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Drug overview for AMBIEN CR (zolpidem tartrate):
Generic name: ZOLPIDEM TARTRATE (ZOL-pi-dem)
Drug class: Hypnotics
Therapeutic class: Central Nervous System Agents
Zolpidem tartrate, a type A gamma-aminobutyric acid (GABAA)-receptor positive modulator of the imidazopyridine class, is a sedative and hypnotic agent structurally unrelated to the benzodiazepines and other sedative and hypnotic agents.
No enhanced Uses information available for this drug.
Generic name: ZOLPIDEM TARTRATE (ZOL-pi-dem)
Drug class: Hypnotics
Therapeutic class: Central Nervous System Agents
Zolpidem tartrate, a type A gamma-aminobutyric acid (GABAA)-receptor positive modulator of the imidazopyridine class, is a sedative and hypnotic agent structurally unrelated to the benzodiazepines and other sedative and hypnotic agents.
No enhanced Uses information available for this drug.
DRUG IMAGES
AMBIEN CR 6.25 MG TABLET
The following indications for AMBIEN CR (zolpidem tartrate) have been approved by the FDA:
Indications:
Insomnia
Sleep maintenance insomnia
Professional Synonyms:
Agrypnia
Ahypnia
Middle insomnia
Indications:
Insomnia
Sleep maintenance insomnia
Professional Synonyms:
Agrypnia
Ahypnia
Middle insomnia
The following dosing information is available for AMBIEN CR (zolpidem tartrate):
The lowest effective dosage of zolpidem tartrate should be used. Long-term use of zolpidem is not recommended; treatment duration should be as short as possible. Extended treatment should not take place without re-evaluation of the patient's status; risk of abuse and dependence increases with the duration of treatment.
The recommended initial doses of zolpidem tartrate for women and men differ because clearance of the drug is slower in women.
Because manifestations of withdrawal have been reported following abrupt discontinuance or rapid reduction in dosage of zolpidem, patients should be monitored for tolerance, abuse, and dependence. There also is evidence that abrupt discontinuance of sedative and hypnotic drugs, including zolpidem tartrate, may result in rebound insomnia, which usually persists for 1 or 2 nights; this effect may occur with some sedative and hypnotic drugs even after relatively short periods of therapy (e.g., 1 week). Therefore, some clinicians suggest that gradual dosage reduction (e.g., over several nights) be considered when discontinuing therapy, since the development of rebound insomnia can perpetuate continued use of hypnotics in patients with insomnia.
For the management of insomnia characterized by difficulties with sleep initiation, the recommended initial dose of zolpidem tartrate as an oral immediate-release preparation (conventional tablets) is a single dose of 5 mg in women and either 5 or 10 mg in men. If the 5-mg dose of immediate-release zolpidem tartrate is not effective in men or women, the dose may be increased to 10 mg.
For the management of insomnia characterized by difficulties with sleep initiation or sleep maintenance, the recommended initial dose of zolpidem tartrate as extended-release tablets is 6.25 mg in women and either 6.25 or 12.5
mg in men. If the 6.25-mg dose of extended-release zolpidem tartrate is not effective in men or women, the dose may be increased to 12.5
mg.
In some patients, higher morning blood concentrations following use of a 10-mg dose of immediate-release zolpidem tartrate or a 12.5-mg dose of extended-release zolpidem tartrate increase the risk of next-day impairment of driving and other activities that require full alertness. Total dosage should not exceed 10 mg of immediate-release zolpidem tartrate or 12.5
mg of extended-release zolpidem tartrate given once daily immediately before bedtime.
If zolpidem is used concomitantly with other CNS depressants, dosage adjustment of zolpidem and the concomitantly administered agent(s) may be necessary because of potentially additive effects.
For the short-term management of insomnia characterized by difficulties with sleep initiation, the recommended initial dose of zolpidem tartrate sublingual tablets is 5 mg for women and either 5 or 10 mg for men. If the 5-mg dose is not effective in men or women, the dose may be increased to 10 mg. In some patients, higher morning blood concentrations following use of a 10-mg dose increase the risk of next-day impairment of driving and other activities that require full alertness.
Total dosage should not exceed 10 mg given once daily immediately before bedtime. If zolpidem is used concomitantly with other CNS depressants, dosage adjustment of zolpidem and the concomitantly administered agent(s) may be necessary because of potentially additive effects.
For as-needed use in the management of insomnia when middle-of-the-night awakening is followed by difficulty returning to sleep, the recommended and maximum dose of zolpidem tartrate sublingual tablets is 1.75 mg for women and 3.5 mg for men.
In patients receiving other CNS depressants concomitantly, the recommended sublingual dose of zolpidem tartrate for middle-of-the-night awakening is 1.75 mg; dosage adjustment of the concomitant CNS depressant may be necessary because of potentially additive effects.
The recommended initial doses of zolpidem tartrate for women and men differ because clearance of the drug is slower in women.
Because manifestations of withdrawal have been reported following abrupt discontinuance or rapid reduction in dosage of zolpidem, patients should be monitored for tolerance, abuse, and dependence. There also is evidence that abrupt discontinuance of sedative and hypnotic drugs, including zolpidem tartrate, may result in rebound insomnia, which usually persists for 1 or 2 nights; this effect may occur with some sedative and hypnotic drugs even after relatively short periods of therapy (e.g., 1 week). Therefore, some clinicians suggest that gradual dosage reduction (e.g., over several nights) be considered when discontinuing therapy, since the development of rebound insomnia can perpetuate continued use of hypnotics in patients with insomnia.
For the management of insomnia characterized by difficulties with sleep initiation, the recommended initial dose of zolpidem tartrate as an oral immediate-release preparation (conventional tablets) is a single dose of 5 mg in women and either 5 or 10 mg in men. If the 5-mg dose of immediate-release zolpidem tartrate is not effective in men or women, the dose may be increased to 10 mg.
For the management of insomnia characterized by difficulties with sleep initiation or sleep maintenance, the recommended initial dose of zolpidem tartrate as extended-release tablets is 6.25 mg in women and either 6.25 or 12.5
mg in men. If the 6.25-mg dose of extended-release zolpidem tartrate is not effective in men or women, the dose may be increased to 12.5
mg.
In some patients, higher morning blood concentrations following use of a 10-mg dose of immediate-release zolpidem tartrate or a 12.5-mg dose of extended-release zolpidem tartrate increase the risk of next-day impairment of driving and other activities that require full alertness. Total dosage should not exceed 10 mg of immediate-release zolpidem tartrate or 12.5
mg of extended-release zolpidem tartrate given once daily immediately before bedtime.
If zolpidem is used concomitantly with other CNS depressants, dosage adjustment of zolpidem and the concomitantly administered agent(s) may be necessary because of potentially additive effects.
For the short-term management of insomnia characterized by difficulties with sleep initiation, the recommended initial dose of zolpidem tartrate sublingual tablets is 5 mg for women and either 5 or 10 mg for men. If the 5-mg dose is not effective in men or women, the dose may be increased to 10 mg. In some patients, higher morning blood concentrations following use of a 10-mg dose increase the risk of next-day impairment of driving and other activities that require full alertness.
Total dosage should not exceed 10 mg given once daily immediately before bedtime. If zolpidem is used concomitantly with other CNS depressants, dosage adjustment of zolpidem and the concomitantly administered agent(s) may be necessary because of potentially additive effects.
For as-needed use in the management of insomnia when middle-of-the-night awakening is followed by difficulty returning to sleep, the recommended and maximum dose of zolpidem tartrate sublingual tablets is 1.75 mg for women and 3.5 mg for men.
In patients receiving other CNS depressants concomitantly, the recommended sublingual dose of zolpidem tartrate for middle-of-the-night awakening is 1.75 mg; dosage adjustment of the concomitant CNS depressant may be necessary because of potentially additive effects.
Zolpidem tartrate is administered orally (as conventional tablets or extended-release tablets) or sublingually (as sublingual tablets).
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| AMBIEN CR 6.25 MG TABLET | Maintenance | Adults take 1 tablet (6.25 mg) by oral route once daily at bedtime |
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| ZOLPIDEM TART ER 6.25 MG TAB | Maintenance | Adults take 1 tablet (6.25 mg) by oral route once daily at bedtime |
The following drug interaction information is available for AMBIEN CR (zolpidem tartrate):
There are 1 contraindications.
These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.
| Drug Interaction | Drug Names |
|---|---|
| Sodium Oxybate/Sedative Hypnotics; Alcohol SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Oxybate may be associated with respiratory depression. As oxybate is taken at bedtime, concurrent use with alcohol or hypnotics may increase the risk for respiratory depression or loss of consciousness.(1-3) Primidone is metabolized to phenobarbital. CLINICAL EFFECTS: Concurrent use of sodium oxybate and sedative hypnotics or alcohol may further increase the risk for respiratory depression and profound sedation or coma.(1,2) Fatalities have been reported.(3) PREDISPOSING FACTORS: Based upon FDA evaluation of deaths in patients taking sodium oxybate, risk factors may include: use of multiple drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Note that in oxybate clinical trials for narcolepsy 78% - 85% of patients were also receiving concomitant CNS stimulants.(1-3) PATIENT MANAGEMENT: The FDA states that sodium oxybate is contraindicated in patients also taking hypnotics or alcohol.(1,2) Significant quantities of alcohol may be present in medicinal products. Alcohol is is used to improve docetaxel and paclitaxel solubility. - The quantity of alcohol in paclitaxel injection formulations (0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg dose contains approximately 13 grams of alcohol. - The quantity of alcohol in docetaxel formulations varies approximately 3-fold depending upon the manufacturer. FDA data on alcohol content (4): Product Manufacturer Alcohol/200 mg dose Docetaxel Inj. Pfizer 6.4 grams Docetaxel Inj. Sandoz 5.5 grams Docetaxel Inj. Accord 4.0 grams Taxotere-one vial Sanofi 4.0 grams formulation Docetaxel Inj. Hospira 3.7 grams Docefrez Sun Pharma 2.9 grams Taxotere-two vial Sanofi 2.0 grams formulation DISCUSSION: The FDA evaluated sodium oxybate postmarket fatal adverse event reports from the FDA Adverse Event Reporting System(AERS)and from the manufacturer. Although report documentation was not always optimal or complete, useful information was obtained. Factors which may have contributed to fatal outcome: concomitant use of one or more drugs which depress the CNS, more rapid than recommended upward dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Many deaths occurred in patients with serious psychiatric disorders such as depression and substance abuse. Other concomitant diseases may have also contributed to respiratory and CNS depressant effects of oxybate.(3) |
LUMRYZ, LUMRYZ STARTER PACK, SODIUM OXYBATE, XYREM, XYWAV |
There are 1 severe interactions.
These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.
| Drug Interaction | Drug Names |
|---|---|
| Opioids (Cough and Cold)/Sleep Drugs SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concurrent use of opioids and sleep drugs or tranquilizers may result in additive CNS depression and sleep-related disorders.(1) CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as sleep drugs or tranquilizers, may result in profound sedation, respiratory depression, coma, and/or death.(1) Concurrent use of opioids with eszopiclone, zaleplon, or zolpidem may increase the risk of sleep-related disorders including central sleep apnea and sleep-related hypoxemia, and complex sleep behaviors like sleepwalking, sleep driving, and other activities while not fully awake. Rarely, serious injuries or death have resulted from complex sleep behaviors.(2) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Avoid prescribing opioid-including cough medications for patients taking CNS depressants such as sleep drugs or tranquilizers.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(3) If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who have had a previous episode of complex sleep behavior.(2) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(4) DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10) As of April 2019, the FDA had identified 66 cases of complex sleep behaviors with eszopiclone, zaleplon, or zolpidem, of which 20 cases resulted in death and the remainder resulted in serious injuries. It was not reported how many of the cases involved concomitant use of other CNS depressants.(2) |
HYCODAN, HYDROCODONE-CHLORPHENIRAMNE ER, HYDROCODONE-HOMATROPINE MBR, HYDROMET, PROMETHAZINE-CODEINE, TUXARIN ER |
There are 9 moderate interactions.
The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.
| Drug Interaction | Drug Names |
|---|---|
| Eszopiclone; Zopiclone; Zolpidem/Strong CYP3A4 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Strong inhibitors of CYP3A4 impair the metabolism of eszopiclone, zopiclone, and zolpidem.(1-5,8) CLINICAL EFFECTS: Concurrent use of eszopiclone, zopiclone, or zolpidem with a strong CYP3A4 inhibitor may result in an increase in hypnotic levels and clinical effects, as well as toxic effects such as profound sedation, respiratory depression, coma, and/or death. PREDISPOSING FACTORS: Systemic exposure may also be increased in patients with severe hepatic impairment. Elderly and debilitated patients are more likely to have impaired motor or cognitive performance when treated with hypnotics. PATIENT MANAGEMENT: The US manufacturer of eszopiclone states the total dose should not exceed 2 mg in patients taking strong CYP3A4 inhibitors.(1) The Canadian manufacturer of zopiclone states the prescribed dose should not exceed 5 mg in patients treated with strong CYP3A4 inhibitors.(8) Patients should be counseled that concurrent use of a strong CYP3A4 inhibitor with eszopiclone, zopiclone, or zolpidem may result in an increase in side effects such as confusion, memory loss, sleep-walking or sleep-driving behaviors, or daytime drowsiness. DISCUSSION: Concurrent administration of ketoconazole (400 mg daily for 5 days) increased the area-under-curve (AUC) of eszopiclone by 2.2-fold. Eszopiclone maximum concentration (Cmax) and half-life were increased 1.4-fold and 1.3-fold, respectively.(1) An in vitro study in human liver microsomes found that ketoconazole inhibited the metabolism of zopiclone.(2) In a study in 10 subjects, itraconazole (200 mg daily for 4 days) increased the AUC, Cmax, and half-life of zopiclone by 73%, 29%, and 40%, respectively. However, there were no significant differences in clinical effects when compared to placebo.(6) In a randomized, double-blind, cross-over study in 12 healthy subjects, concurrent use of ketoconazole (200 mg twice daily) and zolpidem (5 mg) decreased zolpidem clearance by 64% and increased its AUC 1.83-fold. In the same study, concurrent use of itraconazole and fluconazole with zolpidem had no clinically significant effects on zolpidem pharmacokinetics.(3,5) In a randomized, cross-over study in 10 healthy subjects, concurrent use of itraconazole (200 mg daily for 4 days) with a single dose of zolpidem (10 mg on day 4) increased the AUC of zolpidem by 34% when compared to placebo. However, there were no significant differences in clinical effects when compared to placebo.(5,7) Strong CYP3A4 inhibitors linked to this monograph are: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin, lonafarnib, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, ribociclib, ritonavir, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole. |
APTIVUS, CLARITHROMYCIN, CLARITHROMYCIN ER, EVOTAZ, GENVOYA, ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KALETRA, KETOCONAZOLE, KISQALI, KORLYM, KRAZATI, LANSOPRAZOL-AMOXICIL-CLARITHRO, LOPINAVIR-RITONAVIR, MIFEPREX, MIFEPRISTONE, NEFAZODONE HCL, NOXAFIL, OMECLAMOX-PAK, PAXLOVID, POSACONAZOLE, PREZCOBIX, RECORLEV, SPORANOX, STRIBILD, SYMTUZA, TOLSURA, TUKYSA, TYBOST, VFEND, VFEND IV, VIRACEPT, VOQUEZNA TRIPLE PAK, VORICONAZOLE, ZOKINVY, ZYDELIG, ZYKADIA |
| Select Sedative Hypnotics; Buspirone/Strong CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of buspirone,(1-3) eszopiclone,(4) zopiclone,(5) and zolpidem.(6) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may result in decreased levels and clinical effectiveness of buspirone,(1-3) eszopiclone,(4) zopiclone,(5) and zolpidem.(6) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The dose of buspirone may need adjusting to maintain anxiolytic effect.(1) Concurrent use of strong CYP3A4 inducers with zolpidem is not recommended.(6) If concomitant therapy is warranted, patients should be counseled about possible decreased buspirone or hypnotic effectiveness. DISCUSSION: In a randomized, placebo-controlled, cross-over study in 10 subjects, rifampin (600 mg daily) decreased buspirone (30 mg single dose) maximum concentration (Cmax), area-under-curve (AUC), and half-life by 89.6%, 83.7%, and 54%, respectively. During the placebo phase, all subjects had measurable plasma buspirone concentrations at 10 hours after administration; however, no subject had measurable plasma buspirone concentrations at 6 hours after administration during the rifampin phase.(2) The Cmax of the buspirone piperazine metabolite increased by 35%.(3) There were significant decreases in the effects of buspirone in the postural sway test with eyes closed, the visual analogue scale (VAS) test for subjective drowsiness, and the VAS test for overall drug effect during concurrent rifampin. Buspirone side effects were reported more often during the placebo phase.(2) In a study in 8 subjects, rifampin (600 mg daily for 6 days) decreased the area-under-curve (AUC) of a single dose of zopiclone (10 mg) by 82%. The maximum concentration (Cmax) and half-life of zopiclone were decreased by 71% and 15%, respectively. A significant reduction in zopiclone effects were seen in 3 of 5 psychomotor tests.(5) In a randomized cross-over study in 8 subjects, rifampin (600 mg daily for 6 days) decreased the AUC, Cmax, and half-life of a single dose of zolpidem (20 mg) by 73%, 58%, and 36%, respectively. A significant reduction in zolpidem effects were seen in all 6 psychomotor tests.(6,7) Similar effects are expected with eszopiclone.(4) |
ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BRAFTOVI, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTALBITAL, BUTALBITAL-ACETAMINOPHEN, BUTALBITAL-ACETAMINOPHEN-CAFFE, BUTALBITAL-ASPIRIN-CAFFEINE, CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, CEREBYX, DILANTIN, DILANTIN-125, DONNATAL, EPITOL, EQUETRO, ERLEADA, FIORICET, FIORICET WITH CODEINE, FOSPHENYTOIN SODIUM, LYSODREN, MITOTANE, MYSOLINE, ORKAMBI, PENTOBARBITAL SODIUM, PHENOBARBITAL, PHENOBARBITAL SODIUM, PHENOBARBITAL-BELLADONNA, PHENOBARBITAL-HYOSC-ATROP-SCOP, PHENOHYTRO, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED, PRIFTIN, PRIMIDONE, RIFADIN, RIFAMPIN, SEZABY, TEGRETOL, TEGRETOL XR, TENCON, TIBSOVO, XTANDI |
| Zolpidem/Ciprofloxacin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Ciprofloxacin, a weak CYP3A4 inhibitor and a moderate CYP1A2 inhibitor, may inhibit metabolism of zolpidem via these pathways.(1,2) CLINICAL EFFECTS: Concurrent use of zolpidem with ciprofloxacin may result in an increase in zolpidem systemic concentrations and clinical effects, including profound sedation, respiratory depression, coma, and/or death. PREDISPOSING FACTORS: Adult women clear zolpidem at lower rate than men resulting in approximately 50% higher exposure compared with men taking the same dose.(3) Elderly or debilitated patients are more likely to have impaired motor or cognitive performance when treated with zolpidem.(3) PATIENT MANAGEMENT: Monitor for adverse effects or consider lowering the zolpidem dose, particularly in elderly patients or adult women on higher doses of zolpidem.(3) The US, UK, Australian, and Canadian manufacturers of ciprofloxacin state the concurrent use of zolpidem with ciprofloxacin is not recommended.(4-7) Patients should be counseled that concurrent use of ciprofloxacin and zolpidem may result in an increase in side effects such as confusion, amnesia, sleep-walking or sleep-driving behaviors, or daytime drowsiness. DISCUSSION: An interaction study was conducted in 18 healthy, non-smoking men. The pharmacokinetics of zolpidem 5 mg was evaluated before and after ciprofloxacin 500 mg daily for 5 days. Zolpidem half-life increased from 2.39 to 3.34 hours and exposure (area-under-curve, AUC) was increased by 46%.(8) |
CIPRO, CIPROFLOXACIN, CIPROFLOXACIN HCL, CIPROFLOXACIN-D5W |
| Opioids (Extended Release)/Sleep Drugs SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of opioids and sleep drugs may result in additive CNS depression and sleep-related disorders.(1) CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as sleep drugs, may result in profound sedation, respiratory depression, coma, and/or death.(1) Concurrent use of opioids with eszopiclone, zaleplon, or zolpidem may increase the risk of sleep-related disorders including central sleep apnea and sleep-related hypoxemia and complex sleep behaviors like sleepwalking, sleep driving, and other activities while not fully awake. Rarely, serious injuries or death have resulted from complex sleep behaviors.(2) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as sleep drugs to patients for whom alternatives are inadequate.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(3) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who have had a previous episode of complex sleep behavior.(2) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(4) DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10) As of April 2019, the FDA had identified 66 cases of complex sleep behaviors with eszopiclone, zaleplon, or zolpidem, of which 20 cases resulted in death and the remainder resulted in serious injuries. It was not reported how many of the cases involved concomitant use of other CNS depressants.(2) |
BUPRENORPHINE, BUTRANS, CONZIP, FENTANYL, HYDROCODONE BITARTRATE ER, HYDROMORPHONE ER, HYSINGLA ER, MORPHINE SULFATE ER, MS CONTIN, NUCYNTA ER, OXYCODONE HCL ER, OXYCONTIN, OXYMORPHONE HCL ER, TRAMADOL HCL ER, XTAMPZA ER |
| Opioids (Immediate Release)/Sleep Drugs SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of opioids and sleep drugs may result in additive CNS depression and sleep-related disorders.(1) CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as sleep drugs, may result in profound sedation, respiratory depression, coma, and/or death.(1) Concurrent use of opioids with eszopiclone, zaleplon, or zolpidem may increase the risk of sleep-related disorders including central sleep apnea and sleep-related hypoxemia and complex sleep behaviors like sleepwalking, sleep driving, and other activities while not fully awake. Rarely, serious injuries or death have resulted from complex sleep behaviors.(2) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as sleep drugs to patients for whom alternatives are inadequate.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(3) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who have had a previous episode of complex sleep behavior.(2) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(4) DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10) As of April 2019, the FDA had identified 66 cases of complex sleep behaviors with eszopiclone, zaleplon, or zolpidem, of which 20 cases resulted in death and the remainder resulted in serious injuries. It was not reported how many of the cases involved concomitant use of other CNS depressants.(2) |
ACETAMIN-CAFF-DIHYDROCODEINE, ACETAMINOPHEN-CODEINE, APADAZ, ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BELBUCA, BELLADONNA-OPIUM, BENZHYDROCODONE-ACETAMINOPHEN, BUPRENORPHINE HCL, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTORPHANOL TARTRATE, CARISOPRODOL-ASPIRIN-CODEINE, CODEINE PHOSPHATE, CODEINE SULFATE, DEMEROL, DIHYDROCODEINE BITARTRATE, DILAUDID, DSUVIA, DURAMORPH, ENDOCET, FENTANYL CITRATE, FENTANYL CITRATE-0.9% NACL, FENTANYL CITRATE-D5W, FENTANYL CITRATE-STERILE WATER, FENTANYL CITRATE-WATER, FENTANYL-BUPIVACAINE-0.9% NACL, FENTANYL-BUPIVACAINE-NACL, FENTANYL-ROPIVACAINE-0.9% NACL, FENTANYL-ROPIVACAINE-NACL, FIORICET WITH CODEINE, HYDROCODONE BITARTRATE, HYDROCODONE-ACETAMINOPHEN, HYDROCODONE-IBUPROFEN, HYDROMORPHONE HCL, HYDROMORPHONE HCL-0.9% NACL, HYDROMORPHONE HCL-D5W, HYDROMORPHONE HCL-NACL, HYDROMORPHONE HCL-WATER, INFUMORPH, LEVORPHANOL TARTRATE, MEPERIDINE HCL, MEPERIDINE HCL-0.9% NACL, MITIGO, MORPHINE SULFATE, MORPHINE SULFATE-0.9% NACL, MORPHINE SULFATE-NACL, NALBUPHINE HCL, NALOCET, NUCYNTA, OLINVYK, OPIUM TINCTURE, OXYCODONE HCL, OXYCODONE HYDROCHLORIDE, OXYCODONE-ACETAMINOPHEN, OXYMORPHONE HCL, PENTAZOCINE-NALOXONE HCL, PERCOCET, PRIMLEV, PROLATE, QDOLO, REMIFENTANIL HCL, ROXICODONE, ROXYBOND, SUFENTANIL CITRATE, TRAMADOL HCL, TRAMADOL HCL-ACETAMINOPHEN, TREZIX, ULTIVA |
| Zolpidem/Dabrafenib SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Dabrafenib is a CYP3A4 inducer.(1) Agents that induce CYP3A4 may induce the metabolism of zolpidem.(2) CLINICAL EFFECTS: Concurrent use of CYP3A4 inducers may decrease levels of and effects from zolpidem.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Consider alternative therapy for sleep or dose adjustment in patients undergoing therapy with dabrafenib.(1,2) DISCUSSION: Coadministration of dabrafenib (150 mg twice daily for 15 days) followed by midazolam 3 mg (CYP3A4 substrate) decreased midazolam area-under-curve (AUC) 74%.(1) In a study in eight healthy subjects, rifampin (600 mg daily for 5 days) decreased zolpidem AUC and maximum concentration (Cmax) by 73% and 58%, respectively.(2) |
TAFINLAR |
| Selected Opioids for MAT/Sleep Drugs SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of buprenorphine or diacetylmorphine and sleep drugs may result in additive CNS depression and sleep-related disorders.(1-3) CLINICAL EFFECTS: Concurrent use of buprenorphine or diacetylmorphine and other CNS depressants, such as sleep drugs, may result in profound sedation, respiratory depression, coma, and/or death.(1-3) Concurrent use of opioids with eszopiclone, zaleplon, or zolpidem may increase the risk of sleep-related disorders including central sleep apnea and sleep-related hypoxemia, and complex sleep behaviors like sleepwalking, sleep driving, and other activities while not fully awake. Rarely, serious injuries or death have resulted from complex sleep behaviors.(4) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Medication assisted treatment (MAT) with buprenorphine or diacetylmorphine is not contraindicated in patients taking CNS depressants; however, discontinuation of CNS depressants is preferred in most cases. In some cases, monitoring at a higher level of care may be appropriate. In others, gradual tapering or decreasing to the lowest effective dose of the CNS depressant is appropriate. Consider other medications and nonpharmacologic treatments to address anxiety or insomnia. Ensure that other health care providers prescribing other CNS depressants are aware of the patient's buprenorphine or diacetylmorphine treatment.(2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(5) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who have had a previous episode of complex sleep behavior.(4) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(6) DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(7) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(8) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(9) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(10) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(11) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(12) While concomitant use of MAT with CNS depressants increases the risk of adverse reactions, barriers to MAT can pose a greater risk of morbidity and mortality due to opioid use disorder.(2) As of April 2019, the FDA had identified 66 cases of complex sleep behaviors with eszopiclone, zaleplon, or zolpidem, of which 20 cases resulted in death and the remainder resulted in serious injuries. It was not reported how many of the cases involved concomitant use of other CNS depressants.(4) |
BRIXADI, BUPRENORPHINE HCL, BUPRENORPHINE-NALOXONE, SUBLOCADE, SUBOXONE, ZUBSOLV |
| Levomethadone;Methadone (Immediate Release)/Sleep Drugs; Tranquilizers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of methadone and sleep drugs or tranquilizers may result in additive CNS depression and sleep-related disorders.(1) Levomethadone is an enantiomer of methadone.(2) CLINICAL EFFECTS: Concurrent use of methadone and other CNS depressants, such as sleep drugs or tranquilizers, may result in profound sedation, respiratory depression, coma, and/or death.(1) Concurrent use of opioids with eszopiclone, zaleplon, or zolpidem may increase the risk of sleep-related disorders including central sleep apnea and sleep-related hypoxemia, and complex sleep behaviors like sleepwalking, sleep driving, and other activities while not fully awake. Rarely, serious injuries or death have resulted from complex sleep behaviors.(3) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as sleep drugs or tranquilizers to patients for whom alternatives are inadequate.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(4) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who have had a previous episode of complex sleep behavior.(3) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(5) DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(6) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(7) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(8) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(9) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(10) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(11) As of April 2019, the FDA had identified 66 cases of complex sleep behaviors with eszopiclone, zaleplon, or zolpidem, of which 20 cases resulted in death and the remainder resulted in serious injuries. It was not reported how many of the cases involved concomitant use of other CNS depressants.(2) |
METHADONE HCL, METHADONE HCL-0.9% NACL, METHADONE HCL-NACL |
| Levomethadone; Methadone for MAT/Sleep Drugs; Tranquilizers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of methadone and sleep drugs or tranquilizers may result in additive CNS depression and sleep-related disorders.(1,2) Levomethadone is an enantiomer of methadone.(3) CLINICAL EFFECTS: Concurrent use of methadone and other CNS depressants, such as sleep drugs or tranquilizers, may result in profound sedation, respiratory depression, coma, and/or death.(1,2) Concurrent use of opioids with eszopiclone, zaleplon, or zolpidem may increase the risk of sleep-related disorders including central sleep apnea and sleep-related hypoxemia, and complex sleep behaviors like sleepwalking, sleep driving, and other activities while not fully awake. Rarely, serious injuries or death have resulted from complex sleep behaviors.(4) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Medication assisted treatment (MAT) with methadone is not contraindicated in patients taking CNS depressants; however, discontinuation of CNS depressants is preferred in most cases. In some cases, monitoring at a higher level of care may be appropriate. In others, gradual tapering or decreasing to the lowest effective dose of the CNS depressant is appropriate. Consider other medications and nonpharmacologic treatments to address anxiety or insomnia. Ensure that other health care providers prescribing other CNS depressants are aware of the patient's buprenorphine or methadone treatment.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who have had a previous episode of complex sleep behavior.(4) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(5) DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(6) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(7) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(8) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(9) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(10) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(11) While concomitant use of MAT with CNS depressants increases the risk of adverse reactions, barriers to MAT can pose a greater risk of morbidity and mortality due to opioid use disorder.(2) As of April 2019, the FDA had identified 66 cases of complex sleep behaviors with eszopiclone, zaleplon, or zolpidem, of which 20 cases resulted in death and the remainder resulted in serious injuries. It was not reported how many of the cases involved concomitant use of other CNS depressants.(4) |
DISKETS, METHADONE HCL, METHADONE INTENSOL, METHADOSE |
The following contraindication information is available for AMBIEN CR (zolpidem tartrate):
Drug contraindication overview.
*History of a complex sleep behavior while taking eszopiclone, zaleplon, or zolpidem. *Known hypersensitivity to zolpidem.
*History of a complex sleep behavior while taking eszopiclone, zaleplon, or zolpidem. *Known hypersensitivity to zolpidem.
There are 0 contraindications.
There are 5 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Alcohol intoxication |
| Depression |
| Disease of liver |
| Sleep apnea |
| Suicidal ideation |
There are 9 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Acute cognitive impairment |
| Aggressive behavior |
| Attention-deficit hyperactivity disorder |
| Debilitation |
| Drug abuse |
| Hallucinations |
| Memory impairment |
| Myasthenia gravis |
| Severe chronic obstructive pulmonary disease |
The following adverse reaction information is available for AMBIEN CR (zolpidem tartrate):
Adverse reaction overview.
Zolpidem tartrate conventional tablets generally are well tolerated at recommended doses (i.e., up to 10 mg). Adverse effects of the drug tend to be dose-related, particularly in geriatric patients and at doses exceeding those recommended. The most common adverse reactions with zolpidem conventional tablets when used in the short-term (<10 nights) include drowsiness, dizziness, and diarrhea; common adverse reactions reported with long-term use (28-35 nights) of the conventional tablets include dizziness and drugged feeling.
Adverse effects of zolpidem tartrate as extended-release tablets tend to be dose-related, particularly for certain adverse nervous system and GI effects. The most common adverse effects of zolpidem tartrate as extended-release tablets (occurring in >10% of adult patients) include headache, next-day somnolence, and dizziness. The incidence of adverse effects in patients receiving zolpidem tartrate as 1.75-
or 3.5-mg sublingual tablets were headache, fatigue, and nausea.
Zolpidem tartrate conventional tablets generally are well tolerated at recommended doses (i.e., up to 10 mg). Adverse effects of the drug tend to be dose-related, particularly in geriatric patients and at doses exceeding those recommended. The most common adverse reactions with zolpidem conventional tablets when used in the short-term (<10 nights) include drowsiness, dizziness, and diarrhea; common adverse reactions reported with long-term use (28-35 nights) of the conventional tablets include dizziness and drugged feeling.
Adverse effects of zolpidem tartrate as extended-release tablets tend to be dose-related, particularly for certain adverse nervous system and GI effects. The most common adverse effects of zolpidem tartrate as extended-release tablets (occurring in >10% of adult patients) include headache, next-day somnolence, and dizziness. The incidence of adverse effects in patients receiving zolpidem tartrate as 1.75-
or 3.5-mg sublingual tablets were headache, fatigue, and nausea.
There are 23 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
| None. |
CNS depression Orthostatic hypotension |
| Rare/Very Rare |
|---|
|
Abnormal hepatic function tests Accidental fall Acute myocardial infarction Acute respiratory failure Altered consciousness Anaphylaxis Anemia Angioedema Cardiac arrhythmia Cholestasis Complex sleep behavior Delirium Hallucinations Hepatocellular damage Hypotension Infection Lower respiratory infection Pulmonary thromboembolism Skin rash Sleep walking disorder Suicidal ideation |
There are 57 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Diarrhea Dizziness Drowsy Fatigue Headache disorder Hiccups Nausea |
Acute abdominal pain Acute cognitive impairment Arthralgia Blurred vision Constipation Depression Diplopia Dream disorder Dyspepsia General weakness Lethargy Malaise Memory impairment Myalgia Rhinitis Sedation hangover effect Urinary tract infection Vertigo Visual changes Vomiting Xerostomia |
| Rare/Very Rare |
|---|
|
Accommodation disorder Aggressive behavior Agitation Angina Anorexia Ataxia Back pain Chest pain Concentration difficulty Depersonalization Disturbance in thinking Drug dependence Euphoria Flu-like symptoms Hemorrhoids Hyperhidrosis Irritability Libido changes Nervousness Pallor Palpitations Panic disorder Phlebitis Sinusitis Stomatitis Stupor Symptoms of anxiety Tenesmus Upper respiratory infection |
The following precautions are available for AMBIEN CR (zolpidem tartrate):
Zolpidem tartrate is not recommended for use in pediatric patients. Safety and efficacy of the drug have not been established in pediatric patients younger than 18 years of age. In an 8-week clinical study in pediatric patients (6-17 years of age) with insomnia associated with attention deficit hyperactivity disorder (ADHD), zolpidem tartrate (0.25 mg/kg administered as an oral solution at bedtime) did not appear to decrease sleep latency as compared with placebo.
In this study, the most frequent treatment-emergent adverse effects (compared with placebo) were nervous system effects, including dizziness (23.5 versus 1.5%), headache (12.5 versus 9.2%), and hallucinations (7 versus 0%).
Contraindicated
Severe Precaution
Management or Monitoring Precaution
In this study, the most frequent treatment-emergent adverse effects (compared with placebo) were nervous system effects, including dizziness (23.5 versus 1.5%), headache (12.5 versus 9.2%), and hallucinations (7 versus 0%).
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
Published data from observational studies, birth registries, and case reports do not report a clear association between use of zolpidem and major birth defects. There are limited postmarketing reports of moderate to severe neonatal respiratory depression requiring artificial ventilation or intratracheal intubation when zolpidem was used late in the third trimester of pregnancy; the majority of neonates recovered within hours to a few weeks after birth once treated. Zolpidem crosses the placenta and may cause respiratory depression and sedation in neonates.
Neonates exposed to zolpidem during pregnancy and labor should be monitored for signs of excess sedation, hypotonia, and respiratory depression and treated as clinically appropriate. Reproduction studies in animals were performed using zolpidem rather than zolpidem tartrate; dosages are expressed in terms of the base. Administration of zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring development at dosages exceeding the maximum recommended human dosage (MRHD) of zolpidem tartrate as conventional tablets (10 mg daily); however, teratogenicity was not observed.
When zolpidem was administered at oral dosages of 4, 20, and 100 mg/kg daily to pregnant rats during the period of organogenesis, delayed fetal development (incomplete fetal skull ossification) occurred at all but the lowest dosage (4 mg/kg daily, which is approximately 5 times the MRHD of zolpidem tartrate as conventional tablets on a mg/m2 basis). In addition, administration of zolpidem to rats at oral dosages of 4, 20, and 100 mg/kg daily from day 15 of gestation through lactation delayed offspring growth and decreased survival at all but the lowest dosage. In rabbits receiving zolpidem during organogenesis at oral dosages of 1, 4, and 16 mg/kg daily, increased embryofetal death and incomplete fetal skeletal ossification occurred at the highest dosage studied. No risk of adverse effects on fetal development was observed following oral administration of zolpidem to pregnant rats and rabbits at clinically relevant doses.
Neonates exposed to zolpidem during pregnancy and labor should be monitored for signs of excess sedation, hypotonia, and respiratory depression and treated as clinically appropriate. Reproduction studies in animals were performed using zolpidem rather than zolpidem tartrate; dosages are expressed in terms of the base. Administration of zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring development at dosages exceeding the maximum recommended human dosage (MRHD) of zolpidem tartrate as conventional tablets (10 mg daily); however, teratogenicity was not observed.
When zolpidem was administered at oral dosages of 4, 20, and 100 mg/kg daily to pregnant rats during the period of organogenesis, delayed fetal development (incomplete fetal skull ossification) occurred at all but the lowest dosage (4 mg/kg daily, which is approximately 5 times the MRHD of zolpidem tartrate as conventional tablets on a mg/m2 basis). In addition, administration of zolpidem to rats at oral dosages of 4, 20, and 100 mg/kg daily from day 15 of gestation through lactation delayed offspring growth and decreased survival at all but the lowest dosage. In rabbits receiving zolpidem during organogenesis at oral dosages of 1, 4, and 16 mg/kg daily, increased embryofetal death and incomplete fetal skeletal ossification occurred at the highest dosage studied. No risk of adverse effects on fetal development was observed following oral administration of zolpidem to pregnant rats and rabbits at clinically relevant doses.
Zolpidem is distributed into milk in small amounts in humans. Excess sedation has been reported in nursing infants exposed to zolpidem through breast milk. The effects of zolpidem on milk production are not known.
Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for zolpidem and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition. Infants exposed to zolpidem through breast milk should be monitored for excess sedation, hypotonia, and respiratory depression. Nursing women may consider interrupting breast-feeding and pumping and discarding breast milk during treatment and for 23 hours after administration of zolpidem to minimize drug exposure to a breast-fed infant.
Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for zolpidem and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition. Infants exposed to zolpidem through breast milk should be monitored for excess sedation, hypotonia, and respiratory depression. Nursing women may consider interrupting breast-feeding and pumping and discarding breast milk during treatment and for 23 hours after administration of zolpidem to minimize drug exposure to a breast-fed infant.
Safety and efficacy of zolpidem for the treatment of insomnia in geriatric patients have been evaluated in controlled, double-blind studies. Geriatric or debilitated patients may be particularly sensitive to the effects of zolpidem. Adverse effects of the drug tend to be dose-related, particularly in geriatric patients.
In addition, peak plasma zolpidem concentrations, elimination half-life, and AUC are increased substantially in geriatric patients compared with younger adults receiving zolpidem tartrate as conventional tablets. In placebo-controlled clinical trials in geriatric patients receiving zolpidem tartrate doses of 10 mg or less (as conventional tablets), the most frequent adverse effects were dizziness, drowsiness, and diarrhea. In placebo-controlled clinical trials in geriatric patients receiving zolpidem tartrate 6.25
mg as extended-release tablets, the most frequent adverse effects were headache, dizziness, and next-day somnolence. In clinical trials performed outside the US, involving approximately 2000 patients, falls were reported in about 1.5% of patients (93% of those being 70 years of age or older); 82% of the patients 70 years of age or older who experienced falls received zolpidem tartrate doses exceeding 10 mg (as conventional tablets).
In these clinical trials, confusion was reported in 1.2% of patients (75% of those being 70 years of age or older); 78% of the patients 70 years of age or older who experienced confusion were receiving doses exceeding 10 mg (as conventional tablets). The manufacturers recommend that zolpidem dosage be reduced in geriatric and/or debilitated patients to minimize adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative and hypnotic drugs.
Sedatives may cause confusion and oversedation in geriatric patients; geriatric patients should be observed closely. Geriatric patients are at a higher risk of falls related to drowsiness and CNS depression caused by zolpidem.
In addition, peak plasma zolpidem concentrations, elimination half-life, and AUC are increased substantially in geriatric patients compared with younger adults receiving zolpidem tartrate as conventional tablets. In placebo-controlled clinical trials in geriatric patients receiving zolpidem tartrate doses of 10 mg or less (as conventional tablets), the most frequent adverse effects were dizziness, drowsiness, and diarrhea. In placebo-controlled clinical trials in geriatric patients receiving zolpidem tartrate 6.25
mg as extended-release tablets, the most frequent adverse effects were headache, dizziness, and next-day somnolence. In clinical trials performed outside the US, involving approximately 2000 patients, falls were reported in about 1.5% of patients (93% of those being 70 years of age or older); 82% of the patients 70 years of age or older who experienced falls received zolpidem tartrate doses exceeding 10 mg (as conventional tablets).
In these clinical trials, confusion was reported in 1.2% of patients (75% of those being 70 years of age or older); 78% of the patients 70 years of age or older who experienced confusion were receiving doses exceeding 10 mg (as conventional tablets). The manufacturers recommend that zolpidem dosage be reduced in geriatric and/or debilitated patients to minimize adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative and hypnotic drugs.
Sedatives may cause confusion and oversedation in geriatric patients; geriatric patients should be observed closely. Geriatric patients are at a higher risk of falls related to drowsiness and CNS depression caused by zolpidem.
The following prioritized warning is available for AMBIEN CR (zolpidem tartrate):
WARNING: Rarely, after taking this drug, people have gotten out of bed and driven vehicles while not fully awake ("sleep-driving"). People have also sleepwalked, prepared/eaten food, made phone calls, or had sex while not fully awake. Often, these people do not remember these events.
This problem can be dangerous (possibly fatal) to you or to others. If you find out that you have done any of these activities after taking this medication, tell your doctor right away. You should not take this medication or similar medications (such as eszopiclone, zaleplon) if you have this reaction to the medication.
WARNING: Rarely, after taking this drug, people have gotten out of bed and driven vehicles while not fully awake ("sleep-driving"). People have also sleepwalked, prepared/eaten food, made phone calls, or had sex while not fully awake. Often, these people do not remember these events.
This problem can be dangerous (possibly fatal) to you or to others. If you find out that you have done any of these activities after taking this medication, tell your doctor right away. You should not take this medication or similar medications (such as eszopiclone, zaleplon) if you have this reaction to the medication.
The following icd codes are available for AMBIEN CR (zolpidem tartrate)'s list of indications:
| Insomnia | |
| F51.0 | Insomnia not due to a substance or known physiological condition |
| F51.01 | Primary insomnia |
| F51.02 | Adjustment insomnia |
| F51.03 | Paradoxical insomnia |
| F51.04 | Psychophysiologic insomnia |
| F51.05 | Insomnia due to other mental disorder |
| F51.09 | Other insomnia not due to a substance or known physiological condition |
| G47.0 | Insomnia |
| G47.00 | Insomnia, unspecified |
| G47.01 | Insomnia due to medical condition |
| G47.09 | Other insomnia |
| Sleep maintenance insomnia | |
| F51.0 | Insomnia not due to a substance or known physiological condition |
| F51.01 | Primary insomnia |
| F51.02 | Adjustment insomnia |
| F51.04 | Psychophysiologic insomnia |
| F51.05 | Insomnia due to other mental disorder |
| F51.09 | Other insomnia not due to a substance or known physiological condition |
| G47.0 | Insomnia |
| G47.00 | Insomnia, unspecified |
| G47.01 | Insomnia due to medical condition |
| G47.09 | Other insomnia |
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