Complex sleep behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake may occur following the use of zolpidem. Some of these events may result in serious injuries, including death. Discontinue zolpidem immediately if a patient experiences a complex sleep behavior.
Insomnia:
Note: Limit long-term use (>4 weeks) to cases for which nonpharmacologic treatments are not available or not effective and benefits are felt to outweigh risks (ACP [Qaseem 2016]; ESRS [Riemann 2017]). Use of the higher dose can increase the risk of next-day impairment of driving and activities requiring full alertness.
Sleep-onset insomnia:
ER tablet: Oral: Initial: 6.25 mg (females) or 6.25 to 12.5 mg (males) immediately before bedtime with ≥7 to 8 hours of planned sleep before waking. Use lowest effective dose, not to exceed 12.5 mg.
IR tablet, spray, sublingual tablet: Oral: Initial: 5 mg (females) or 5 to 10 mg (males) immediately before bedtime with ≥7 to 8 hours of planned sleep before waking. Use lowest effective dose, not to exceed 10 mg.
Sleep-maintenance insomnia, 7 to 8 hours planned sleep:
ER tablet: Oral: Initial: 6.25 mg (females) or 6.25 to 12.5 mg (males) immediately before bedtime with ≥7 to 8 hours of planned sleep before waking. Use lowest effective dose, not to exceed 12.5 mg.
IR tablet, spray, sublingual tablet (off-label use): Oral: Initial: 5 mg (females) or 5 to 10 mg (males) immediately before bedtime with ≥7 to 8 hours of planned sleep before waking. Use lowest effective dose, not to exceed 10 mg.
Sleep-maintenance insomnia, awakening with 4 hours planned sleep: IR sublingual tablet: Oral: 1.75 mg (females) or 1.75 to 3.5 mg (males) once per night upon awakening in the middle of the night with ≥4 hours of planned sleep remaining.
Discontinuation of therapy: Reduce by the smallest available dosage form every week or every other week; ER tablets cannot be split. For patients taking higher doses of zolpidem (eg, 10 to 12.5 mg/day) for an extended period, tapering zolpidem even more slowly in conjunction with cognitive behavioral therapy for insomnia is encouraged (Bélanger 2009). Because the ER tablets cannot be split, the taper is generally done with IR tablets.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: No dosage adjustment necessary for any degree of kidney dysfunction (Fillastre 1993; manufacturer's labeling).
Hemodialysis, intermittent (thrice weekly): Not significantly dialyzed (Fillastre 1993; manufacturer's labeling): No supplemental dose or dosage adjustment necessary (expert opinion).
Peritoneal dialysis: Unlikely to be significantly dialyzed: No dosage adjustment necessary (expert opinion).
ER tablet:
Mild to moderate impairment: 6.25 mg immediately before bedtime.
Severe impairment: Avoid use.
IR tablet:
Mild to moderate impairment: 5 mg immediately before bedtime.
Severe impairment: Avoid use.
Oral spray: 5 mg immediately before bedtime.
Sublingual tablet:
Edluar: 5 mg immediately before bedtime.
Intermezzo: Females and males: 1.75 mg once per night as needed. Note: Take in bed only if ≥4 hours left before waking and there is difficulty in returning to sleep.
Sublinox [Canadian product]:
Mild to moderate impairment: 5 mg immediately before bedtime.
Severe impairment: Use is contraindicated.
(For additional information see "Zolpidem: Pediatric drug information")
Note: The lowest effective dose should be used; higher doses may be more likely to impair next-morning activities.
Insomnia:
Children and Adolescents ≤17 years: Limited data available; efficacy results variable and have not been demonstrated in randomized placebo-controlled trials (Anand 2017). Oral: Immediate-release tablets: Usual reported dose: 0.25 mg/kg at bedtime; maximum dose: 10 mg/dose (Blumer 2008; Blumer 2009; Hanna 2018); dosing based on reported experience from an open-label, dose escalation pharmacokinetic evaluation showed zolpidem was well-tolerated in pediatric patients 2 to 18 years of age and recommended a dose of 0.25 mg/kg at bedtime for evaluation in future efficacy trials (Blumer 2008). However, zolpidem has not been shown to be effective in a randomized placebo-controlled trial (n=201) of children aged 6 to 17 years with ADHD-associated insomnia; zolpidem 0.25 mg/kg/dose (maximum dose: 10 mg) administered nightly did not decrease sleep latency; in addition, hallucinations occurred in 7.4% of patients (Blumer 2009). A comparative, randomized controlled trial of zolpidem and haloperidol in pediatric burn patients (n=40, mean age: 9.4 ± 0.7 years) showed zolpidem dosed at 0.5 mg/kg nightly for 1 week (maximum dose: 20 mg) minimally increased Stage 3/4 sleep and REM but not total sleep time; the authors no longer use zolpidem to try to improve sleep in their pediatric burn patients (Armour 2008). A retrospective study compared effectiveness of zolpidem (no dose noted in study) in pediatric burn patients (n=46, mean age: 11 ± 3.7 years) with and without ADHD and found that sleep dysfunction was similar between the groups and those with ADHD required a sleep medication change sooner, concluding that zolpidem was not an effective drug in managing sleep in pediatric burn patients with or without ADHD (Cronin 2015). A prospective, randomized double-blind clinical trial of children between ages 2 to 9 years reported that zolpidem at 0.25 mg/kg (maximum dose: 10 mg/dose) was similar to midazolam with regards to anxiety scoring and inferior with regard to mask acceptance score when used as premedication for perioperative anxiety (Hanna 2018).
Adolescents ≥18 years (non-debilitated patients): Note: The lowest effective dose should be used; higher doses may be more likely to impair next morning activities.
Oral:
Immediate-release tablet (eg, Ambien), spray (Zolpimist): 5 mg (females) or 5 to 10 mg (males) immediately before bedtime; maximum dose: 10 mg/dose.
Extended-release tablet (eg, Ambien CR): 6.25 mg (females) or 6.25 to 12.5 mg (males) immediately before bedtime; maximum dose: 12.5 mg/dose.
Sublingual tablet:
Edluar: 5 mg (females) or 5 to 10 mg (males) immediately before bedtime; maximum daily dose: 10 mg/day.
Intermezzo: Note: Should be taken if patient awakens in middle of night, has difficulty returning to sleep, and has at least 4 hours left before waking.
Females: 1.75 mg once per night as needed; maximum dose: 1.75 mg/night.
Males: 3.5 mg once per night as needed; maximum dose: 3.5 mg/night.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no pediatric-specific recommendations; based on experience in adult patients, no adjustment may be necessary.
Hemodialysis: Not dialyzable.
Adolescents ≥ 18 years:
Immediate-release tablet:
Mild to moderate impairment: 5 mg immediately before bedtime
Severe impairment: Avoid use
Extended-release tablet:
Mild to moderate impairment: 6.25 mg immediately before bedtime
Severe impairment: Avoid use
Oral spray: 5 mg immediately before bedtime
Sublingual tablet:
Edluar: 5 mg immediately before bedtime
Intermezzo: Females and males: 1.75 mg once per night as needed. Note: Take in bed only if ≥4 hours left before waking and there is difficulty in returning to sleep.
Avoid use (Beers Criteria [AGS 2019]).
Discontinuation of therapy: Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, Oral, as tartrate:
Zolpimist: 5 mg/actuation (4.5 mL [DSC], 7.7 mL [DSC]) [contains benzoic acid, propylene glycol]
Zolpimist: 5 mg/actuation (4.5 mL, 7.7 mL) [contains benzoic acid, propylene glycol; cherry flavor]
Tablet, Oral, as tartrate:
Ambien: 5 mg [contains fd&c red #40 (allura red ac dye), polysorbate 80]
Ambien: 10 mg
Generic: 5 mg, 10 mg
Tablet Extended Release, Oral, as tartrate:
Ambien CR: 6.25 mg
Ambien CR: 12.5 mg [contains fd&c blue #2 (indigotine)]
Generic: 6.25 mg, 12.5 mg
Tablet Sublingual, Sublingual, as tartrate:
Edluar: 5 mg, 10 mg [contains saccharin sodium]
Intermezzo: 1.75 mg [DSC]
Generic: 1.75 mg, 3.5 mg
May be product dependent
Zolpimist oral spray 4.5 mL containers contain 30 actuations and 7.7 mL containers contain 60 actuations.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet Sublingual, Sublingual, as tartrate:
Sublinox: 5 mg, 10 mg [contains saccharin sodium]
Generic: 5 mg, 10 mg
C-IV
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Ambien: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/019908s40s044s047lbl.pdf#page=24
Ambien CR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/021774s021s025s028lbl.pdf#page=27
Edluar: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021997s011lbl.pdf#page=23
Intermezzo: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022328s008lbl.pdf#page=20
Zolpidem tablets: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/Zolpidem.pdf
Zolpimist: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022196s012lbl.pdf#page=19
Oral: Administer immediately before bedtime due to rapid onset of action. Regardless of dosage form, do not administer with or immediately after a meal (may delay onset). With the exception of Intermezzo, zolpidem should be taken as a single dose at bedtime with at least 7 to 8 hours remaining before planned time of awakening and should not be readministered during the same night. Intermezzo should be taken in bed if patient awakes in the middle of the night (ie, if ≥4 hours left before waking) and there is difficulty in returning to sleep.
ER tablet: Swallow tablet whole; do not divide, crush, or chew.
Bariatric surgery: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. IR tablet, sublingual tablet, and oral spray formulations are available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery.
Sublingual tablet: Place sublingual tablet under the tongue and allow to disintegrate; do not swallow or administer Edluar or Sublinox with water.
Oral spray: Spray directly into the mouth over the tongue. Prior to initial use, prime pump by spraying 5 times. If pump is not used for at least 14 days, reprime pump with 1 spray.
Oral:
All formulations: Regardless of dosage form, do not administer with or immediately after a meal (may delay onset). With the exception of Intermezzo, zolpidem should be taken as a single dose immediately before bedtime (due to rapid onset) with at least 7 to 8 hours remaining before planned time of awakening and should not be readministered during the same night. Intermezzo should be taken in bed if patient awakens in the middle of the night (ie, if ≥4 hours left before waking) and there is difficulty in returning to sleep.
Extended-release tablets (Ambien CR): Swallow whole; do not divide, crush, or chew.
Sublingual tablets (Edluar, Intermezzo): Examine blisterpack before use; do not use if blisters are broken, torn, or missing. Separate individual blisters at perforation; peel off top layer of paper; push tablet through foil. Place under the tongue and allow to disintegrate; do not swallow or administer with water.
Oral spray (Zolpimist): Spray directly into the mouth over the tongue. Prior to initial use, pump should be primed by spraying 5 times. If pump is not used for at least 14 days, reprime pump with 1 spray.
Insomnia:
IR and sublingual tablets (Edluar only) and oral spray: Short-term treatment of insomnia with difficulty of sleep onset.
ER tablet: Short-term treatment of insomnia with difficulty of sleep onset and/or sleep maintenance.
Sublingual tablet (Intermezzo only): As-needed treatment of insomnia when middle-of-the-night awakening is followed by difficulty returning to sleep and the patient has ≥4 hours of sleep time remaining.
Sublingual tablet (Sublinox only [Canadian product]): Short-term treatment of insomnia (with difficulty of sleep onset, frequent awakenings, and/or early awakenings).
Ambien may be confused with Abilify, Ativan, Ambi 10
Sublinox may be confused with Suboxone
Zolpidem may be confused with lorazepam, zaleplon, Zyloprim
Beers Criteria: Zolpidem, a nonbenzodiazepine benzodiazepine-receptor agonist hypnotic, is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older (independent of diagnosis or condition) due to adverse events similar to benzodiazepines in older adults (eg, delirium, falls, fractures) and an increase in emergency room visits, hospitalizations, and motor vehicle crashes. In addition, improvement in sleep latency and duration is minimal (Beers Criteria [AGS 2019]).
Pharmacy Quality Alliance (PQA): Zolpidem (when cumulative day supply is >90 days) is identified as a high-risk medication in patients 65 years and older on the PQA’s, Use of High-Risk Medications in the Elderly (HRM) performance measure, a safety measure used by the Centers for Medicare and Medicaid Services (CMS) for Medicare plans (PQA 2017).
Ambien [US, Argentina, Israel] may be confused with Amyben brand name for amiodarone [Great Britain]
Sedative-hypnotic agents, including zolpidem, are associated with next-day drowsiness, and decreased mental alertness (Ref). In patients taking zolpidem, these effects have led to impaired driving, accidental injury, and trauma, such as motor vehicle accidents, falling, bone fracture (including femoral neck fracture), and intracranial injuries (Ref). Patients may feel fully awake, despite this impairment in mental alertness. Zolpidem is included in the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults (Ref).
Mechanism: Serum concentration-related; related to the pharmacologic action (ie, sedative-hypnotic effects).
Onset: Rapid; occurs within 24 hours after dose; may occur after the first dose (Ref).
Risk factors:
• Conditions or states leading to increased serum concentrations (eg, age ≥65 years, females) (Ref)
• Concurrent CNS depressants (eg, medications, alcohol)
• Concurrent drugs that increase zolpidem concentrations (eg, CYP 3A4 inhibitors)
• Extended-release formulation (Ref)
• Sleeping less than 7 to 8 hours after zolpidem administration
Complex sleep-related disorder may occur, including somnambulism, and eating, driving, cooking, and having sex while sleeping have been reported (Ref). Patients usually have no recollection of these sleep-related behaviors (Ref). In some cases, these behaviors led to serious injury or death (Ref). Non-fatal effects were reversible upon drug discontinuation (Ref).
Mechanism: Dose-related; idiosyncratic (Ref).
Onset: Varied; typically occurs 30 minutes after a single dose (Ref). May occur after years of therapy (Ref).
Risk factors:
• Dose: May occur at any dose; more likely with higher doses (Ref)
• Females (Ref)
• Concurrent use of serotonergic antidepressants (Ref)
• Concurrent use of alcohol or CNS depressants (Ref)
• Concurrent use of CYP3A4 inhibitors (Ref)
• Preexisting sleep disorder (eg, obstructive sleep apnea, restless leg syndrome) (Ref)
• Administration earlier than immediately before sleep (Ref)
• Substance use disorder (Ref)
Various other psychiatric and behavioral effects (aside from complex sleep-related disorder; see above for more information) have been reported, including hallucination (visual and auditory), delirium, abnormality in thinking, increased aggressive behavior, disinhibition, bizarre behavior, agitation, amnesia, anxiety, and worsening of depression in pediatric and adult patients (Ref). These effects have occurred unpredictably in patients with and without previously diagnosed psychiatric illness or risk factors. Hallucination was reported more frequently with zolpidem than placebo in pediatric patients treated for insomnia associated with attention-deficit/hyperactivity disorder (ADHD) (Ref). These effects were reversible upon discontinuation (Ref).
Mechanism: Dose-related; idiosyncratic (Ref).
Onset: Varied; typically occurs within 15 to 30 minutes after initial dose (Ref).
Risk factors:
• Dose: May occur at any dose; more likely with higher doses (Ref)
• Females (Ref)
• Age ≥65 years (Ref)
• Concurrent psychoactive medications (eg, SSRIs, opioids, other anti-anxiety or insomnia medications) (Ref)
• Concurrent alcohol (Ref)
• Concurrent ADHD, neurodevelopmental disorder, or other underlying psychiatric illness (Ref)
• Substance use disorder (Ref)
Suicidal ideation and suicidal tendencies have occurred in patients with and without previously diagnosed psychiatric illness (Ref). May be related to zolpidem-induced “dream-like” confusion, bizarre behavior, hallucination, or paranoia (Ref). Some reports have been connected to complex sleep-related disorder (see above for more information) (Ref).
Mechanism: Dose-related; idiosyncratic (Ref).
Onset: Intermediate; typically occurs within the first 7 days of therapy (Ref).
Risk factors:
• Dose: May occur at any dose; more likely with higher doses (Ref)
• History of psychiatric illness (eg, anxiety, bipolar disorder, depression, schizophrenia) (Ref)
• Concurrent alcohol or illicit drug use (Ref)
Withdrawal symptoms following discontinuation of GABA-mediate (GABAergic) medications are generally mild and infrequent (Ref). Transient rebound sleep disturbances (eg, longer sleep-onset latency and increased awakenings) may occur for 1 to 2 days after discontinuation (Ref). Less commonly, a withdrawal syndrome, with symptoms including abdominal cramps, anxiety, disorientation, dysphoria, insomnia, irritability, muscle cramps, restlessness, seizures, sweating, tremor, and vomiting may occur, especially after rapid dose decreases or abrupt discontinuation of chronic supratherapeutic doses (Ref). Withdrawal syndrome symptoms generally resolve within a few weeks of drug discontinuation or with resumption of therapy (Ref).
Mechanism: Withdrawal; long-term therapy induces changes in the GABAA benzodiazepine receptor that decrease the effects of endogenous GABA after drug discontinuation (Ref). Chronic use of supratherapeutic zolpidem doses may result in loss of receptor selectivity and benzodiazepine-like drug effects (Ref). Therefore, rapid dose decreases or abrupt discontinuation may mimic benzodiazepine withdrawal.
Onset: Rapid; typically occurs within 48 hours of rapid dose decrease or abrupt drug discontinuation (Ref).
Risk factor:
• Chronic administration of supratherapeutic doses (eg, >100 mg/day for months to years) (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. As reported with oral administration, unless otherwise noted.
>10%: Nervous system: Dizziness (1% to 12%) (Blumer 2009), drowsiness (2% to 15%) (table 1) , headache (oral: 7% to 19%; sublingual: 3%)
Drug (Zolpidem) |
Placebo |
Dose |
Dosage Form |
Number of Patients (Zolpidem) |
Number of Patients (Placebo) |
---|---|---|---|---|---|
15% |
2% |
12.5 mg |
Extended-release oral |
102 |
110 |
8% |
5% |
≤10 mg |
Immediate-release oral |
152 |
161 |
2% |
0% |
≤10 mg |
Immediate-release oral |
685 |
473 |
1% to 10%:
Cardiovascular: Chest discomfort (1%), chest pain (1%), edema (≤1%), hypertension (≤1%), increased blood pressure (1%), orthostatic hypotension (≤1%), palpitations (2%), syncope (≤1%), tachycardia (≤1%)
Dermatologic: Diaphoresis (≤1%), pallor (≤1%), pruritus (≤1%), skin rash (1% to 2%), urticaria (≤1%), wrinkling of skin (1%)
Endocrine & metabolic: Heavy menstrual bleeding (1%), hyperglycemia (≤1%), increased thirst (≤1%), menstrual disease (≤1%)
Gastrointestinal: Abdominal distress (1%), abdominal tenderness (1%), anorexia (≤1%), change in appetite (1%), constipation (2%), diarrhea (1% to 3%), dysgeusia (≤1%), dyspepsia (>1%), dysphagia (≤1%), flatulence (≤1%), frequent bowel movements (1%), gastroenteritis (1%) (Blumer 2009), gastroesophageal reflux disease (1%), hiccups (>1%), nausea (7%), vomiting (1%), xerostomia (3%)
Genitourinary: Cystitis (≤1%), urinary incontinence (≤1%) (Blumer 2009), urinary tract infection (>1%), vaginitis (≤1%)
Hematologic & oncologic: Bruise (1%)
Hepatic: Abnormal hepatic function tests (≤1%)
Hypersensitivity: Hypersensitivity reaction (4%)
Infection: Infection (≤1%), influenza (3%)
Nervous system: Abnormal dreams (1%), agitation (≤1%), amnesia (1%) (table 2) , anxiety (2% to 6%) (table 3) , ataxia (1%) (table 4) , balance impairment (2%) (table 5) , cerebrovascular disease (≤1%), cognitive dysfunction (≤1%), confusion (>1%), depersonalization (1%), depression (2%) (table 6) , disinhibition (1%) (table 7) , disorientation (3%), disturbance in attention (2%) (table 8) , dysarthria (≤1%), eating disorder (1%; binge eating), emotional lability (≤1%), euphoria (>1%), falling (≤1%), fatigue (oral: 3%; sublingual: 1%) (table 9) , hallucination (4%), hypoesthesia (2%), illusion (≤1%), increased body temperature (1%), insomnia (>1%), intoxicated feeling (3%), lethargy (3%), malaise (≤1%), memory impairment (3%), migraine (≤1%), nervousness (≤1%), paresthesia (1%), psychomotor impairment (2%), sleep disorder (1%), speech disturbance (≤1%), stress (1%), stupor (≤1%), vertigo (2%)
Drug (Zolpidem) |
Placebo |
Dose |
Dosage Form |
Number of Patients (Zolpidem) |
Number of Patients (Placebo) |
---|---|---|---|---|---|
1% |
0% |
≤10 mg |
Immediate-release oral |
152 |
161 |
Drug (Zolpidem) |
Placebo |
Dose |
Dosage Form |
Number of Patients (Zolpidem) |
Number of Patients (Placebo) |
---|---|---|---|---|---|
6% |
3% |
12.5 mg |
Extended-release oral |
N/A |
N/A |
2% |
0% |
12.5 mg |
Extended-release oral |
102 |
110 |
Drug (Zolpidem) |
Placebo |
Dose |
Dosage Form |
Number of Patients (Zolpidem) |
Number of Patients (Placebo) |
---|---|---|---|---|---|
1% |
0% |
12.5 mg |
Extended-release oral |
102 |
110 |
Drug (Zolpidem) |
Placebo |
Dose |
Dosage Form |
Number of Patients (Zolpidem) |
Number of Patients (Placebo) |
---|---|---|---|---|---|
2% |
0% |
12.5 mg |
Extended-release oral |
102 |
110 |
Drug (Zolpidem) |
Placebo |
Dose |
Dosage Form |
Number of Patients (Zolpidem) |
Number of Patients (Placebo) |
---|---|---|---|---|---|
2% |
0% |
12.5 mg |
Extended-release oral |
102 |
110 |
2% |
1% |
≤10 mg |
Immediate-release oral |
152 |
161 |
Drug (Zolpidem) |
Placebo |
Dose |
Dosage Form |
Number of Patients (Zolpidem) |
Number of Patients (Placebo) |
---|---|---|---|---|---|
1% |
0% |
12.5 mg |
Extended-release oral |
102 |
110 |
Drug (Zolpidem) |
Placebo |
Dose |
Dosage Form |
Number of Patients (Zolpidem) |
Number of Patients (Placebo) |
---|---|---|---|---|---|
2% |
0% |
12.5 mg |
Extended-release oral |
102 |
110 |
Drug (Zolpidem) |
Placebo |
Dose |
Dosage Form |
Number of Patients (Zolpidem) |
Number of Patients (Placebo) |
---|---|---|---|---|---|
3% |
2% |
12.5 mg |
Extended-release oral |
102 |
110 |
1% |
0% |
3.5 mg |
Sublingual |
150 |
145 |
Neuromuscular & skeletal: Arthralgia (>1%), arthritis (≤1%), asthenia (1%), back pain (3% to 4%), lower limb cramp (≤1%), myalgia (4%), neck pain (1%), tremor (≤1%)
Ophthalmic: Asthenopia (1%), blurred vision (2%), diplopia (>1%), eye irritation (≤1%), eye pain (≤1%), eye redness (2%), scleritis (≤1%), visual disturbance (1% to 3%; including altered depth perception)
Otic: Labyrinthitis (1%), tinnitus (1%)
Respiratory: Bronchitis (≤1%), cough (≤1%), dyspnea (≤1%), flu-like symptoms (1% to 2%), lower respiratory tract infection (>1%), pharyngitis (3%), rhinitis (≤1%), sinusitis (4%), throat irritation (1%), upper respiratory tract infection (>1%)
Miscellaneous: Fever (≤1%), trauma (≤1%)
<1%:
Cardiovascular: Acute myocardial infarction, angina pectoris, arteritis, cardiac arrhythmia, circulatory shock, exacerbation of hypertension, extrasystoles, facial edema, flushing, hypotension, phlebitis, pulmonary embolism, thrombosis, varicose veins, ventricular tachycardia
Dermatologic: Acne vulgaris, bullous rash, dermatitis, furunculosis, skin photosensitivity
Endocrine & metabolic: Decreased libido, gout, hot flash, hypercholesteremia, hyperlipidemia, weight loss
Gastrointestinal: Alteration of saliva, dental caries, enteritis, eructation, esophageal spasm, gastritis, hemorrhoids, increased appetite, intestinal obstruction, sialorrhea, tenesmus
Genitourinary: Breast fibroadenosis, dysuria, impotence, mastalgia, nocturia, urinary frequency, urinary retention
Hematologic & oncologic: Anemia, breast neoplasm, hyperhemoglobinemia, increased erythrocyte sedimentation rate, leukopenia, lymphadenopathy, macrocytic anemia, purpuric disease, rectal hemorrhage
Hepatic: Hyperbilirubinemia, increased serum alkaline phosphatase
Hypersensitivity: Anaphylactic shock
Infection: Abscess, herpes simplex infection, herpes zoster infection
Nervous system: Abnormal gait, abnormality in thinking, aggressive behavior, altered sense of smell, apathy, delusion, dementia, drug dependence, dysphasia, hypotonia, hysteria, manic reaction, myasthenia, neuralgia, neuritis, neuropathy, neurosis, numbness of tongue, pain, panic disorder, paresis, personality disorder, restless leg syndrome, rigors, sciatica, strange feeling, yawning
Neuromuscular & skeletal: Hypokinesia, osteoarthritis, tendinopathy, tetany
Ophthalmic: Abnormal lacrimation, accommodation disturbance, conjunctivitis, corneal ulcer, glaucoma, periorbital edema, photopsia
Otic: Otitis externa, otitis media
Renal: Acute kidney injury, polyuria, pyelonephritis, renal pain
Respiratory: Bronchospasm, epistaxis, hypoxia, laryngitis, pneumonia, pulmonary edema, respiratory depression
Postmarketing:
Hepatic: Cholestatic hepatitis, hepatocellular hepatitis
Hypersensitivity: Anaphylaxis, angioedema
Nervous system: Complex sleep-related disorder (Harbourt 2020), delirium (Inagaki 2010), somnambulism (Inagaki 2010), suicidal ideation, suicidal tendencies, withdrawal syndrome (Wilson 2019)
Neuromuscular & skeletal: Bone fracture (Treves 2018), femoral neck fracture (Wang 2001)
Miscellaneous: Accidental injury (Chung 2013)
Hypersensitivity to zolpidem or any component of the formulation; patients who have experienced complex sleep behaviors after taking zolpidem
Canadian labeling: Additional contraindications (not in US labeling): Significant obstructive sleep apnea syndrome and acute and/or severe impairment of respiratory function; myasthenia gravis; severe hepatic impairment; personal or family history of sleepwalking
Disease-related concerns:
• Depression: Use with caution in patients with depression, particularly if suicidal risk may be present.
• Drug abuse: Use with caution in patients with a history of drug dependence. Risk of abuse is increased in patients with a history or family history of alcohol or drug abuse or mental illness.
• Hepatic impairment: GABA agonists, including zolpidem, have been associated with precipitation of hepatic encephalopathy in patients with hepatic impairment. Patients with hepatic impairment do not clear zolpidem as rapidly as patients with normal hepatic function. Use with caution in patients with mild to moderate hepatic impairment; dose adjustment recommended. Avoid use of immediate and extended-release tablets in patients with severe hepatic impairment; may result in encephalopathy.
• Myasthenia gravis: Use with caution in patients with myasthenia gravis.
• Respiratory disease: Use with caution in patients with respiratory compromise, COPD, or sleep apnea.
Special populations:
• Debilitated: Use with caution in debilitated patients; potential for oversedation, impaired coordination, and confusion with use; dosage adjustment recommended.
• Older adult: Use with caution in older adult patients; dose adjustment recommended. Monitor for impaired cognitive and/or motor performance, confusion, and potential for falling.
• Females: Dosage adjustment is recommended for females; pharmacokinetic studies involving zolpidem showed a significant increase in maximum concentration and exposure in females compared to males at the same dose.
• Pediatric: When studied for the unapproved use of insomnia associated with ADHD in children, a higher incidence (~7%) of hallucinations was reported. In addition, sleep latency did not decrease compared to placebo.
Dosage form specific issues:
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.
Other warnings/precautions:
• Appropriate use: Symptomatic treatment of insomnia should be initiated only after careful evaluation of potential causes of sleep disturbance. Failure of sleep disturbance to resolve after 7 to 10 days may indicate the need for psychiatric and/or medical illness reevaluation. Long-term use is not recommended; reevaluation of patient’s status should occur before extending treatment due to risk of abuse and dependence.
• Rapid onset: Because of the rapid onset of action, administer Intermezzo immediately prior to bedtime, after the patient has gone to bed and is having difficulty falling asleep, or during the middle of the night when at least 4 hours are left before waking.
Some dosage forms may contain propylene glycol; in neonates large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009).
Substrate of CYP1A2 (minor), CYP2C19 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
Ciprofloxacin (Systemic): May increase the serum concentration of Zolpidem. Management: Consider avoiding the combination of ciprofloxacin and zolpidem if possible. If combined, monitor for signs of zolpidem toxicity (eg, somnolence, dizziness, lethargy). Risk D: Consider therapy modification
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CNS Depressants: May enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Zolpidem. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Zolpidem. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Zolpidem. Risk C: Monitor therapy
Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
FluvoxaMINE: May enhance the CNS depressant effect of Zolpidem. FluvoxaMINE may increase the serum concentration of Zolpidem. Risk C: Monitor therapy
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Melatonin: May enhance the sedative effect of Hypnotics (Nonbenzodiazepine). Risk C: Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: Hypnotics (Nonbenzodiazepine) may enhance the CNS depressant effect of Oxybate Salt Products. Risk X: Avoid combination
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
St John's Wort: May decrease the serum concentration of Zolpidem. Risk X: Avoid combination
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Maximum plasma concentration and bioavailability are decreased with food; time to peak plasma concentration is increased; half-life remains unchanged. Management: Do not administer with (or immediately after) a meal.
Zolpidem crosses the placenta (Juric 2009; Saito 2021).
According to product labeling, severe neonatal respiratory depression (requiring artificial ventilation or intratracheal intubation) and sedation have been reported following maternal use late in the third trimester. Exposed neonates should be monitored for excess sedation, hypotonia, and respiratory depression. Additional adverse effects, including low birth weight or preterm delivery, have been observed in some studies (Juric 2009; Sharma 2011; Wang 2010; Wikner 2011).
Zolpidem is present in breast milk (Pons 1989).
Data related to the presence of zolpidem in breast milk are available following administration of a single oral dose of IR zolpidem 20 mg to 5 breastfeeding women, 3 or 4 days following delivery. The amount of zolpidem recovered in milk samples 3 hours postadministration ranged from 0.76 to 3.88 mcg (0.004% to 0.019% of the administered maternal dose). Zolpidem was undetectable at 13 and 16 hours postadministration in all women. Infants in this study were not breastfed (Pons 1989).
Data are also available from a case report. Zolpidem 5 to 10 mg (IR) was administered daily throughout pregnancy and postpartum. Breast milk was sampled at random times once daily for the first 3 days after delivery. Breast milk concentrations of zolpidem ranged from 6.4 ng/mL (9.1 hours after the maternal dose) to 26.5 ng/mL (2.2 hours after the maternal dose). Authors of this study calculated the estimated exposure of zolpidem to the breastfeeding infant to be 4 mcg/kg/day (relative infant dose [RID] 2.7% based on a weight-adjusted maternal dose of 0.15 mg/kg/day). This patient was taking ramelteon for 5 days in addition to zolpidem; adverse events were not observed in the infant who was partially breastfed (Saito 2021). In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000).
Excess sedation in breastfed infants has been reported. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Monitor the infant for excess sedation, hypotonia, and respiratory depression. Consider pumping and discarding breast milk during treatment and for 23 hours after the last dose to minimize exposure to the infant.
Do not administer with or immediately after a meal (may delay onset).
Daytime alertness; fall risk, respiratory rate (patients with compromised respiration); behavior profile; tolerance, abuse, and dependence; reevaluate if insomnia persists after 7 to 10 days of use.
Zolpidem, an imidazopyridine hypnotic that is structurally dissimilar to benzodiazepines, enhances the activity of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), via selective agonism at the benzodiazepine-1 (BZ1) receptor; the result is increased chloride conductance, neuronal hyperpolarization, inhibition of the action potential, and a decrease in neuronal excitability leading to sedative and hypnotic effects. Because of its selectivity for the BZ1 receptor site over the BZ2 receptor site, zolpidem exhibits minimal anxiolytic, myorelaxant, and antiseizure properties (effects largely attributed to agonism at the BZ2 receptor site).
Onset of action: Immediate release: 30 minutes.
Duration: Immediate release: 6 to 8 hours.
Absorption: Cmax and AUC is increased by ~45% in females compared to male subjects.
Immediate release and sublingual: Rapid.
Extended release: Biphasic absorption; rapid initial absorption (similar to immediate release product); then provides extended concentrations in the plasma beyond 3 hours postadministration.
Distribution: Vd:
Children 2 to 6 years: 1.8 ± 0.8 L/kg (Blumer 2008).
Children >6 to 12 years: 2.2 ± 1.7 L/kg (Blumer 2008).
Adolescents: 1.2 ± 0.4 L/kg (Blumer 2008).
Adults: 0.54 L/kg after an IV dose (Holm 2000).
Protein binding: ~93%.
Metabolism: Hepatic methylation and hydroxylation via CYP3A4 (~60%), CYP2C9 (~22%), CYP1A2 (~14%), CYP2D6 (~3%), and CYP2C19 (~3%) to 3 inactive metabolites (Holm 2000).
Bioavailability: Immediate release: 70% (Holm 2000).
Half-life elimination:
Children 2 to 6 years: Immediate release: 1.8 hours (Blumer 2008).
Children >6 years and Adolescents: Immediate release: 2.3 hours (Blumer 2008).
Adults:
Immediate release, Extended release: ~2.5 hours (range: 1.4 to 4.5 hours); Cirrhosis: Up to 9.9 hours; Elderly: Prolonged up to 32%.
Spray: ~3 hours (range: 1.7 to 8.4).
Sublingual tablet: ~3 hours (range: 1.4 to 6.7 hours).
Time to peak, plasma:
Children 2 to 6 years: Immediate release: 0.9 hours (Blumer 2008).
Children >6 to 12 years: Immediate release: 1.1 hours (Blumer 2008).
Adolescents: Immediate release: 1.3 hours (Blumer 2008).
Adults:
Immediate release: 1.6 hours; 2.2 hours with food.
Extended release: 1.5 hours; 4 hours with food.
Spray: ~0.9 hours.
Sublingual tablet: Edluar: ~1.4 hours, ~1.8 hours with food; Intermezzo: 0.6 to 1.3 hours, ~3 hours with food.
Excretion: Urine (48% to 67%, primarily as metabolites); feces (29% to 42%, primarily as metabolites).
Clearance, apparent:
Children 2 to 6 years: 11.7 ± 7.9 mL/minute/kg (Blumer 2008).
Children >6 to 12 years: 9.7 ± 10.3 mL/minute/kg (Blumer 2008).
Adolescents: 4.8 ± 2 mL/minute/kg (Blumer 2008).
Adults: Intermezzo: Males: 4 mL/minute/kg; Females: 2.7 mL/minute/kg.
Hepatic function impairment: Cmax and AUC were found to be 2 and 5 times higher, respectively, in hepatically compromised patients. The mean half-life in cirrhotic patients of 9.9 hours was greater than that observed in normal subjects of 2.2 hours.
Older adult:
Immediate release: Cmax, half-life, and AUC were significantly increased when compared with results in younger adults.
Extended release: Mean Cmax and mean AUC are 70.6 ng/mL and 413 ng•h/mL, respectively, while the median Tmax is 2 hours.
Sex: Cmax and AUC were higher when comparing the same dose in women with men. Women clear zolpidem from the body at a lower rate than men. In geriatric patients, clearance is similar between men and women.
Solution (Zolpimist Oral)
5 mg/ACT (per mL): $96.56
Sublingual (Edluar Sublingual)
5 mg (per each): $14.96
10 mg (per each): $15.70
Sublingual (Zolpidem Tartrate Sublingual)
1.75 mg (per each): $10.04
3.5 mg (per each): $10.04
Tablet, controlled release (Ambien CR Oral)
6.25 mg (per each): $24.56
12.5 mg (per each): $24.56
Tablet, controlled release (Zolpidem Tartrate ER Oral)
6.25 mg (per each): $1.61 - $6.12
12.5 mg (per each): $1.61 - $6.12
Tablets (Ambien Oral)
5 mg (per each): $24.56
10 mg (per each): $24.56
Tablets (Zolpidem Tartrate Oral)
5 mg (per each): $0.10 - $5.14
10 mg (per each): $4.62 - $5.14
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