ゾルピデム

193-197

196 °C

2788

2908.2；2797.5；2814.4；2756

177.6 Ų [M+H]+ [CCS Type: DT; Method: single field calibrated]

177.2 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

This chemical does not meet GHS hazard criteria for 10% (1 of 10) of reports.

Warning

H302 (90%): Harmful if swallowed [Warning Acute toxicity, oral]；H336 (90%): May cause drowsiness or dizziness [Warning Specific target organ toxicity, single exposure; Narcotic effects]；H411 (90%): Toxic to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]

P261, P264, P270, P271, P273, P301+P317, P304+P340, P319, P330, P391, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 10 reports by companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.；Reported as not meeting GHS hazard criteria per 1 of 10 reports by companies.；There are 2 notifications provided by 9 of 10 reports by companies with hazard statement code(s).；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

DEA schedule IV controlled substance

Status: Active Update: 29-05-2018 https://echa.europa.eu/registration-dossier/-/registered-dossier/22051

General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. sedative hypnotic effect was shown to be reduced by flumazenil and therefore may be useful; however, flumazenil administration may contribute to the appearance of neurological symptoms (convulsions). As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate signs should be monitored and general supportive measures employed. Hypotension and CNS depression should be monitored and treated by appropriate medical intervention. Sedating drugs should be withheld following zolpidem overdosage, even if excitation occurs. The value of dialysis in the treatment of overdosage has not been determined, although hemodialysis studies in patients with renal failure receiving therapeutic doses have demonstrated that zolpidem is not dialyzable. (L1712)

In multiple premarketing randomized controlled trials, zolpidem was not associated with an increased rate of serum enzyme elevations in comparison to placebo therapy. A single instance of clinically apparent liver injury has been reported. The onset of injury was 2 days after a single dose of zolpidem and was accompanied by abdominal pain, but no jaundice. The pattern of liver enzyme elevations was hepatocellular and the abnormalities were self-limited, although they seemed to recur on reexposure. Zolpidem is metabolized in the liver by the cytochrome P450 system (predominantly CYP 3A4) and can cause drug-drug interactions, although such interactions are rare. Thus, zolpidem has not been linked to cases of liver injury with jaundice, but rarely may cause transient, mild-to-moderate serum enzyme elevations with or without symptoms.；Likelihood score: E (unlikely cause of clinically apparent liver injury).；Drug Class: Sedatives and Hypnotics；Other Drugs in the Subclass, Benzodiazepine Receptor Agonists: Eszopiclone, Zaleplon

Adverse effects of zolpidem include anaphylaxis, changes in behavior, withdrawal, and central nervous system (CNS) depression. In rare situations, patients have reported tongue, larynx, or glottis swelling in the form of angioedema. Also, patients have reported shortness of breath, airway closure, nausea, and vomiting. If these events are reported, do not use zolpidem. Patients who experience closure in the throat, glottis, or larynx should be sent to the emergency department.；Drug-Drug Interactions；Alcohol and CNS depressants: Concurrent use of CNS depressants or alcohol with zolpidem may result in additive impairment of psychomotor performance and an increased risk of CNS depression. Due to potential additive effects, adjustments in the dosage of zolpidem and other concomitant CNS depressants may be necessary. For the 5 mg dose of zolpidem immediate-release, consider employing an alternative immediate-release product. Avoid combining zolpidem with other sedative-hypnotics at bedtime or during the night.；Opioids: Concurrent administration of zolpidem and opioids may elevate the risk of respiratory depression. Restrict the dosage and duration of simultaneous use of zolpidem and opioids; monitor for respiratory depression.；Imipramine and chlorpromazine: Concurrent use of imipramine or chlorpromazine with zolpidem may produce an additive effect, decreasing alertness and psychomotor performance. In patients who are prescribed opioids, concurrent use of Z-drugs (eg, zolpidem) significantly raises the risk of overdose, even after accounting for confounding factors. This finding is particularly significant given the widespread use of Z-drugs among patients treated with opioids.；Sertraline: Concurrent administration of zolpidem and sertraline increases exposure to zolpidem. Consider using another immediate-release product with a lower zolpidem dose (5 mg).；CYP3A4 inducers: Simultaneous zolpidem use with CYP3A4 inducers like rifampin may decrease zolpidem exposure, impacting its metabolism. St. John's Wort induces hepatic CYP enzymes, including CYP3A4 and CYP2B6. This accelerates the metabolism of zolpidem, potentially reducing its effectiveness.；CYP3A4 inhibitors: Simultaneous use of CYP3A4 inhibitors increases zolpidem exposure. Consider using another immediate-release product with a lower zolpidem dose. Additionally, clinicians should be aware that ciprofloxacin (a strong inhibitor of CYP1A2, a moderate inhibitor of CYP3A4) and fluvoxamine (a strong inhibitor of CYP1A2, a weak inhibitor of CYP2C9 and CYP3A4) can inhibit the metabolism of zolpidem, increasing the exposure to zolpidem.

Drug overdose with zolpidem involves CNS depression, cognitive impairments leading to drowsiness or coma, cardiovascular and respiratory depression, and other fatalities. The acute toxicity of zolpidem is less in severity than other short-acting benzodiazepines like triazolam and midazolam. However, in combined intoxication with other CNS depressant drugs, zolpidem can induce coma in patients even with a low concentration. Single-drug poisoning is benign and should not require therapeutic intervention.；In cases of zolpidem overdose, gastric lavage should be considered within the first hour of ingestion to optimize its benefits. This procedure is most appropriate for conscious patients with a functional gag reflex, as it minimizes the risk of aspiration. Patients can also benefit from the administration of flumazenil and intravenous fluids as well. Flumazenil is a known reversal agent for benzodiazepine toxicity. However, it can exacerbate other neurological symptoms, such as convulsions. In the event of drug toxicity, the patient's respiratory function, oxygen saturation, blood pressure, pulse, and other vitals should be monitored.

Zolpidem modulates the alpha-subunit, known as the benzodiazepine receptor, within the GABA_A receptor chloride channel macromolecular complex. Unlike the benzodiazepines, which non-selectively interact with all three alpha-receptor subtypes, Zolpidem preferentially binds to the alpha-1 receptor.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

zolpidem

DILI Negative

Oral

DOI:10.1016/j.drudis.2019.09.022

◉ Summary of Use during Lactation；The levels of zolpidem in breastmilk are low and is rapidly eliminated from milk, so it would not be expected to cause any adverse effects in older breastfed infants who does not breastfeed during the night after the mother’s dose. The manufacturer states that excess sedation in infants exposed to zolpidem through breastmilk has been reported, although details are lacking. Some expert opinion recommends against zolpidem use during breastfeeding, primarily because of the lack of robust documentation. Monitor the infant for sedation, poor feeding and poor weight gain.；◉ Effects in Breastfed Infants；The mother of a newborn was taking 5 to 10 mg of zolpidem nightly. At the one-month checkup, no adverse effects were noted by the patient’s pediatrician.；Three infants were breastfed by mothers taking zolpidem 5 mg daily (n = 2) or as needed (n = 1). No abnormalities were found at the one-month checkup.；An infant was partially breastfed by a mother taking zolpidem 5 mg daily and bromazepam 6 mg daily. No abnormalities were found at the infant’s 1-month and the 3-month checkups.；◉ Effects on Lactation and Breastmilk；Relevant published information was not found as of the revision date.

◈ What is zolpidem?；Zolpidem is a sedative-hypnotic medication (causes calm and sleep) that has been used to treat insomnia (not being able to fall asleep or stay asleep). It belongs to a group of medications called hypnotic benzodiazepine receptor agonists, or HBRAs (sometimes called z-hypnotics or z-drugs). HBRAs are not benzodiazepines, but they work in a similar way. Some brand names of zolpidem are Ambien®, Edluar®, and Intermezzo®.Sometimes when women find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take your medication. Some people who stop taking zolpidem suddenly might experience withdrawal symptoms like fatigue, nausea, vomiting, flushing, lightheadedness, crying, and nervousness. Your healthcare providers can talk with you about the benefits of treating insomnia, and the risks of untreated insomnia during pregnancy.；◈ I take zolpidem. Can it make it harder for me to get pregnant?；Studies have not been done to see if taking zolpidem can make it harder to get pregnant.；◈ Does taking zolpidem increase the chance of miscarriage?；Miscarriage is common and can occur in any pregnancy for many different reasons. It is not known if zolpidem can increase the chance of miscarriage.；◈ Does taking zolpidem increase the chance of birth defects?；Birth defects can happen in any pregnancy for different reasons. Out of all babies born each year, about 3 out of 100 (3%) will have a birth defect. We look at research studies to try to understand if an exposure, like zolpidem, can increase the chance of birth defects in a pregnancy. Several studies have reported no increased chance of birth defects with the use of zolpidem during pregnancy.；◈ Does taking zolpidem in pregnancy increase the chance of other pregnancy-related problems?；Several studies have found that using zolpidem during pregnancy does not greatly increase the chance of other pregnancy-related problems, such as preterm delivery (birth before week 37) or low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth). Other studies have found that women who took zolpidem during pregnancy were slightly more likely to deliver early or have smaller babies compared with women who did not take these medications during pregnancy. These studies did not consider other factors, such as the use of other medications, smoking, alcohol or drug use, or the underlying medical condition that the medication was used to treat. This makes it hard to know if the medication, illnesses being treated, or other factors are the reason for the reported issues.；◈ Does taking zolpidem in pregnancy affect future behavior or learning for the child?；It is not known if zolpidem can increase the chance of behavior or learning issues for the child.；◈ Breastfeeding while taking zolpidem:；Zolpidem passes into breast milk in small amounts. One small study and a case report found that 6 women who took zolpidem during the days after delivery had small amounts of the medication in their breast milk three hours after taking it. No problems were reported in their babies. If you suspect the baby has any symptoms (being very sleepy, trouble gaining weight, low muscle tone or floppiness, or slow breathing), contact the child’s healthcare provider. Be sure to talk to your healthcare provider about all your breastfeeding questions.；◈ If a man takes zolpidem, could it affect fertility or increase the chance of birth defects?；Studies have not been done to see if zolpidem could affect men’s fertility (ability to get a woman pregnant) or increase the chance of birth defects. In general, exposures that fathers or sperm donors have are unlikely to increase risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

DEA schedule IV controlled substance

Status: Active Update: 29-05-2018 https://echa.europa.eu/registration-dossier/-/registered-dossier/22051

N05CF02

N - Nervous system；N05 - Psycholeptics；N05C - Hypnotics and sedatives；N05CF - Benzodiazepine related drugs；N05CF02 - Zolpidem

QN - Nervous system；QN05 - Psycholeptics；QN05C - Hypnotics and sedatives；QN05CF - Benzodiazepine related drugs；QN05CF02 - Zolpidem

**Effects on the central nervous system (CNS)** This drug has CNS depressant effects, which may include somnolence, decreased alertness, sedation, drowsiness, dizziness, and other changes in psychomotor function. Due to the above effects, the FDA has recommended an initial dose of zolpidem (immediate-acting) is a single dose of 5 mg for women and a single dose of 5 or 10 mg for men, immediately before bedtime with at least 7-8 hours remaining before the planned time of awakening. Refer to product labeling for detailed information,. **Effects on memory** Controlled studies in adults using objective measures of memory demonstrated no significant evidence of next-day memory impairment after the administration of zolpidem. On the contrary, in a clinical study involving the administration of zolpidem doses of 10 and 20 mg, a marked reduction in a next-morning recall of information relayed to subjects during peak drug effect (90 minutes after dosing) was observed. These subjects experienced a condition known as _anterograde amnesia_. Subjective evidence from adverse event data has suggested that anterograde amnesia may occur after zolpidem administration, mainly at doses above 10 mg. **Effects on psychomotor function** This drug may cause decreased psychomotor performance. Additive psychomotor effects may occur with other drugs that cause depression of psychomotor function, including alcohol. Patients taking zolpidem should be cautioned against participating in hazardous activities or occupations requiring complete mental alertness or motor coordination, including operating machinery or driving a motor vehicle after ingesting the drug. Potential impairment of the performance of the above types of activities may also occur the day after zolpidem ingestion, especially at higher doses and ingestion of the extended-release form,. **Effects on insomnia and sleep stages** Evidence suggests that this drug is associated with minimal rebound insomnia. During clinical t

Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic substance with a chemical structure that is not related to the structure benzodiazepines, barbiturates, pyrrolopyrazines, pyrazolopyrimidines or other drugs exerting hypnotic effects. It interacts with a _GABA-BZ_ receptor complex and shares various pharmacological properties with the _benzodiazepine_ class of drugs. Subunit binding of the _GABAA_ receptor chloride channel macromolecular complex is thought to lead to the sedative, anticonvulsant, anxiolytic, and myorelaxant drug effects of zolpidem. The main regulatory site of the GABAA receptor complex can be found on its _alpha (α) subunit_ and is called the _benzodiazepine_ (BZ) or _omega (ω)_ receptor. At least three different subtypes of the (ω) receptor have been identified to this date. In contrast to benzodiazepine drugs, which are found to modulate all benzodiazepine receptor subtypes in a non-selective fashion, zolpidem binds the (BZ1) receptor specifically with a potent affinity for the alpha 1/alpha 5 subunits (in vitro). More recent studies suggest that zolpidem binds primarily to the alpha 1, 2, and 3 subunits of the GABA receptor,,, and not the alpha 5 subunit. The (_BZ1_) receptor is found primarily on the Lamina IV of the brain sensorimotor cortical regions, substantia nigra (pars reticulata), cerebellum molecular layer, olfactory bulb, ventral thalamic complex, pons, inferior colliculus, and globus pallidus. Specific and selective binding of zolpidem on the (BZ1) receptor is not considered absolute, however, this binding could potentially explain the relative lack of myorelaxant and anticonvulsant activity in animal studies in addition to the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem at hypnotic doses.

Zolpidem is metabolized to three pharmacologically by various hepatic cytochrome P450 (CYP) isoenzymes, mainly CYP3A4, but also CYP1A2 and CYP2C9,. Although zolpidem is heavily metabolized, all three metabolites are inactive. The major metabolic routes in humans are oxidation of the methyl group on the phenyl ring or the methyl group on the imidazopyridine moiety, to produce carboxylic acids (metabolites I and II), and hydroxylation of one of the imidazopyridine groups (to produce metabolite X). Another less common pathway is by the oxidation of the methyl groups on the substituted amide.

Zolpidem has known human metabolites that include methoxyzolpidem.

Zolpidem is converted to inactive metabolites in the liver. Route of Elimination: Zolpidem tartrate tablets are converted to inactive metabolites that are eliminated primarily by renal excretion. Half Life: 2.6 hours

7K383OQI23

ZOLPIDEM

Established Pharmacologic Class [EPC] - gamma-Aminobutyric Acid A Receptor Positive Modulator

Mechanisms of Action [MoA] - GABA A Receptor Positive Modulators

Physiologic Effects [PE] - Central Nervous System Depression

Zolpidem is a gamma-Aminobutyric Acid A Receptor Positive Modulator. The mechanism of action of zolpidem is as a GABA A Receptor Positive Modulator. The physiologic effect of zolpidem is by means of Central Nervous System Depression.

Drugs used to induce SLEEP, prevent SLEEPLESSNESS, or treat SLEEP INITIATION AND MAINTENANCE DISORDERS.

Endogenous compounds and drugs that bind to and activate GABA-A RECEPTORS.

Zolpidem is rapidly absorbed from the gastrointestinal tract. In a single-dose crossover study in 45 healthy subjects given 5 and 10 mg zolpidem tartrate tablets, the average peak zolpidem concentrations (Cmax) were 59 and 121 ng/mL, respectively, occurring at a mean time (Tmax) of 1.6 hours for both doses.

Zolpidem tartrate tablets are converted to inactive metabolites that are eliminated mainly by renal excretion.

0.54 to 0.68 L/kg (in humans). In patients with long term renal insufficiency who were not yet on hemodialysis, the volume of distribution was found to increase significantly, AUC increased by 60%, and half-life nearly doubled.

In a clinical trial, after a 20mg dose, total clearance of zolpidem 0.24 to 0.27 ml/min/kg.

Use (kg; approx.) in Germany (2009): >750；Use (kg) in USA (2002): 3900；Use (kg) in France (2004): 3344；Consumption (g per capita; approx.) in Germany (2009): 0.00916；Consumption (g per capita) in the USA (2002): 0.0138；Consumption (g per capita) in France (2004): 0.0553；Calculated removal (%): 39.2

For the short-term treatment of insomnia.