Sonata

Non-Benzodiazepine, Benzodiazepine Receptor Agonists (NBRA)s

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.

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
corneal erosion / Delayed / 0-0.1
hearing loss / Delayed / 0-0.1
ocular hemorrhage / Delayed / 0-0.1
retinal detachment / Delayed / 0-0.1
apnea / Delayed / 0-0.1
pleural effusion / Delayed / 0-0.1
bradycardia / Rapid / 0-0.1
cyanosis / Early / 0-0.1
pericardial effusion / Delayed / 0-0.1
pulmonary embolism / Delayed / 0-0.1
ventricular tachycardia / Early / 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
colitis / Delayed / 0-1.0
esophagitis / Delayed / 0.1-1.0
gastritis / Delayed / 0.1-1.0
glossitis / Early / 0.1-1.0
melena / Delayed / 0.1-1.0
oral ulceration / Delayed / 0.1-1.0
stomatitis / Delayed / 0.1-1.0
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
cystitis / Delayed / 0.1-1.0
dysuria / Early / 0.1-1.0
hematuria / Delayed / 0.1-1.0
impotence (erectile dysfunction) / Delayed / 0.1-1.0
nephrolithiasis / Delayed / 0.1-1.0
urinary incontinence / Early / 0.1-1.0
vaginitis / Delayed / 0.1-1.0
gout / Delayed / 0.1-1.0
hypercholesterolemia / Delayed / 0.1-1.0
peripheral edema / Delayed / 0-1.0
angina / Early / 0.1-1.0
bundle-branch block / Early / 0.1-1.0
hypertension / Early / 0.1-1.0
hypotension / Rapid / 0.1-1.0
palpitations / Early / 0.1-1.0
peripheral vasodilation / Rapid / 0.1-1.0
sinus tachycardia / Rapid / 0.1-1.0
anemia / Delayed / 0.1-1.0
lymphadenopathy / Delayed / 0.1-1.0
cholelithiasis / Delayed / 0-0.1
dysphagia / Delayed / 0-0.1
elevated hepatic enzymes / Delayed / 0-0.1
teeth grinding (bruxism) / 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
proteinuria / Delayed / 0-0.1
urinary retention / Early / 0-0.1
vaginal bleeding / Delayed / 0-0.1
hyperbilirubinemia / Delayed / 0-0.1
hyperglycemia / Delayed / 0-0.1
hyperuricemia / Delayed / 0-0.1
hypoglycemia / Early / 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
tongue discoloration / Delayed / 0.1-1.0
appetite stimulation / Delayed / 0.1-1.0
eructation / Early / 0.1-1.0
flatulence / Early / 0.1-1.0
gingivitis / 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
otalgia / Early / 0-1.0
diplopia / Early / 0.1-1.0
tinnitus / Delayed / 0.1-1.0
xerophthalmia / Early / 0.1-1.0
acne vulgaris / Delayed / 0.1-1.0
alopecia / Delayed / 0.1-1.0
hyperhidrosis / Delayed / 0.1-1.0
maculopapular rash / Early / 0.1-1.0
urticaria / Rapid / 0.1-1.0
xerosis / Delayed / 0.1-1.0
photosensitivity / Delayed / 0-1.0
epistaxis / Delayed / 0-1.0
laryngitis / Delayed / 0.1-1.0
arthropathy / Delayed / 0.1-1.0
increased urinary frequency / Early / 0.1-1.0
mastalgia / Delayed / 0.1-1.0
menorrhagia / 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
leukorrhea / Delayed / 0-0.1
menstrual irregularity / Delayed / 0-0.1
lactose intolerance / Early / 0-0.1
weight loss / Delayed / 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
pruritus / Rapid / 1.0
rash / Early / 1.0
arthralgia / Delayed / 1.0
myalgia / Early / 1.0
nightmares / Early / Incidence not known
abnormal dreams / Early / Incidence not known
insomnia / Early / Incidence not known

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]

Sonata

Rx, schedule IV

Short-acting non-benzodiazepine sedative-hypnotic
Approved for short-term treatment of insomnia; shown to decrease time to sleep onset in clinical trials
Risk of complex sleep behaviors, CNS-depressant effects, and next-day impairment; patients should be informed of risks prior to treatment initiation

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.

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.

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; Aspirin; Diphenhydramine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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; Pyrilamine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary. (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) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Acrivastine; Pseudoephedrine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Adagrasib: (Moderate) Monitor for an increase in zaleplon-related adverse reactions, including excessive sedation and confusion, if coadministered with adagrasib. Routine dosage adjustments of zaleplon are not required. Zaleplon is partially metabolized by CYP3A. Adagrasib is a strong CYP3A inhibitor. Coadministration with a single dose of another strong CYP3A inhibitor increased the AUC of zaleplon by 20%.
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: (Major) Monitor for excessive sedation and somnolence during coadministration of zaleplon and benzodiazepines. Concurrent use may result in additive CNS depression. If used together, a reduction in the dose of one or both drugs may be needed.
Amitriptyline: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of tricyclic antidepressants and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary. Coadministration of single doses of a tricyclic antidepressant and zaleplon produced additive effects on decreased alertness and impaired psychomotor performance for 2 to 4 hours after administration.
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) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Asenapine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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; 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; 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) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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 coadministration 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; 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: (Major) Monitor for excessive sedation and somnolence during coadministration of zaleplon and benzodiazepines. Concurrent use may result in additive CNS depression. 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) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Brompheniramine; Phenylephrine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Brompheniramine; Pseudoephedrine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Buprenorphine: (Major) Reserve concomitant prescribing of buprenorphine and zaleplon for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. Gradually tapering a patient off other CNS depressants or decreasing to the lowest effective dose is preferred in most cases of patients being treated for opioid use disorder. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Buprenorphine; Naloxone: (Major) Reserve concomitant prescribing of buprenorphine and zaleplon for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. Gradually tapering a patient off other CNS depressants or decreasing to the lowest effective dose is preferred in most cases of patients being treated for opioid use disorder. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Buspirone: (Moderate) The combination of buspirone and other CNS depressants, such as sedative hypnotics including zaleplon, may increase the risk for drowsiness or sedation. Because the effects of the use of buspirone with most other psychotropic drugs have not been studied, the concomitant use of buspirone with other CNS-active drugs should be approached with caution.
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.
Butalbital; Aspirin; 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 when zaleplon is coadministered with carbamazepine due to decreased zaleplon exposure. Zaleplon is partially metabolized by CYP3A4; carbamazepine 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%.
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) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Cariprazine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Carisoprodol: (Moderate) Carisoprodol can cause additive CNS depression if used concomitantly with other CNS depressants.
Celecoxib; 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.
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) Monitor for unusual drowsiness and sedation during coadministration of cetirizine and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Cetirizine; Pseudoephedrine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of cetirizine and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Chlophedianol; Dexbrompheniramine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Chlordiazepoxide: (Major) Monitor for excessive sedation and somnolence during coadministration of zaleplon and benzodiazepines. Concurrent use may result in additive CNS depression. If used together, a reduction in the dose of one or both drugs may be needed.
Chlordiazepoxide; Amitriptyline: (Major) Monitor for excessive sedation and somnolence during coadministration of zaleplon and benzodiazepines. Concurrent use may result in additive CNS depression. If used together, a reduction in the dose of one or both drugs may be needed. (Moderate) Monitor for unusual drowsiness and sedation during coadministration of tricyclic antidepressants and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary. Coadministration of single doses of a tricyclic antidepressant and zaleplon produced additive effects on decreased alertness and impaired psychomotor performance for 2 to 4 hours after administration.
Chlordiazepoxide; Clidinium: (Major) Monitor for excessive sedation and somnolence during coadministration of zaleplon and benzodiazepines. Concurrent use may result in additive CNS depression. If used together, a reduction in the dose of one or both drugs may be needed.
Chlorpheniramine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Chlorpheniramine; Dextromethorphan: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Chlorpheniramine; Phenylephrine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Chlorpheniramine; Pseudoephedrine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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. Concomitant administration of cimetidine 800 mg with zaleplon 10 mg resulted in an 85% increase in the Cmax and AUC of zaleplon. 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) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Clobazam: (Moderate) Concomitant administration of clobazam with other CNS depressant drugs including sedatives and hypnotics, can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent.
Clomipramine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of tricyclic antidepressants and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary. Coadministration of single doses of a tricyclic antidepressant and zaleplon produced additive effects on decreased alertness and impaired psychomotor performance for 2 to 4 hours after administration.
Clonazepam: (Major) Monitor for excessive sedation and somnolence during coadministration of zaleplon and benzodiazepines. Concurrent use may result in additive CNS depression. If used together, a reduction in the dose of one or both drugs may be needed.
Clorazepate: (Major) Monitor for excessive sedation and somnolence during coadministration of zaleplon and benzodiazepines. Concurrent use may result in additive CNS depression. If used together, a reduction in the dose of one or both drugs may be needed.
Clozapine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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.
Daridorexant: (Major) Use of daridorexant 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 daridorexant, a reduction in dose of one or both agents may be needed.
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.
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) Monitor for unusual drowsiness and sedation during coadministration of tricyclic antidepressants and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary. Coadministration of single doses of a tricyclic antidepressant and zaleplon produced additive effects on decreased alertness and impaired psychomotor performance for 2 to 4 hours after administration.
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) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Dexbrompheniramine; Pseudoephedrine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Dexchlorpheniramine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Diazepam: (Major) Monitor for excessive sedation and somnolence during coadministration of zaleplon and benzodiazepines. Concurrent use may result in additive CNS depression. 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.
Difelikefalin: (Moderate) Monitor for dizziness, somnolence, mental status changes, and gait disturbances if concomitant use of difelikefalin with CNS depressants is necessary. Concomitant use may increase the risk for these adverse reactions.
Dimenhydrinate: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Diphenhydramine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Diphenhydramine; Ibuprofen: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Diphenhydramine; Naproxen: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Diphenhydramine; Phenylephrine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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) Monitor for unusual drowsiness and sedation during coadministration of tricyclic antidepressants and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary. Coadministration of single doses of a tricyclic antidepressant and zaleplon produced additive effects on decreased alertness and impaired psychomotor performance for 2 to 4 hours after administration.
Doxylamine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Doxylamine; Pyridoxine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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 de

crease 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.
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) Monitor for an increase in zaleplon-related adverse effects if concomitant use with erythromycin is necessary. Concomitant use has been observed to increase zaleplon concentrations which may increase the risk for adverse effects. Coadministration of single oral doses of erythromycin 800 mg and zaleplon 10 mg resulted in a 34% increase in zaleplon peak concentrations and a 20% increase in zaleplon exposure. Zaleplon is a CYP3A substrate and erythromycin is a CYP3A inhibitor.
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: (Major) Monitor for excessive sedation and somnolence during coadministration of zaleplon and benzodiazepines. Concurrent use may result in additive CNS depression. 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 alcohol 0.75 g/kg on balance testing and reaction time for 1 hour after alcohol 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 alcohol administration. The potentiation resuls from a CNS pharmacodynamic interaction; zaleplon did not affect the pharmacokinetics of alcohol.
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.
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: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation and somnolence. 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. 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: (Major) Monitor for excessive sedation and somnolence during coadministration of zaleplon and benzodiazepines. Concurrent use may result in additive CNS depression. 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. (Major) Advise patients to avoid cannabis use while taking CNS depressants due to the risk for additive CNS depression and potential for other cognitive adverse reactions.
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 when zaleplon is coadministered with fosphenytoin due to decreased zaleplon exposure. Zaleplon is partially metabolized by CYP3A; phenytoin is a strong CYP3A inducer. Consider using an alternative non-CYP3A substrate hypnotic in patients taking strong CYP3A inducers. Coadministration with another strong CYP3A inducer reduced zaleplon exposure by approximately 80%.
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.
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.
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; 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) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Imipramine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of tricyclic antidepressants and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary. Coadministration of single doses of a tricyclic antidepressant and zaleplon produced additive effects on decreased alertness and impaired psychomotor performance for 2 to 4 hours after administration.
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) Monitor for unusual drowsiness and sedation during coadministration of anxiolytics, sedatives, and hypnotics and monoamine oxidase inhibitors (MAOIs) due to the risk for additive CNS depression.
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) Monitor for an increase in zaleplon-related adverse reactions, including excessive sedation and confusion, if coadministered with ketoconazole. Routine dosage adjustments of zaleplon are not required. CYP3A4 is a minor metabolic pathway for zaleplon elimination as sum of desethylzaleplon (formed via CYP3A4) and its metabolites (5-oxo-desethylzaleplon and 5-oxo-desethylzaleplon glucuronide) account for only 9% of the urinary recovery of a zaleplon dose. Use of a strong, selective CYP3A4 inhibitor produced a 34% increase in zaleplon's Cmax and a 20% increase in the exposure. Other strong selective CYP3A4 inhibitors such as ketoconazole can be expected to have similar effects.
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) Monitor for unusual drowsiness and sedation during coadministration of cetirizine and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Levoketoconazole: (Moderate) Monitor for an increase in zaleplon-related adverse reactions, including excessive sedation and confusion, if coadministered with ketoconazole. Routine dosage adjustments of zaleplon are not required. CYP3A4 is a minor metabolic pathway for zaleplon elimination as sum of desethylzaleplon (formed via CYP3A4) and its metabolites (5-oxo-desethylzaleplon and 5-oxo-desethylzaleplon glucuronide) account for only 9% of the urinary recovery of a zaleplon dose. Use of a strong, selective CYP3A4 inhibitor produced a 34% increase in zaleplon's Cmax and a 20% increase in the exposure. Other strong selective CYP3A4 inhibitors such as ketoconazole can be expected to have similar effects.
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: (Major) Monitor for excessive sedation and somnolence during coadministration of zaleplon and benzodiazepines. Concurrent use may result in additive CNS depression. 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) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Lurasidone: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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.
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.
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: (Major) Monitor for excessive sedation and somnolence during coadministration of zaleplon and benzodiazepines. Concurrent use may result in additive CNS depression. If used together, a reduction in the dose of one or both drugs may be needed.
Mifepristone: (Moderate) Monitor for an increase in zaleplon-related adverse reactions, including excessive sedation and confusion, if coadministered with mifepristone. Routine dosage adjustments of zaleplon are not required. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown. Zaleplon is partially metabolized by CYP3A. Mifepristone is a strong CYP3A inhibitor. Coadministration with a single dose of another strong CYP3A inhibitor increased the AUC of zaleplon by 20%.
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 anxiolytics, sedatives, and hypnotics.
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) Monitor for unusual drowsiness and sedation during coadministration of anxiolytics, sedatives, and hypnotics and monoamine oxidase inhibitors (MAOIs) due to the risk for additive CNS depression.
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) Monitor for unusual drowsiness and sedation during coadministration of tricyclic antidepressants and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary. Coadministration of single doses of a tricyclic antidepressant and zaleplon produced additive effects on decreased alertness and impaired psychomotor performance for 2 to 4 hours after administration.
Olanzapine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Olanzapine; Fluoxetine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Olanzapine; Samidorphan: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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.
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: (Major) Monitor for excessive sedation and somnolence during coadministration of zaleplon and benzodiazepines. Concurrent use may result in additive CNS depression. If used together, a reduction in the dose of one or both drugs may be needed.
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) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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) Monitor for unusual drowsiness and sedation during coadministration of tricyclic antidepressants and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary. Coadministration of single doses of a tricyclic antidepressant and zaleplon produced additive effects on decreased alertness and impaired psychomotor performance for 2 to 4 hours after administration.
Phenelzine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of anxiolytics, sedatives, and hypnotics and monoamine oxidase inhibitors (MAOIs) due to the risk for additive CNS depression.
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: (Moderate) 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 when zaleplon is coadministered with phenytoin due to decreased zaleplon exposure. Zaleplon is partially metabolized by CYP3A; phenytoin is a strong CYP3A inducer. Consider using an alternative non-CYP3A substrate hypnotic in patients taking strong CYP3A inducers. Coadministration with another strong CYP3A inducer reduced zaleplon exposure by approximately 80%.
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.
Protriptyline: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of tricyclic antidepressants and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary. Coadministration of single doses of a tricyclic antidepressant and zaleplon produced additive effects on decreased alertness and impaired psychomotor performance for 2 to 4 hours after administration.
Pseudoephedrine; Triprolidine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Pyrilamine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Quazepam: (Major) Monitor for excessive sedation and somnolence during coadministration of zaleplon and benzodiazepines. Concurrent use may result in additive CNS depression. If used together, a reduction in the dose of one or both drugs may be needed.
Quetiapine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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: (Major) Monitor for excessive sedation and somnolence during coadministration of zaleplon and benzodiazepines. Concurrent use may result in additive CNS depression. 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) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Selegiline: (Moderate) Monitor for excessive sedation and somnolence during coadministration of selegiline with 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/ineffectiveness 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%. An alternative non-CYP3A4 substrate hypnotic agent may be considered in patients taking strong CYP3A4 inducers.
Stiripentol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of stiripentol and zaleplon. CNS depressants can potentiate the effects of stiripentol.
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.
Temazepam: (Major) Monitor for excessive sedation and somnolence during coadministration of zaleplon and benzodiazepines. Concurrent use may result in additive CNS depression. 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.
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) Monitor for excessive sedation and somnolence during coadministration of tizanidine with anxiolytics, sedatives, and hypnotics. Concurrent use may result in 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: (Moderate) 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) Monitor for unusual drowsiness and sedation during coadministration of anxiolytics, sedatives, and hypnotics and monoamine oxidase inhibitors (MAOIs) due to the risk for additive CNS depression.
Trazodone: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of zaleplon and other CNS depressants, such as trazodone, due to the risk for additive CNS depression and next-day psychomotor impairment; dosage adjustments may be necessary.
Triazolam: (Major) Monitor for excessive sedation and somnolence during coadministration of zaleplon and benzodiazepines. Concurrent use may result in additive CNS depression. If used together, a reduction in the dose of one or both drugs may be needed.
Tricyclic antidepressants: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of tricyclic antidepressants and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary. Coadministration of single doses of a tricyclic antidepressant and zaleplon produced additive effects on decreased alertness and impaired psychomotor performance for 2 to 4 hours after administration.
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) Monitor for unusual drowsiness and sedation during coadministration of tricyclic antidepressants and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary. Coadministration of single doses of a tricyclic antidepressant and zaleplon produced additive effects on decreased alertness and impaired psychomotor performance for 2 to 4 hours after administration.
Triprolidine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
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.
Vonoprazan; 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.
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) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.

Sonata/Zaleplon Oral Cap: 5mg, 10mg

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.

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. Nonspecific subunit modulation of this complex is also hypothesized to be responsible for some pharmacological properties of benzodiazepines, including sedative, anticonvulsant, anxiolytic, and myorelaxant effects. However, zaleplon demonstrates higher affinity for the alpha1 subunit and lower affinity for alpha2 and alpha3 subunits, making it more selective for sedative and hypnotic effects while also showing less activity as an anxiolytic than benzodiazepines.

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.

Pregnancy

The use of zaleplon during pregnancy is not recommended by the manufacturer due to a lack of safety data; in preclinical animal studies high doses were associated with adverse effects on female (but not male) fertility, stillbirth, decreased pup growth, and delayed development in rats. Hypnotic benzodiazepine receptor agonists (HBRA) like zaleplon have been shown to cross the human placenta and rapidly clear the fetal circulation. In a small study examining data from the Swedish Medical Birth Registry, the birth outcomes for 32 infants who were exposed to zaleplon in early pregnancy were compared to nonexposed infants. In this study, the use of zaleplon was not associated with an increased risk for congenital malformations. While 4 cases of intestinal malformations were reported in infants exposed to other HBRA medications, there were no reports of these effects with zaleplon use. The authors noted the presence of several potential confounders, such as exposure to other medications, smoking status, and maternal age, that may have contributed to these malformations. Published studies of other HBRAs used during pregnancy do not indicate an increased risk of congenital malformations at typical doses. However, one study has reported neural tube defects in an infant following high-dose exposure to an HBRA (zolpidem) in the first trimester of pregnancy. In a systematic review and meta-analysis developed to assess for risks associated with use of HBRAs in pregnancy, the authors noted that pregnancy exposure to HBRAs was not associated with an increased risk of congenital malformations but was associated with increased risks of preterm birth, low birth weight, and being small for gestational age compared to unexposed infants. Similarly, a population-based cohort study determined that HBRA use in early pregnancy may be associated with an increased risk of infants being born small for gestational age, even after controlling for numerous confounding variables. Additional studies are needed to determine the true risk and incidence of these effects. The risk of zaleplon in pregnancy should be carefully weighed against the risk of untreated sleep disorders in the pregnant patient. Zaleplon has no established use in labor and obstetric delivery.