and hypnotics can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Doxepin: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other tricyclic antidepressants. If used together, a reduction in the dose of one or both drugs may be needed.
    Doxylamine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Doxylamine; Pyridoxine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Dronabinol: (Moderate) Concomitant use of dronabinol with other CNS depressants, such as zaleplon, can potentiate the effects of dronabinol on respiratory depression.
    Droperidol: (Moderate) Central nervous system (CNS) depressants like zaleplon have additive or potentiating effects with droperidol. Following administration of droperidol, the dose of the other CNS depressant should be reduced.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as cobicistat, may decrease the clearance of zaleplon. Coadministration with a moderate CYP3A4 inhibitor increased zaleplon exposure by 20%. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as cobicistat, may decrease the clearance of zaleplon. Coadministration with a moderate CYP3A4 inhibitor increased zaleplon exposure by 20%. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Enflurane: (Moderate) Coadministration of zaleplon and general anesthetics may result in additive CNS depressant effects. In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. A similar interaction may occur with zaleplon and other CNS depressants including general anesthetics. If concurrent use is necessary, monitor for additive side effects. A temporary dose reduction of zaleplon should be considered following administration of general anesthetics. 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.
    Entacapone: (Major) Additive CNS depressant effects are possible during concurrent use of COMT inhibitors and zaleplon. If concurrent use is necessary, monitor for additive side effects. A reduction in the dose of one or both drugs may be needed. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
    Enzalutamide: (Major) Consider an alternative to enzalutamide if treatment with zaleplon is necessary due to decreased plasma concentrations of zaleplon. Zaleplon is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Although CYP3A4 is normally a minor metabolizing enzyme of zaleplon, coadministration with another strong CYP3A4 inducer reduced zaleplon exposure by approximately 80%.
    Ergotamine; Caffeine: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zaleplon 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.
    Erythromycin: (Moderate) Zaleplon is partially metabolized by CYP3A4 and concurrent use of CYP3A4 inhibitors, such as erythromycin, can decrease the clearance of zaleplon. Coadministration of 10 mg doses of zaleplon with 800 mg of erythromycin produced a 34% increase in the maximum plasma concentrations of zaleplon and a 20% increase in AUC. The magnitude of interaction with multiple doses of erythromycin is unknown; however, routine dosage adjustments are not required.
    Erythromycin; Sulfisoxazole: (Moderate) Zaleplon is partially metabolized by CYP3A4 and concurrent use of CYP3A4 inhibitors, such as erythromycin, can decrease the clearance of zaleplon. Coadministration of 10 mg doses of zaleplon with 800 mg of erythromycin produced a 34% increase in the maximum plasma concentrations of zaleplon and a 20% increase in AUC. The magnitude of interaction with multiple doses of erythromycin is unknown; however, routine dosage adjustments are not required.
    Esketamine: (Major) Use of zaleplon during treatment with esketamine may increase sedation and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Instruct patients to contact their provider immediately if these symptoms or behaviors occur and not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
    Estazolam: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include benzodiazepines. If used together, a reduction in the dose of one or both drugs may be needed.
    Ethanol: (Major) Advise patients not to use zaleplon if they drank alcohol that evening or before bed. There are additive effects of alcohol with zaleplon, leading to additive CNS depression and psychomotor impairment. Zaleplon potentiated the CNS-impairing effects of ethanol 0.75 g/kg on balance testing and reaction time for 1 hour after ethanol administration and on the digit symbol substitution test (DSST), symbol copying test, and the variability component of the divided attention test for 2.5 hours after ethanol administration. The potentiation resuls from a CNS pharmacodynamic interaction; zaleplon did not affect the pharmacokinetics of ethanol.
    Etomidate: (Moderate) Coadministration of zaleplon and general anesthetics may result in additive CNS depressant effects. In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. A similar interaction may occur with zaleplon and other CNS depressants including general anesthetics. If concurrent use is necessary, monitor for additive side effects. A temporary dose reduction of zaleplon should be considered following administration of general anesthetics. 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.
    Ezogabine: (Moderate) Due to the CNS effects of ezogabine, an enhanced CNS depressant effect may occur when it is combined with other centrally-acting medications such as anxiolytics, sedatives, and hypnotics. Patients should be monitored for excessive somnolence during concurrent therapy with these agents.
    Fenfluramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of fenfluramine and zaleplon. Concurrent use increases the risk for CNS depression and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake).
    Fentanyl: (Moderate) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Flumazenil: (Major) Flumazenil, a benzodiazepine antagonist, can reverse the sedative/hypnotic effects of zaleplon. Flumazenil and zaleplon are pharmacological opposites.
    Flurazepam: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include benzodiazepines. If used together, a reduction in the dose of one or both drugs may be needed.
    Food: (Major) Administration with or immediately after heavy, high-fat food slows the absorption of zaleplon. This is expected to reduce the effect of zaleplon on sleep latency.
    Fosamprenavir: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as fosamprenavir, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Fosphenytoin: (Moderate) Monitor for decreased efficacy of zaleplon if coadministration with fosphenytoin is necessary. Zaleplon is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Although CYP3A4 is normally a minor metabolizing enzyme of zaleplon, coadministration with another strong CYP3A4 inducer reduced zaleplon exposure by approximately 80%. Coadministration with fosphenytoin could lead to ineffectiveness of zaleplon.
    Fospropofol: (Moderate) Coadministration of zaleplon and general anesthetics may result in additive CNS depressant effects. In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. A similar interaction may occur with zaleplon and other CNS depressants including general anesthetics. If concurrent use is necessary, monitor for additive side effects. A temporary dose reduction of zaleplon should be considered following administration of general anesthetics. 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.
    Gabapentin: (Major) Initiate gabapentin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of gabapentin and zaleplon. Concomitant use of gabapentin with zaleplon may cause additive CNS depression and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Educate patients about the risks and symptoms of excessive CNS depression. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur.
    General anesthetics: (Moderate) Coadministration of zaleplon and general anesthetics may result in additive CNS depressant effects. In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. A similar interaction may occur with zaleplon and other CNS depressants including general anesthetics. If concurrent use is necessary, monitor for additive side effects. A temporary dose reduction of zaleplon should be considered following administration of general anesthetics. 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.
    Grapefruit juice: (Moderate) Grapefruit and grapefruit juice should be avoided if possible in patients taking zaleplon. Because zaleplon is partially metabolized by CYP3A4, an interaction is possible with CYP3A4 inhibitors such as grapefruit juice. Grapefruit and grapefruit juice inhibit CYP3A4 metabolism in gut enterocytes, and therefore may cause increased systemic concentrations of zaleplon potentially resulting in somnolence, ataxia, sleep-related behaviors, or other adverse CNS effects.
    Guaifenesin; Hydrocodone: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Haloperidol: (Moderate) Haloperidol can potentiate the actions of other CNS depressants such as anxiolytics, sedatives, and hypnotics, and they should be used cautiously in combination.
    Halothane: (Moderate) Coadministration of zaleplon and general anesthetics may result in additive CNS depressant effects. In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. A similar interaction may occur with zaleplon and other CNS depressants including general anesthetics. If concurrent use is necessary, monitor for additive side effects. A temporary dose reduction of zaleplon should be considered following administration of general anesthetics. 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.
    Homatropine; Hydrocodone: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Ibuprofen: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking zaleplon. Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydromorphone: (Moderate) Concomitant use of hydromorphone with zaleplon can potentiate the effects of hydromorphone and may lead to additive CNS or respiratory depression, profound sedation, or coma. 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 hydromorphone is used concurrently with zaleplon, a reduced dosage of hydromorphone and/or zaleplon is recommended; start with one-third to one-half of the estimated hydromorphone starting dose when using hydromorphone extended-release tablets. 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: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Ibuprofen; Oxycodone: (Moderate) Concomitant use of oxycodone with zaleplon may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. 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 zaleplon is used concurrently with oxycodone, a reduced dosage of oxycodone and/or zaleplon is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression.
    Idelalisib: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as idelalisib, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Iloperidone: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zaleplon. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of CNS depressants than with zaleplon alone. In premarketing studies, zaleplon potentiated the CNS effects of a phenothiazine antipsychotic for at least 2 to 4 hours. Other antipsychotics may also have additive CNS effects with zaleplon.
    Imipramine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other tricyclic antidepressants. If used together, a reduction in the dose of one or both drugs may be needed.
    Indinavir: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as indinavir, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Isocarboxazid: (Moderate) The manufacturers of MAOIs contraindicate the use of MAOIs with some CNS depressant drugs due to additive CNS depressant effects. If combination therapy is necessary, use caution; warn patients to avoid driving or performing other hazardous activities until they know how the combination affects them. A dose reduction of one or both medications may be required.
    Isoflurane: (Moderate) Coadministration of zaleplon and general anesthetics may result in additive CNS depressant effects. In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. A similar interaction may occur with zaleplon and other CNS depressants including general anesthetics. If concurrent use is necessary, monitor for additive side effects. A temporary dose reduction of zaleplon should be considered following administration of general anesthetics. 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.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Monitor for decreased efficacy of zaleplon if coadministration with rifampin is necessary. Zaleplon is a partial CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Although CYP3A4 is normally a minor metabolizing enzyme of zaleplon, multiple-dose administration of rifampin (600 mg every 24 hours for 14 days) reduced zaleplon Cmax and AUC by approximately 80%.
    Isoniazid, INH; Rifampin: (Moderate) Monitor for decreased efficacy of zaleplon if coadministration with rifampin is necessary. Zaleplon is a partial CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Although CYP3A4 is normally a minor metabolizing enzyme of zaleplon, multiple-dose administration of rifampin (600 mg every 24 hours for 14 days) reduced zaleplon Cmax and AUC by approximately 80%.
    Itraconazole: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as itraconazole, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Ketamine: (Moderate) Coadministration of zaleplon and general anesthetics may result in additive CNS depressant effects. In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. A similar interaction may occur with zaleplon and other CNS depressants including general anesthetics. If concurrent use is necessary, monitor for additive side effects. A temporary dose reduction of zaleplon should be considered following administration of general anesthetics. 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.
    Ketoconazole: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as ketoconazole, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as clarithromycin, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Lasmiditan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lasmiditan and zaleplon. Concurrent use increases the risk for CNS depression and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Patients should be instructed to contact their provider immediately if these symptoms or behaviors occur.
    Lemborexant: (Moderate) Use of lemborexant with other sedatives and hypnotics should generally be avoided due to duplication of treatments and due to the additive CNS depressant and complex sleep-related behaviors that may occur. While anxiolytic medications may be used concurrently with lemborexant, a reduction in dose of one or both agents may be needed.
    Levocetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with zaleplon should generally be avoided. Concurrent use of zaleplon with other CNS depressants increases the risk for CNS depression and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). If concurrent use is necessary, patients should be instructed to contact their provider immediately if these symptoms or behaviors occur.
    Levoketoconazole: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as ketoconazole, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Levomethadyl: (Moderate) Concomitant use of CNS depressants can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses.
    Levorphanol: (Moderate) Concomitant use of levorphanol with zaleplon can potentiate the effects of levorphanol on respiration, blood pressure, and alertness. Severe hypotension, respiratory depression, profound sedation, or coma may occur. 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 with levorphanol with another CNS depressant 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.
    Lithium: (Moderate) Because lithium has the potential to impair cognitive and motor skills, caution is advisable during concurrent use of other medications with centrally-acting effects including anxiolytics, sedatives, and hypnotics.
    Lofexidine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and anxiolytics, sedatives, and hypnotics. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
    Lonafarnib: (Moderate) Monitor for an increase in zaleplon-related adverse reactions, including excessive sedation and confusion, if coadministered with lonafarnib. Routine dosage adjustments of zaleplon are not required. Zaleplon is partially metabolized by CYP3A4 and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with a single dose of another strong CYP3A4 inhibitor increased the AUC of zaleplon by 20%.
    Lopinavir; Ritonavir: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as ritonavir, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Lorazepam: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include benzodiazepines. If used together, a reduction in the dose of one or both drugs may be needed.
    Loxapine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other antipsychotics may also have additive CNS effects with zaleplon.
    Lumacaftor; Ivacaftor: (Moderate) Monitor for decreased efficacy of zaleplon if coadministration with lumacaftor; ivacaftor is necessary. Zaleplon is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Although CYP3A4 is normally a minor metabolizing enzyme of zaleplon, coadministration with another strong CYP3A4 inducer reduced zaleplon exposure by approximately 80%. Coadministration with lumacaftor; ivacaftor could lead to ineffectiveness of zaleplon.
    Lumacaftor; Ivacaftor: (Moderate) Monitor for decreased efficacy of zaleplon if coadministration with lumacaftor; ivacaftor is necessary. Zaleplon is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Although CYP3A4 is normally a minor metabolizing enzyme of zaleplon, coadministration with another strong CYP3A4 inducer reduced zaleplon exposure by approximately 80%. Coadministration with lumacaftor; ivacaftor could lead to ineffectiveness of zaleplon.
    Lumateperone: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zaleplon. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of CNS depressants than with zaleplon alone. In premarketing studies, zaleplon potentiated the CNS effects of a phenothiazine antipsychotic for at least 2 to 4 hours. Other antipsychotics may also have additive CNS effects with zaleplon.
    Lurasidone: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zaleplon. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of CNS depressants than with zaleplon alone. In premarketing studies, zaleplon potentiated the CNS effects of a phenothiazine antipsychotic for at least 2 to 4 hours. Other antipsychotics may also have additive CNS effects with zaleplon.
    Maprotiline: (Moderate) CNS depressants should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension.
    Meclizine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Melatonin: (Major) Pharmacodynamic interactions often occur when sedative agents are used together. Until more data are available, avoid combining melatonin with other hypnotics, including zaleplon. In a clinical trial, there was clear evidence for a transitory pharmacodynamic interaction between melatonin and another hypnotic agent one hour following co-dosing. Concomitant administration resulted in increased impairment of attention, memory and coordination compared to the hypnotic agent alone. Use of more than one agent for hypnotic purposes may increase the risk for over-sedation, CNS effects, or sleep-related behaviors. Be alert for unusual changes in moods or behaviors. Patients reporting unusual sleep-related behaviors likely should discontinue melatonin use.
    Mepenzolate: (Moderate) CNS depression can be increased when mepenzolate is combined with other CNS depressants such as any anxiolytics, sedatives, and hypnotics.
    Meperidine: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Meperidine; Promethazine: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Mephobarbital: (Major) Coadministration of zaleplon and barbiturates may result in additive CNS depression. Caution should be exercised during concomitant use of anxiolytics, sedatives, and hypnotics and any barbiturate. In addition, zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inducers, such as barbiturates, may increase the clearance of zaleplon. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Metaxalone: (Moderate) Concomitant administration of metaxalone with other CNS depressants, such as certain sedatives and hypnotics, can potentiate the sedative effects of either agent. A reduction in the dose of these medications may be considered to minimize additive sedative effects, if they occur. With hypnotic medications, the risk of next-day psychomotor impairment is increased during co-administration of other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Methadone: (Moderate) Concomitant use of methadone with zaleplon can lead to additive respiratory depression, hypotension, profound sedation, or coma. 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 zaleplon. Monitor patients for sedation and respiratory depression.
    Methocarbamol: (Moderate) Methocarbamol may cause additive CNS depression if used concomitantly with other CNS depressants. Dosage reduction of one or both agents may be necessary.
    Methohexital: (Major) Coadministration of zaleplon and barbiturates may result in additive CNS depression. Caution should be exercised during concomitant use of anxiolytics, sedatives, and hypnotics and any barbiturate. In addition, zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inducers, such as barbiturates, may increase the clearance of zaleplon. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Methscopolamine: (Moderate) CNS depression can be increased when methscopolamine is combined with other CNS depressants such as any anxiolytics, sedatives, and hypnotics.
    Metoclopramide: (Minor) Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.
    Midazolam: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include benzodiazepines. If used together, a reduction in the dose of one or both drugs may be needed.
    Mifepristone: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as mifepristone, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Mirtazapine: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including benzodiazepines.
    Mitotane: (Moderate) Monitor for decreased efficacy of zaleplon if coadministration with mitotane is necessary. Zaleplon is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Although CYP3A4 is normally a minor metabolizing enzyme of zaleplon, coadministration with another strong CYP3A4 inducer reduced zaleplon exposure by approximately 80%. Coadministration with mitotane could lead to ineffectiveness of zaleplon.
    Molindone: (Moderate) Consistent with the pharmacology of molindone, additive central nervous system (CNS) effects may occur with other CNS active drugs such as zaleplon. Caution is advisable during concurrent use.
    Monoamine oxidase inhibitors: (Moderate) The manufacturers of MAOIs contraindicate the use of MAOIs with some CNS depressant drugs due to additive CNS depressant effects. If combination therapy is necessary, use caution; warn patients to avoid driving or performing other hazardous activities until they know how the combination affects them. A dose reduction of one or both medications may be required.
    Morphine: (Moderate) Concomitant use of morphine with zaleplon can potentiate the effects of morphine on respiration, blood pressure, and alertness. 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 zaleplon is used concurrently with morphine, a reduced dosage of morphine and/or the zaleplon 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). Monitor patients for sedation and respiratory depression.
    Morphine; Naltrexone: (Moderate) Concomitant use of morphine with zaleplon can potentiate the effects of morphine on respiration, blood pressure, and alertness. 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 zaleplon is used concurrently with morphine, a reduced dosage of morphine and/or the zaleplon 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). Monitor patients for sedation and respiratory depression.
    Nabilone: (Moderate) Additive respiratory and CNS depressant effects are possible during concurrent use of nabilone and zaleplon. In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Similar interactions may occur with other CNS depressants including nabilone. If concurrent use is necessary, monitor for additive side effects. A reduction in the dose of one or both drugs may be needed.
    Nalbuphine: (Moderate) Concomitant use of nalbuphine with other CNS depressants, such as zaleplon, can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Nefazodone: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as nefazodone, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Nelfinavir: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as nelfinavir, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Nirmatrelvir; Ritonavir: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as ritonavir, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Nortriptyline: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other tricyclic antidepressants. If used together, a reduction in the dose of one or both drugs may be needed.
    Olanzapine: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zaleplon. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of CNS depressants than with zaleplon alone. In premarketing studies, zaleplon potentiated the CNS effects of a phenothiazine antipsychotic for at least 2 to 4 hours. Other antipsychotics may also have additive CNS effects with zaleplon.
    Olanzapine; Fluoxetine: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zaleplon. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of CNS depressants than with zaleplon alone. In premarketing studies, zaleplon potentiated the CNS effects of a phenothiazine antipsychotic for at least 2 to 4 hours. Other antipsychotics may also have additive CNS effects with zaleplon.
    Olanzapine; Samidorphan: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zaleplon. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of CNS depressants than with zaleplon alone. In premarketing studies, zaleplon potentiated the CNS effects of a phenothiazine antipsychotic for at least 2 to 4 hours. Other antipsychotics may also have additive CNS effects with zaleplon.
    Oliceridine: (Major) Concomitant use of oliceridine with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of oliceridine with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as ritonavir, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Opicapone: (Major) Additive CNS depressant effects are possible during concurrent use of COMT inhibitors and zaleplon. If concurrent use is necessary, monitor for additive side effects. A reduction in the dose of one or both drugs may be needed. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
    Orphenadrine: (Moderate) Additive CNS depressant effects may be seen with combination use of orphenadrine and anxiolytics, sedatives, and hypnotics.
    Oxazepam: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include benzodiazepines. If used together, a reduction in the dose of one or both drugs may be needed.
    Oxybutynin: (Moderate) Oxybutynin causes CNS-depressant effects including somnolence and drowsiness; concurrent use with other CNS-depressant drugs, including anxiolytics, sedatives, and hypnotics, can increase the total sedative effects of oxybutynin.
    Oxycodone: (Moderate) Concomitant use of oxycodone with zaleplon may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. 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 zaleplon is used concurrently with oxycodone, a reduced dosage of oxycodone and/or zaleplon is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression.
    Oxymorphone: (Moderate) Concomitant use of oxymorphone with zaleplon may produce additive CNS depressant effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. 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 zaleplon is used concurrently with oxymorphone, a reduced dosage of oxymorphone (1/3 to 1/2 of the usual dose) and/or zaleplon is recommended. If the extended-release oxymorphone tablets are used concurrently with a CNS depressant, it is recommended to use an initial dosage of 5 mg PO every 12 hours. Monitor for sedation or respiratory depression.
    Paliperidone: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zaleplon. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of CNS depressants than with zaleplon alone. In premarketing studies, zaleplon potentiated the CNS effects of a phenothiazine antipsychotic for at least 2 to 4 hours. Other antipsychotics may also have additive CNS effects with zaleplon.
    Papaverine: (Moderate) Papaverine is a benzylisoquinoline alkaloid of opium and may have synergistic effects with potent CNS depressants such as anxiolytics, sedatives, and hypnotics, which could lead to enhanced sedation.
    Pentazocine: (Moderate) Concomitant use of pentazocine with zaleplon can potentiate respiratory depression, CNS depression, and sedation. Pentazocine should be used cautiously in any patient receiving zaleplon. If concurrent use is necessary, a dose reduction of one or both medications may be required.
    Pentazocine; Naloxone: (Moderate) Concomitant use of pentazocine with zaleplon can potentiate respiratory depression, CNS depression, and sedation. Pentazocine should be used cautiously in any patient receiving zaleplon. If concurrent use is necessary, a dose reduction of one or both medications may be required.
    Pentobarbital: (Major) Coadministration of zaleplon and barbiturates may result in additive CNS depression. Caution should be exercised during concomitant use of anxiolytics, sedatives, and hypnotics and any barbiturate. In addition, zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inducers, such as barbiturates, may increase the clearance of zaleplon. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Perampanel: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as zaleplon.
    Perphenazine; Amitriptyline: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other tricyclic antidepressants. If used together, a reduction in the dose of one or both drugs may be needed.
    Phenelzine: (Moderate) The manufacturers of MAOIs contraindicate the use of MAOIs with some CNS depressant drugs due to additive CNS depressant effects. If combination therapy is necessary, use caution; warn patients to avoid driving or performing other hazardous activities until they know how the combination affects them. A dose reduction of one or both medications may be required.
    Phenobarbital: (Major) Coadministration of zaleplon and barbiturates may result in additive CNS depression. Caution should be exercised during concomitant use of anxiolytics, sedatives, and hypnotics and any barbiturate. In addition, zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inducers, such as barbiturates, may increase the clearance of zaleplon. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Coadministration of zaleplon and barbiturates may result in additive CNS depression. Caution should be exercised during concomitant use of anxiolytics, sedatives, and hypnotics and any barbiturate. In addition, zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inducers, such as barbiturates, may increase the clearance of zaleplon. Dosage adjustments should be made on an individual basis according to efficacy and tolerability. (Moderate) Scopolamine may cause dizziness and drowsiness. Concurrent use of scopolamine and CNS depressants can adversely increase the risk of CNS depression.
    Phenothiazines: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered with other CNS depressant drugs and they should be used cautiously with anxiolytic, sedative, and hypnotics. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of hypnotics and other CNS depressants than with use of a hypnotic alone.
    Phentermine; Topiramate: (Major) Although not specifically studied, coadministration of CNS depressant drugs (e.g., anxiolytics, sedatives, and hypnotics) with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering.
    Phenytoin: (Moderate) Monitor for decreased efficacy of zaleplon if coadministration with phenytoin is necessary. Zaleplon is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Although CYP3A4 is normally a minor metabolizing enzyme of zaleplon, coadministration with another strong CYP3A4 inducer reduced zaleplon exposure by approximately 80%. Coadministration with phenytoin could lead to ineffectiveness of zaleplon.
    Pimozide: (Moderate) Due to the effects of pimozide on cognition, it should be used cautiously with other CNS depressants including sedatives and hypnotics like zaleplon. In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours and may result in similar interactions with other antipsychotics, including pimozide.
    Posaconazole: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as posaconazole, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Pramipexole: (Moderate) The use of zaleplon in combination with pramipexole may increase the risk of clinically significant sedation via a pharmacodynamic interaction.
    Pregabalin: (Major) Initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of pregabalin and zaleplon. Concomitant use of pregabalin with zaleplon may cause additive CNS depression and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Educate patients about the risks and symptoms of excessive CNS depression. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur.
    Primidone: (Major) Coadministration of zaleplon and barbiturates may result in additive CNS depression. Caution should be exercised during concomitant use of anxiolytics, sedatives, and hypnotics and any barbiturate. In addition, zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inducers, such as barbiturates, may increase the clearance of zaleplon. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Propofol: (Moderate) Coadministration of zaleplon and general anesthetics may result in additive CNS depressant effects. In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. A similar interaction may occur with zaleplon and other CNS depressants including general anesthetics. If concurrent use is necessary, monitor for additive side effects. A temporary dose reduction of zaleplon should be considered following administration of general anesthetics. 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.
    Propoxyphene: (Moderate) Concomitant use of CNS depressants can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses.
    Protriptyline: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other tricyclic antidepressants. If used together, a reduction in the dose of one or both drugs may be needed.
    Pseudoephedrine; Triprolidine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Pyrilamine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Quazepam: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include benzodiazepines. If used together, a reduction in the dose of one or both drugs may be needed.
    Quetiapine: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zaleplon. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of CNS depressants than with zaleplon alone. In premarketing studies, zaleplon potentiated the CNS effects of a phenothiazine antipsychotic for at least 2 to 4 hours. Other antipsychotics may also have additive CNS effects with zaleplon.
    Ramelteon: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
    Rasagiline: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including buprenorphine, butorphanol, dronabinol, THC, nabilone, nalbuphine, and anxiolytics, sedatives, and hypnotics. Use these drugs cautiously with MAOIs; warn patients to not drive or perform other hazardous activities until they know how a particular drug combination affects them. In some cases, the dosages of the CNS depressants may need to be reduced.
    Remifentanil: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Remimazolam: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include benzodiazepines. If used together, a reduction in the dose of one or both drugs may be needed.
    Ribociclib: (Moderate) Monitor for an increase in zaleplon-related adverse reactions if coadministration with ribociclib is necessary. Zaleplon is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased zaleplon exposure by 20%.
    Ribociclib; Letrozole: (Moderate) Monitor for an increase in zaleplon-related adverse reactions if coadministration with ribociclib is necessary. Zaleplon is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased zaleplon exposure by 20%.
    Rifampin: (Moderate) Monitor for decreased efficacy of zaleplon if coadministration with rifampin is necessary. Zaleplon is a partial CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Although CYP3A4 is normally a minor metabolizing enzyme of zaleplon, multiple-dose administration of rifampin (600 mg every 24 hours for 14 days) reduced zaleplon Cmax and AUC by approximately 80%.
    Rifapentine: (Moderate) Monitor for decreased efficacy when zaleplon is coadministered with rifapentine due to decreased zaleplon exposure. Zaleplon is partially metabolized by CYP3A4; rifapentine is a strong CYP3A4 inducer. Consider using an alternative non-CYP3A4 substrate hypnotic in patients taking strong CYP3A4 inducers. Coadministration with another strong CYP3A4 inducer reduced zaleplon exposure by approximately 80%.
    Risperidone: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zaleplon. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of CNS depressants than with zaleplon alone. In premarketing studies, zaleplon potentiated the CNS effects of a phenothiazine antipsychotic for at least 2 to 4 hours. Other antipsychotics may also have additive CNS effects with zaleplon.
    Ritonavir: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as ritonavir, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Ropinirole: (Moderate) Concomitant use of ropinirole with other CNS depressants, such as zaleplon, can potentiate the sedation effects of ropinirole.
    Rotigotine: (Moderate) A reduction in the dose of anxiolytics, sedatives, hypnotics and concomitantly administered dopamine agonists with sedative properties (e.g., ropinirole, pramipexole, rotigotine, apomorphine) should be considered to minimize additive sedative effects. In addition, the risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Safinamide: (Moderate) Dopaminergic medications, including safinamide, may cause a sudden onset of somnolence which sometimes has resulted in motor vehicle accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. Because of possible additive effects, advise patients about the potential for increased somnolence during concurrent use of safinamide with other sedating medications, such as anxiolytics, sedatives, and hypnotics.
    Saquinavir: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as saquinavir, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Scopolamine: (Moderate) Scopolamine may cause dizziness and drowsiness. Concurrent use of scopolamine and CNS depressants can adversely increase the risk of CNS depression.
    Secobarbital: (Major) Coadministration of zaleplon and barbiturates may result in additive CNS depression. Caution should be exercised during concomitant use of anxiolytics, sedatives, and hypnotics and any barbiturate. In addition, zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inducers, such as barbiturates, may increase the clearance of zaleplon. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Sedating H1-blockers: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Selegiline: (Moderate) Monitor for excessive sedation and somnolence during coadministration of selegiline and anxiolytics, sedatives, and hypnotics. Concurrent use may result in additive CNS depression.
    Sevoflurane: (Moderate) Coadministration of zaleplon and general anesthetics may result in additive CNS depressant effects. In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. A similar interaction may occur with zaleplon and other CNS depressants including general anesthetics. If concurrent use is necessary, monitor for additive side effects. A temporary dose reduction of zaleplon should be considered following administration of general anesthetics. 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.
    Sodium Oxybate: (Contraindicated) 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: (Moderate) Monitor for decreased efficacy of zaleplon if coadministration with St. John's Wort is necessary. Zaleplon is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Although CYP3A4 is normally a minor metabolizing enzyme of zaleplon, coadministration with another strong CYP3A4 inducer reduced zaleplon exposure by approximately 80%. Coadministration with St. John's Wort could lead to ineffectiveness of zaleplon.
    Sufentanil: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Suvorexant: (Moderate) Use of suvorexant with other sedatives and hypnotics should generally be avoided due to duplication of treatments and due to the additive CNS depressant and complex sleep-related behaviors that may occur. While anxiolytic medications may be used concurrently with suvorexant, a reduction in dose of one or both of these agents may be needed.
    Tapentadol: (Major) Concomitant use of opioid agonists with other CNS depressants may cause excessive sedation and somnolence. Limit the use of opioid pain medications with anotehr CNS depressant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Telithromycin: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as telithromycin, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Temazepam: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include benzodiazepines. If used together, a reduction in the dose of one or both drugs may be needed.
    Tetrabenazine: (Moderate) Concurrent use of tetrabenazine and drugs that can cause CNS depression, such as anxiolytics, sedatives, and hypnotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Thalidomide: (Major) The use of anxiolytics, sedatives, or hypnotics concomitantly with thalidomide may cause an additive sedative effect and should be avoided. Thalidomide frequently causes drowsiness and somnolence. Dose reductions may be required. Patients should be instructed to avoid situations where drowsiness may be a problem and not to take other medications that may cause drowsiness without adequate medical advice. Advise patients as to the possible impairment of mental and/or physical abilities required for the performance of hazardous tasks, such as driving a car or operating other complex or dangerous machinery.
    Thiopental: (Major) Coadministration of zaleplon and barbiturates may result in additive CNS depression. Caution should be exercised during concomitant use of anxiolytics, sedatives, and hypnotics and any barbiturate. In addition, zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inducers, such as barbiturates, may increase the clearance of zaleplon. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Thiothixene: (Moderate) Coadministration of zaleplon and antipsychotics like thiothixene can result in additive CNS depressant effects. In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. A similar interaction may occur with other antipsychotics.
    Tipranavir: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as tipranavir, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Tizanidine: (Moderate) Concurrent use of tizanidine and CNS depressants such as certain sedatives or hypnotics can cause additive CNS depression. A reduction in the dose of these medications may be considered to minimize additive sedative effects, if they occur. With hypnotic medications, the risk of next-day psychomotor impairment is increased during co-administration of other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Tolcapone: (Major) Additive CNS depressant effects are possible during concurrent use of COMT inhibitors and zaleplon. If concurrent use is necessary, monitor for additive side effects. A reduction in the dose of one or both drugs may be needed. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
    Topiramate: (Major) Although not specifically studied, coadministration of CNS depressant drugs (e.g., anxiolytics, sedatives, and hypnotics) with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering.
    Tramadol: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Tramadol; Acetaminophen: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Tranylcypromine: (Moderate) The manufacturers of MAOIs contraindicate the use of MAOIs with some CNS depressant drugs due to additive CNS depressant effects. If combination therapy is necessary, use caution; warn patients to avoid driving or performing other hazardous activities until they know how the combination affects them. A dose reduction of one or both medications may be required.
    Trazodone: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include trazodone. If used together, a reduction in the dose of one or both drugs may be needed.
    Triazolam: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include benzodiazepines. If used together, a reduction in the dose of one or both drugs may be needed.
    Tricyclic antidepressants: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other tricyclic antidepressants. If used together, a reduction in the dose of one or both drugs may be needed.
    Trihexyphenidyl: (Moderate) CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase the sedative effects of trihexyphenidyl.
    Trimethobenzamide: (Moderate) The concurrent use of trimethobenzamide with other medications that cause CNS depression, like anxiolytics, sedatives and hypnotics, may potentiate the effects of either trimethobenzamide or the anxiolytics, sedatives and hypnotics.
    Trimipramine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other tricyclic antidepressants. If used together, a reduction in the dose of one or both drugs may be needed.
    Triprolidine: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include other sedating H1-blockers. If used together, a reduction in the dose of one or both drugs may be needed.
    Tucatinib: (Moderate) Monitor for an increase in zaleplon-related adverse reactions if coadministration with tucatinib is necessary. Concurrent use may increase zaleplon exposure. Zaleplon is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
    Valerian, Valeriana officinalis: (Major) Patients who are taking sedative/hypnotic drugs should generally avoid concomitant administration of valerian. 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.
    Vigabatrin: (Moderate) Vigabatrin may cause somnolence and fatigue. Drugs that can cause CNS depression, if used concomitantly with vigabatrin, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when vigabatrin is given with anxiolytics, sedatives, and hypnotics.
    Vilazodone: (Moderate) Due to the CNS effects of vilazodone, caution should be used when vilazodone is given in combination with other centrally acting medications such as anxiolytics, sedatives, and hypnotics.
    Voriconazole: (Moderate) Monitor for an increase in zaleplon-related adverse reactions if coadministration with voriconazole is necessary. Dosage adjustments should be made on an individual basis according to efficacy and tolerability. Zaleplon is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased zaleplon exposure by 20%.
    Ziconotide: (Moderate) Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects such as anxiolytics, sedatives, and hypnotics. Coadministration of CNS depressants may increase drowsiness, dizziness, and confusion that are associated with ziconotide. Patients taking sedatives with ziconotide may be at higher risk of depressed levels of consciousness. If altered consciousness occurs, consideration of sedative cessation is warranted in addition to ziconotide discontinuation.
    Ziprasidone: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zaleplon. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of CNS depressants than with zaleplon alone. In premarketing studies, zaleplon potentiated the CNS effects of a phenothiazine antipsychotic for at least 2 to 4 hours. Other antipsychotics may also have additive CNS effects with zaleplon.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no studies of zaleplon use in pregnant women; therefore, the drug is not recommended during pregnancy. Animal studies have shown no evidence of teratogenicity. However, in one pre- and postnatal development study in rats, increased stillbirth and postnatal mortality, decreased growth, and decreased physical development were observed in the offspring of females treated during the latter part of gestation and throughout lactation. These adverse effects appeared to be the result of both in utero and lactational exposure to the drug. In a separate embryofetal development study in rats, pre- and postnatal growth of the offspring were reduced at a maternally administered dose of 100 mg/kg/day. Clinical signs of maternal toxicity also occurred, as well as decreased maternal body weight gain during gestation. No adverse effects on embryofetal development have been observed in rabbits. Zaleplon has no established use in labor and obstetric delivery.

    MECHANISM OF ACTION

    Mechanism of Action: Zaleplon is an agonist at type 1 benzodiazepine (BZ1 or omega1) receptors on the GABA-A/chloride-ion channel complex within the CNS. Specifically, it has been shown that zaleplon binds selectively to the brain omega1 receptor situated on the alpha subunit of the GABA-A receptor complex. Subunit modulation of this complex is hypothesized to be responsible for some of the pharmacological properties of benzodiazepines (and possibly zaleplon). These properties include sedative, anticonvulsant, anxiolytic, and myorelaxant effects. Flumazenil, a benzodiazepine antagonist, can also antagonize the sedative actions of zaleplon. In clinical studies, there was no evidence of tolerance to zaleplon over 5 weeks of treatment.

    PHARMACOKINETICS

    Zaleplon is administered orally. Zaleplon is lipophilic and is distributed substantially into extravascular tissues. The in vitro plasma protein binding of zaleplon is approximately 60%; the drug is not sensitive to alterations in protein binding. The blood to plasma ratio for zaleplon is approximately 1 which indicates that the drug is uniformly distributed throughout the blood with no extensive distribution into red blood cells. Zaleplon is primarily metabolized by aldehyde oxidase to form 5-oxo-zaleplon. To a lesser extent, zaleplon is metabolized by CYP3A4 to form desethylzaleplon, which is quickly converted to 5-oxo-desethylzaleplon. All metabolites are inactive. Based on radiolabeled studies, approximately 70% of an administered dose is recovered in urine within 48 hours (71% recovered within 6 days), mostly as zaleplon metabolites and their glucuronides. An additional 17% is recovered in feces within 6 days, almost all as 5-oxo-zaleplon. The terminal-phase elimination half-life of zaleplon is 1 hour.
     
    Affected cytochrome P450 (CYP450) isoenzymes, other enzymes, and drug transporters: Aldehyde oxidase, CYP3A4
    Aldehyde oxidase (in vitro) and CYP3A4 (in vitro and in vivo) are the primary and secondary enzymes, respectively, responsible for zaleplon metabolism. Cimetidine, an aldehyde oxidase inhibitor and CYP3A inhibitor, will reduce the metabolism of zaleplon. CYP3A4, by itself, is a minor elimination pathway of zaleplon. However, the Cmax and AUC of zaleplon were reduced by 80% during coadministration of rifampin, a strong CYP3A4 inducer. Coadministration of zaleplon and a single dose of a moderate CYP3A4 inhibitor produced a 34% increase in Cmax and 20% increase in AUC of zaleplon. Routine dosage adjustments are not required, although patients should be monitored for a decrease in efficacy or an increase in adverse effects during concurrent use of zaleplon and potent CYP3A4 inducers or potent CYP3A4 inhibitors, respectively.

    Oral Route

    Following oral administration, the drug is rapidly and almost completely absorbed. The oral bioavailability is approximately 30% because of extensive first-pass metabolism. The onset of action is approximately 30 minutes and the duration of action is about 4 hours. Peak zaleplon serum concentrations occur in about 1 hour. Heavy, high-fat meals prolong the absorption of zaleplon compared to the fasted state. Tmax is delayed by approximately 2 hours and Cmax is reduced by about 35%. The AUC and elimination of zaleplon are not significantly affected. Accumulation of the drug does not occur with once-daily dosing and its pharmacokinetics are dose proportional in the therapeutic range. Initial dosage adjustment is recommended for those with hepatic disease, who are taking drugs that decrease zaleplon metabolism, for the elderly, and for debilitated adults.