respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.primidoneMinor (1)primidone will decrease the level or effect of zolpidem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.prochlorperazineMonitor Closely (1)prochlorperazine will increase the level or effect of zolpidem by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Additive effect of decreased alertness and psychomotor performanceprotriptylineMinor (1)zolpidem, protriptyline. Either increases effects of the other by pharmacodynamic synergism. Minor/Significance Unknown. Additive CNS depression.quazepamMinor (1)zolpidem, quazepam. Either increases effects of the other by pharmacodynamic synergism. Minor/Significance Unknown. Additive CNS depression.quinupristin/dalfopristinMinor (1)quinupristin/dalfopristin will increase the level or effect of zolpidem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.remimazolamMonitor Closely (1)remimazolam, zolpidem. Either increases toxicity of the other by sedation. Modify Therapy/Monitor Closely. Coadministration may result in profound sedation, respiratory depression, coma, and/or death. Continuously monitor vital signs during sedation and recovery period if coadministered. Carefully titrate remimazolam dose if administered with opioid analgesics and/or sedative/hypnotics.ribociclibMonitor Closely (1)ribociclib will increase the level or effect of zolpidem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.rifabutinMonitor Closely (1)rifabutin will decrease the level or effect of zolpidem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.rifampinMonitor Closely (1)rifampin will decrease the level or effect of zolpidem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.rifapentineMinor (1)rifapentine will decrease the level or effect of zolpidem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.ritonavirMinor (1)ritonavir will increase the level or effect of zolpidem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.rucaparibMonitor Closely (1)rucaparib will increase the level or effect of zolpidem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adjust dosage of CYP3A4 substrates, if clinically indicated.rufinamideMinor (1)rufinamide will decrease the level or effect of zolpidem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.saquinavirMonitor Closely (1)saquinavir will increase the level or effect of zolpidem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.secobarbitalMinor (1)secobarbital will decrease the level or effect of zolpidem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.selinexorSerious - Use Alternative (1)selinexor, zolpidem. unspecified interaction mechanism. Avoid or Use Alternate Drug. Patients treated with selinexor may experience neurological toxicities. Avoid taking selinexor with other medications that may cause dizziness or confusion.sodium oxybateContraindicated (1)zolpidem, sodium oxybate. Either increases effects of the other by pharmacodynamic synergism. Contraindicated. Coadministration with alcohol or sedative hypnotics are contraindicated because of additive CNS depression.St John's WortMonitor Closely (1)St John's Wort will decrease the level or effect of zolpidem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.stiripentolMonitor Closely (2)stiripentol, zolpidem. Either increases effects of the other by sedation. Use Caution/Monitor. Concomitant use stiripentol with other CNS depressants, including alcohol, may increase the risk of sedation and somnolence. stiripentol, zolpidem. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Stiripentol is a CYP3A4 inhibitor and inducer. Monitor CYP3A4 substrates coadministered with stiripentol for increased or decreased effects. CYP3A4 substrates may require dosage adjustment.sufentanil SLSerious - Use Alternative (1)sufentanil SL, zolpidem. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration may result in hypotension, profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.tazemetostatMonitor Closely (1)tazemetostat will decrease the level or effect of zolpidem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.tecovirimatMonitor Closely (1)tecovirimat will decrease the level or effect of zolpidem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Tecovirimat is a weak CYP3A4 inducer. Monitor sensitive CYP3A4 substrates for effectiveness if coadministered.temazepamMinor (1)zolpidem, temazepam. Either increases effects of the other by pharmacodynamic synergism. Minor/Significance Unknown. Additive CNS depression.thioridazineMonitor Closely (1)thioridazine will increase the level or effect of zolpidem by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Additive effect of decreased alertness and psychomotor performancetopiramateMinor (1)topiramate will decrease the level or effect of zolpidem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.trazodoneMinor (1)zolpidem, trazodone. Either increases effects of the other by pharmacodynamic synergism. Minor/Significance Unknown. Additive CNS depression.triazolamMinor (1)zolpidem, triazolam. Either increases effects of the other by pharmacodynamic synergism. Minor/Significance Unknown. Additive CNS depression.trifluoperazineMonitor Closely (1)trifluoperazine will increase the level or effect of zolpidem by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Additive effect of decreased alertness and psychomotor performancetrimipramineMinor (1)zolpidem, trimipramine. Either increases effects of the other by pharmacodynamic synergism. Minor/Significance Unknown. Additive CNS depression.tucatinibSerious - Use Alternative (1)tucatinib will increase the level or effect of zolpidem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling.valerianSerious - Use Alternative (1)valerian and zolpidem both increase sedation. Avoid or Use Alternate Drug.verapamilMinor (1)verapamil will increase the level or effect of zolpidem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.voriconazoleMinor (1)voriconazole will increase the level or effect of zolpidem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.voxelotorSerious - Use Alternative (1)voxelotor will increase the level or effect of zolpidem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid.zafirlukastMinor (1)zafirlukast will increase the level or effect of zolpidem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown. >10% Dizziness (5-12%) Headache (7-19%) Drowsiness (6-15%) 1-10% Allergy (4%) Hallucinations (4%) Myalgia (4%) Sinusitis (4%) Memory disorder (3%) Visual disturbance (3%) Pharyngitis (3%) Lightheadedness (2%) Palpitation (2%) Rash (2%) Constipation (2%) Depression (2%) Drowsiness (2%) Asthenia (1%) Diarrhea (1%) Dry mouth (1%) Flu-like symptoms (1%) Postmarketing reports Respiratory depression Complex sleep behaviors Sublingual tablet: Oral ulcers, blisters, and mucosal inflammation Liver and biliary system: Acute hepatocellular, cholestatic or mixed liver injury with or without jaundice (i.e., bilirubin greater than 2x ULN, alkaline phosphatase greater than or equal to 2x ULN, transaminase greater than or equal to 5x ULN). Black Box Warnings Complex sleep behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake may occur; some of these events may result in serious injuries, including death Discontinue therapy immediately if a patient experiences complex sleep behaviorContraindications Contraindicated in patients with known hypersensitivity to zolpidem; observed reactions include anaphylaxis and angioedema Patients who have experienced complex sleep behaviors after receiving therapy Cautions The risk of next-day psychomotor impairment, including impaired driving, is increased if taken with less than a full night of sleep remaining (7 to 8 hours); if a higher than the recommended dose is taken; if co-administered with other CNS depressants or alcohol; or if co-administered with other drugs that increase blood levels of zolpidem; patients should be warned against driving and other activities requiring complete mental alertness if drug taken in these circumstances Co-administration with other CNS depressants (eg, benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression; dosage adjustments of zolpidem and of other concomitant CNS depressants may be necessary when zolpidem is administered with such agents because of the potentially additive effects; the use of zolpidem with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended Postmarketing reports of respiratory insufficiency in patients receiving 10 mg dose, most of whom had preexisting respiratory impairment, reported; risk of respiratory depression should be considered prior to prescribing this drug in patients with respiratory impairment including sleep apnea and myasthenia gravis or with concomitant opioid use Vehicle drivers and machine operators should be warned that, there may be a possible risk of adverse reactions including drowsiness, prolonged reaction time, dizziness, sleepiness, blurred/double vision, reduced alertness and impaired driving the morning after therapy; to minimize risk, a full night of sleep (7-8 hours) recommended; this next-morning impairment is highest for the extended-release dosage form and is more prevalent in women because they eliminate more slowly than men Can cause drowsiness and a decreased level of consciousness, which may lead to falls and consequently to severe injuries; severe injuries such as hip fractures and intracranial hemorrhage have been reported Use caution in patients with history of drug dependence (increases risk of abuse) Food increases time to attain peak plasma level and decreases peak plasma concentration Need to evaluate for comorbid diagnoses; reevaluate if insomnia persists after 7-10 days of use Severe anaphylactic/anaphylactoid reactions including angioedema and anaphylaxis reported; do not rechallenge if such reactions occur Abnormal thinking, behavioral changes, complex behaviors: May include “sleep driving” and hallucinations; coadministration of alcohol and other CNS depressants appears to increase the risk of such behaviors Do not use with alcohol Use can impair respiratory drive, alertness, and motor coordination; if used in combination with other CNS depressants, dose reductions of 50% may be needed due to additive effects Consider risk of respiratory depression before prescribing in patients with compromised regulatory functions Worsening of depression or suicidal thinking may occur; prescribe the least amount feasible to avoid intentional overdose Withdrawal symptoms may occur with rapid dose reduction or discontinuation Use lower dose in elderly/debilitated patients due to impaired motor, cognitive performance and increased sensitivity Use with caution and monitor closely in patients with hepatic impairment, mild to moderate COPD, impaired drug metabolism or hemodynamic responses GABA agonists such as zolpidem tartrate have been associated with precipitation of hepatic encephalopathy in patients with hepatic insufficiency; patients with hepatic insufficiency do not clear zolpidem tartrate as rapidly as patients with normal hepatic function; avoid zolpidem use in patients with severe hepatic impairment as it may contribute to encephalopathy Pregnancy Neonates born to mothers using zolpidem late in the third trimester of pregnancy reported to experience symptoms of respiratory depression and sedation; published data on use of zolpidem during pregnancy have not reported clear association with zolpidem and major birth defects There are limited postmarketing reports of severe to moderate cases of respiratory depression that occurred after birth in neonates whose mothers had taken zolpidem during pregnancy; these cases required artificial ventilation or intratracheal intubation; the majority of neonates recovered within hours to a few weeks after birth once treated Zolpidem has been shown to cross the placenta Animal data Oral administration of zolpidem to pregnant rats and rabbits did not indicate a risk for adverse effects on fetal development at clinically relevant doses Lactation Limited data report presence of zolpidem in human milk; there are reports of excess sedation in infants exposed to zolpidem through breastmilk; there is no information on effects on milk production; consider developmental and health benefits of breastfeeding along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from therapy or from underlying maternal condition Monitor, for excess sedation, infants exposed to drug through breastmilk, hypotonia, and respiratory depression; a lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment and for 23 hours (approximately 5 elimination half-lives) after drug administration in order to minimize drug exposure to a breast fed infantPregnancy Categories A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk. B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available. Mechanism of Action Imidazopyridine; modulates omega-1 type GABA receptor via selective antagonism, resulting in increased chloride conductance, neuronal hyperpolarization, inhibition of action potential, and a decrease in neuronal excitability that in turn produce sedative and hypnotic effects Absorption Bioavailability: 70% Peak plasma time 1.6 hr (immediate-release) 1.5 hr (extended-release) 1.4 hr (sublingual Edluar) 1 hr (7.5 mg capsule) 1.4 hr (10 mg SL) Peak plasma time delayed by food intake Peak plasma concentration 59 mg/mL (5 mg tablet) (10 mg) 121 ng/mL (10 mg tablet) 134 ng/mL (12.5 mg CR tablet) 230 ng/mL (7.5 mg capsule) 106 ng/mL (10 mg SL) AUC 740 ngh/mL (extended-release tablet) 942 ngh/mL (7.5 mg capsule) Distribution Protein bound: 92.5% Metabolism Metabolized by CYP3A4 (60%), CYP2C9 (22%), CYP1A2 (14%), CYP2D6 (3%), CYP2C (3%) Metabolized to inactive metabolites Elimination Half-life Immediate release: