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ZOLPIDEM AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Zolpidem is an oral nonbenzodiazepine hypnotic of the imidazopyridine class. Zaleplon is also a nonbenzodiazepine hypnotic, but is in the pyrazolopyrimidine class of medications.

Specific Substances

    A) ZALEPLON
    1) 3'-(3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)-N-ethylacetanilide
    2) CL284846
    3) L846
    4) LJC 10846
    5) CAS 151319-34-5
    ZOLPIDEM
    1) SL-80.0750 (zolpidem)
    2) SL-80.0750-23N (zolpidem tartrate)
    3) N,N,6-trimethyl-2-p-tolyl-imidazo(1, 2-a) pyridine-3-acetamide L-(+)-tartrate (2:1)
    4) N,N-Dimethyl-2-(6-methyl-2-p-tolyimidazo (1,2-a)-pyridin-3-yl) acetamide hemitartrate
    5) Zolpidem Hemitartrate
    6) CAS 82626-48-0 (zolpidem)
    7) CAS 99294-93-6 (zolpidem tartrate)

Available Forms Sources

    A) FORMS
    1) ZALEPLON
    a) Zaleplon is available in the US as 5 mg and 10 mg capsules (Prod Info SONATA(R) oral capsules, 2007).
    2) ZOLPIDEM
    a) Zolpidem is available in the US in the following formulations:
    1) 5 mg and 10 mg oral tablets (Prod Info Ambien(R) oral tablets, 2009).
    2) 6.25 mg and 12.5 mg extended-release oral tablets (Prod Info AMBIEN CR(R) extended-release oral tablets, 2009).
    3) 5 mg and 10 mg sublingual tablets (Prod Info Edluar(R) sublingual tablet, 2009).
    4) 5 mg/actuation metered-dose oral spray; 60 metered actuations in total after the initial priming of 5 actuations (Prod Info ZOLPIMIST(R) oral spray, 2008).
    5) Zolpidem oral spray has a sweet cherry flavor, high concentration (50 mg/mL), and faster onset of action than standard immediate-release zolpidem. It is sprayed into the mouth over the tongue and may be more likely than zolpidem tablets to be used in excess (None Listed, 2012; Owen, 2009).
    B) USES
    1) Zaleplon and zolpidem are indicated for the short term treatment of insomnia (Prod Info Edluar(R) sublingual tablet, 2009; Prod Info SONATA(R) oral capsules, 2007; Prod Info Ambien(R) oral tablets, 2009; Prod Info AMBIEN CR(R) extended-release oral tablets, 2009; Prod Info ZOLPIMIST(R) oral spray, 2008).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Zolpidem and zaleplon are sedative hypnotics used for the treatment of insomnia. They have surpassed benzodiazepines as most frequently prescribed sleep aids. They are thought to have less addiction potential than benzodiazepines. Zolpidem is available as a controlled-release formulation. Zolpidem oral spray has a sweet cherry flavor, high concentration (50 mg/mL), and faster onset of action than immediate-release zolpidem. It may be more likely than zolpidem tablets to be used in excess.
    B) PHARMACOLOGY: Although classified as a non-benzodiazepine drug due to different chemical structure, the hypothesized mechanism of action is similar to benzodiazepines; interaction with GABA-benzodiazepine receptor complexes (specifically GABA(A) alpha-1 subunit), enhancing the function of GABA-mediated chloride channels.
    C) TOXICOLOGY: Toxicology is the extension of the pharmacology. CNS depression is the primary effect and is exacerbated by co-ingestion of other sedatives.
    D) EPIDEMIOLOGY: Overdose is common, but serious toxicity is rare.
    E) WITH THERAPEUTIC USE
    1) Gastrointestinal effects of therapeutic doses of zolpidem included nausea, vomiting, and abdominal pain. Dizziness, confusion, impaired coordination, delusions or psychotic reactions, daytime drowsiness, headache, and sleep-eating or sleep-driving, may develop in some patients. Taking the medication immediately prior to bedtime may minimize some of these effects. Toxic psychosis occurred in two adults after the initial intake of zolpidem at therapeutic doses. Withdrawal from these medications has been reported but is likely to be mild.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Somnolence, slurred speech, confusion, and ataxia may occur.
    2) SEVERE TOXICITY: Severe effects are very rare but may occur after co-ingestion with other sedatives and may include hypotension, coma and respiratory depression. Death is extremely rare but may be caused by respiratory depression. Patients that present with coma are at risk for aspiration pneumonia, rhabdomyolysis, and renal failure. Severe ischemia and gangrene were seen following intraarterial injection of a crushed zolpidem tablet.
    0.2.20) REPRODUCTIVE
    A) Zolpidem is classified as FDA pregnancy category C. Adequate and well-controlled studies with zolpidem have not been conducted in pregnant women. One study of women who received zolpidem during pregnancy found significant risks for preterm, cesarean, low birth weight, small for gestational age births, but not congenital abnormalities, compared with controls. Animal studies note maternal effects of reduced weight gain and sedation in rabbits, and maternal lethargy and ataxia in rats. Adverse fetal effects include postimplantation fetal loss and underossification of sternebrae in rabbits, and incomplete skull bone ossification, decreased offspring growth, and decreased survival in rats. Limited data indicate small amounts of zolpidem are excreted in human breast milk, and caution is advised in nursing women. No impairment of fertility was noted in animal studies, but irregular estrus cycles and prolonged precoital intervals are reported for rats.
    0.2.21) CARCINOGENICITY
    A) No evidence of carcinogenic potential was observed in mice.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Serum drug concentrations are not readily available and not clinically helpful. These medications are not detected on routine urine drug screens.
    C) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity.
    D) Monitor creatinine phosphokinase in patients with prolonged immobilization from coma; monitor renal function and urine output in patients with rhabdomyolysis.
    E) Routine monitoring of electrolytes, renal function, glucose, pulse oximetry and blood gases may be helpful. Other causes of coma should be ruled out if the diagnosis is not clear.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) The majority of patients develop mild to moderate toxicity, and only require supportive care.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Severe toxicity generally occurs if other sedating agents are also ingested. Administer activated charcoal if the ingestion is recent and the patient is alert or the airway is protected. Orotracheal intubation for airway protection should be performed if the patient is increasingly drowsy or comatose.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital decontamination is not recommended because of potential for somnolence and loss of airway protection.
    2) HOSPITAL: In general, decontamination is not indicated for this overdose, but may be considered for large overdoses that present early. Activated charcoal could be considered if the patient is awake and cooperative and if the ingestion was large and relatively recent. There is no evidence for the use of whole bowel irrigation or multiple doses of charcoal. Gastric lavage is not indicated as overdose is not life-threatening.
    D) AIRWAY MANAGEMENT
    1) Perform early in patients with severe intoxication (coma, respiratory depression).
    E) ANTIDOTE
    1) There is no antidote for these drugs. Flumazenil has been used with varying success but has not been well-studied. Routine use of flumazenil is NOT recommended. Flumazenil may be useful in establishing a diagnosis in a patient with CNS depression and possibly in preventing the need for respiratory support. Flumazenil should not be administered to patients with cardiac arrhythmias, seizures or a history of seizures, signs/symptoms of a cyclic antidepressant intoxication, or a suspected multidrug ingestion.
    F) COMA
    1) Treatment is symptomatic and supportive. Perform orotracheal intubation to protect the airway. Evaluate for other causes of coma (eg, hypoglycemia, coingestants, metabolic derangements).
    G) RESPIRATORY ARREST
    1) Respiratory depression may occur with very large overdoses or in mixed overdoses with other sedatives, and can be treated with intubation and mechanical ventilation.
    H) ENHANCED ELIMINATION
    1) Hemodialysis is unlikely to be of benefit because of the high degree of protein binding of zolpidem and zaleplon.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic patients (other than mild drowsiness) with inadvertent ingestions may be monitored at home. Children inadvertently ingesting 1 or 2 tablets may be monitored at home.
    2) OBSERVATION CRITERIA: Patients with deliberate ingestions and symptomatic patients should be sent to a health care facility for observation for at least 4 to 6 hours and/or until symptomatically improved. Consider longer observation periods for patients with ingestion of controlled release formulations.
    3) ADMISSION CRITERIA: Patients with significant persistent central nervous system toxicity (CNS depression, confusion or ataxia), should be admitted. Patients with coma or respiratory depression should be admitted to an intensive care setting.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (coma, respiratory depression), or in whom the diagnosis is not clear.
    J) PITFALLS
    1) Failure to diagnose other causes of coma.
    K) PHARMACOKINETICS
    1) Zolpidem and zaleplon are hepatically metabolized and the metabolites are excreted primarily in the urine. They have no active metabolites. Zolpidem and zaleplon’s protein binding is greater than 90%. Plasma half-life is 1 hour for zaleplon and 1.7 hours for zolpidem. Tmax onset is about an hour. Vd is 0.5 L/kg for zolpidem and 1.4 L/kg for zaleplon.
    L) DIFFERENTIAL DIAGNOSIS
    1) Ethanol/benzodiazepine/barbiturate/opioid/other sedative-hypnotics or anticonvulsant poisoning, carbon monoxide or cyanide poisoning, hypoglycemia, infection, environmental hypothermia, metabolic derangement, biogenic amine syndrome (cocaine or methamphetamine washout), stroke, hypothyroidism.

Range Of Toxicity

    A) TOXICITY: Patients that co-ingest these medications with other sedatives may manifest symptoms at much lower amounts than those ingesting these medications alone. In adults, ingestion of 70 to 600 mg zolpidem resulted in mild toxicity and ingestion of 2 g resulted in coma. Children with inadvertent zolpidem ingestions ranging from 2.5 to 30 mg developed mild toxicity (drowsiness) which resolved in 4 hours.
    B) THERAPEUTIC DOSE: ZALEPLON: 5 to 20 mg; ZOLPIDEM: 5 to 12.5 mg.

Clinical Effects

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) ZOLPIDEM
    1) Dizziness or lightheadedness, somnolence, headache, and irritability have occurred with therapeutic doses (Prod Info AMBIEN(R) oral tablets, 2008).
    2) WITH POISONING/EXPOSURE
    a) ZOLPIDEM
    1) In a series of 204 zolpidem ingestions by young children (0 to 5 years of age), drowsiness (29.4%), ataxia (10.3%), hallucinations (4.9%), agitation (3.9%), and dizziness (2%) were reported; the mean dose in children with these manifestations was 13.3 mg, with a range of 0.5 to 300 mg (Forrester, 2009).
    2) In a retrospective study of 897 zolpidem ingestions, slurred speech was reported in 46 (6.3%) of 734 patients after ingesting immediate-release (IR) tablets (mean dose, 122.3 mg) and 11 (6.7%) of 163 patients after ingesting controlled-release (CR) tablets (mean dose, 197.2 mg); confusion was reported in 30 (4.1%) patients after ingesting zolpidem IR (mean dose, 92 mg) and 3 (1.8%) of patients after ingesting zolpidem CR (mean dose, 177.1 mg) (Forrester, 2009a).
    3) Intentional ingestion of 70 to 390 mg of zolpidem by adults resulted in somnolence (20), dizziness (1), and amnesia (1), with full recovery over several hours in 22 cases (Meram & Descotes, 1989).
    4) Intentional suicidal ingestions of zolpidem by 105 adults resulted in coma grade II (4), drowsiness (84), agitation (3), dizziness (1), hypotonia or hyporeflexia (3), mydriasis (3), blurred vision (1), gait disturbances (1), incoherent speech (1), memory impairment (1), and hallucinations (1) (Garnier et al, 1994).
    5) CASE SERIES: In a retrospective pediatric case series, 7 children aged 20 months to 5 years ingested 2.5 to 30 mg of zolpidem. Drowsiness was most frequently reported (5 of 7 patients); other effects included ataxia (2) and visual hallucinations (1). All symptoms resolved within 4 hours (Kurta et al, 1997).
    a) Three adolescents aged 12 to 16 years in the same study ingested zolpidem alone 12.5 to 100 mg. Effects included drowsiness (2), nervousness (1), slurred speech (1), and ataxia (1) (Kurta et al, 1997). All cases were asymptomatic within 6 hours post-ingestion.
    b) In a series of 2918 patients reported to a poison center with exposure to zolpidem only, CNS manifestations were most common, developing in 55.1% of patients. In this group, 52 patients (2.3%) developed agitation, 94 (3.9%) developed ataxia, 29 (1.2%) developed coma, 80 (3.3%) developed confusion, 87 (3.6%) developed dizziness, 1112 (46.4%) became drowsy, 69 (2.9%) had hallucinations or delusions, and 111 (4.6%) developed slurred speech (Forrester, 2006).
    b) ZALEPLON
    1) INCIDENCE: In a series of 201 patients reported to a poison center with exposure to zaleplon only, CNS manifestations were most common, developing in 40.5% of patients. Eight patients (4%) developed ataxia, 2 (1%) developed coma, 5 (2.5%) became confused, 5 (2.5%) became dizzy, 64 (32%) developed drowsiness, 9 (4.5%) developed hallucinations or delusions, and 12 (6%) had slurred speech (Forrester, 2006).
    2) CASE REPORT: A 14-year-old male developed slurred speech, confusion, loss of coordination, and sleepiness after ingesting an unknown amount of zaleplon (between two and twenty 20 mg tablets). His parents found him in the garage trying to fill the lawn mower with gasoline while apparently sleep walking. His mental status returned to normal 8 hours after hospital admission and was amnestic for the events after his overdose (Liskow & Pikalov, 2004).
    3) CASE REPORT: A 24-year-old woman presented confused and somnolent with blue-green discoloration of lips and mouth after ingesting up to 28 zaleplon tablets. She became restless and confused and experienced visual hallucinations and intermittent myoclonus. Following supportive care, she recovered completely (Louis et al, 2008).
    B) COMA
    1) WITH POISONING/EXPOSURE
    a) INCIDENCE: Coma developed in 29 of 2918 (1.2%) zolpidem exposures and 2 of 201 (1%) zaleplon exposures reported to a poison center (Forrester, 2006).
    b) ZOLPIDEM
    1) OVERDOSE/MIXED INGESTION: Coma and decreased respiratory effort occurred in a 57-year-old woman following an ingestion of 125 mg of zolpidem and alcohol (initial blood alcohol 209 mg/dL) (Burton et al, 1998). Symptoms were successfully treated with a flumazenil infusion.
    2) CASE REPORT: A 50-year-old man who had ingested 300 mg of zolpidem, 600 mg of prothipendyl, and ethanol was found in deep coma with respiratory depression and systolic arterial pressure of 70 mmHg. Treatment included gastric lavage, activated charcoal, and flumazenil 1 mg intravenously and resulted in arousal of the patient and reversal of the respiratory depression (Lheureux et al, 1990).
    3) CASE REPORT: A 40-year-old woman with a history of depression being treated with zolpidem 10 mg, became unconscious on her way to the hospital. Reportedly, she was seeking emergency care for labor and delivery despite the absence of a uterus or ovaries detected on ultrasound and a negative beta hCG. Upon arrival she had a heart rate of 94 beats/min, a Glascow Coma Score of 3, pupils dilated to 5 mm and unresponsive to light, and absent corneal and vestibulo-ocular reflexes. Laboratory analysis was normal. Urine toxicology, alcohol, acetaminophen, and salicylates were negative. Prenatal vitamins were the only other medication that she was taking. Brain CT was also normal. She was intubated for respiratory failure and admitted. On day 2, minimal pupil response was noted and ECG revealed a moderate degree of diffuse, nonspecific slow-wave abnormalities with no epileptiform activity. On day 3 she experienced a spontaneous, full recovery and was extubated. She was transferred to a psychiatric ward on day 4. Zolpidem overdose was suspected but not confirmed (Kuzniar et al, 2010).
    c) ZALEPLON
    1) CASE REPORTS: Coma was seen in 2 cases of zaleplon overdose. Case 1 ingested an unknown amount of zaleplon and alcohol; Case 2 ingested an unknown amount of zaleplon and trimipramine. The first patient recovered completely after receiving flumazenil. Although flumazenil administration was ineffective in the second patient, he did gradually regain consciousness within 2 days post-ingestion (Hojer et al, 2002).
    C) DROWSY
    1) WITH THERAPEUTIC USE
    a) ZOLPIDEM
    1) SUMMARY: Somnolence occurred among 5.2% of patients taking zolpidem at therapeutic doses (Meram & Descotes, 1989; Langtry & Benfield, 1990a).
    2) Drowsiness was reported in 8% of chronic insomnia patients receiving immediate-release zolpidem tartrate 5 mg or 10 mg per night (n=152) compared with 5% of patients receiving placebo (n=161) during long-term efficacy trials (28 to 35 nights) (Prod Info AMBIEN(R) oral tablets, 2008).
    3) During a three-week clinical trial (n=212), somnolence was reported in 15% of patients who received extended-release zolpidem 12.5 mg; this adverse effect occurred in 2% of patients in the placebo group. In another 3-week trial involving 205 elderly patients who received either zolpidem tartrate extended-release 6.25 mg or placebo, somnolence was reported in 6% compared with 5% in the placebo group (Prod Info AMBIEN CR oral extended-release tablets, 2007).
    2) WITH POISONING/EXPOSURE
    a) ZOLPIDEM
    1) SUMMARY: Somnolence occurred with overdose of zolpidem (Meram & Descotes, 1989; Langtry & Benfield, 1990a).
    2) In a series of 204 zolpidem ingestions by young children (0 to 5 years of age), drowsiness was reported in 60 (29.4%) patients; the mean dose ingested by children who developed drowsiness was 18.9 mg, with a range of 1 to 150 mg (Forrester, 2009).
    3) In a retrospective study of 897 zolpidem ingestions, drowsiness/lethargy was reported in 399 (54.4%) of 734 patients after ingesting immediate-release tablets (mean dose, 114.8 mg) and 69 (42.3%) of 163 patients after ingesting controlled-release tablets (mean dose, 129.8 mg) (Forrester, 2009a).
    4) Twenty-two young adults (14 females and 8 males) ingested between 7 and 39 zolpidem tablets (mean 15 tablets) in intentional acute poisonings. Two patients remained asymptomatic, all others experienced somnolence. Full recovery occurred over several hours in all cases (Meram & Descotes, 1989).
    5) In a retrospective review of 105 patients with acute zolpidem overdoses (no mixed ingestions), drowsiness was apparent in 84 patients. Associated symptoms in these patients included tachycardia, vomiting, bradypnea, hypotonia, dizziness, hyperthermia, hallucinations, confusion, and mydriasis (Garnier et al, 1994).
    6) In a controlled study (n=1028), 5.2% of patients reported somnolence after 10 to 30 mg zolpidem ingestion (Langtry & Benfield, 1990a).
    b) ZALEPLON
    1) Somnolence has been reported with zaleplon overdose (Louis et al, 2008).
    D) ATAXIA
    1) WITH POISONING/EXPOSURE
    a) In a series of 204 zolpidem ingestions by young children (0 to 5 years of age), ataxia was reported in 21 (10.3%) patients; the mean dose ingested by children who developed ataxia was 27.4 mg, with a range of 2.5 to 300 mg (Forrester, 2009).
    b) In a retrospective study of 897 zolpidem ingestions, ataxia was reported in 46 (6.3%) of 734 patients after ingesting immediate-release tablets (mean dose, 61.9 mg) and 19 (11.7%) of 163 patients after ingesting controlled-release tablets (mean dose, 90.5 mg) (Forrester, 2009a).
    E) ANXIETY DISORDER
    1) WITH THERAPEUTIC USE
    a) ZOLPIDEM
    1) In a 6-month trial among 1018 adult patients aged 18 and 64 years, anxiety was reported in 6.3% of patients who received zolpidem extended-release 12.5 mg compared with 2.6% of patients who received placebo, resulting in discontinuation rate of 1.5% and 0.3%, respectively (Prod Info AMBIEN CR oral extended-release tablets, 2007).
    2) WITH POISONING/EXPOSURE
    a) In a series of 204 zolpidem ingestions by young children (0 to 5 years of age), agitation was reported in 8 (3.9%) patients; the mean dose ingested by children who developed agitation was 28.3 mg, with a range of 5 to 150 mg (Forrester, 2009).
    b) In a retrospective study of 897 zolpidem ingestions, agitation/irritability was reported in 21 (2.9%) of 734 patients after ingesting immediate-release tablets (mean dose, 168.6 mg) and 6 (3.7%) of 163 patients after ingesting controlled-release tablets (mean dose, 146.9 mg) (Forrester, 2009a).
    F) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) ZOLPIDEM
    1) Dizziness was reported in 5% of chronic insomnia patients receiving immediate-release zolpidem tartrate 5 mg or 10 mg per night (n=152) compared with 1% of patients receiving placebo (n=161) during long-term efficacy trials (28 to 35 nights), and was one of the most commonly-reported adverse events during these trials (Prod Info AMBIEN(R) oral tablets, 2008).
    2) During a three-week clinical trial, dizziness was reported in 12% of patients who received extended-release zolpidem 12.5 mg; this adverse effect occurred in 5% of patients in the placebo group. In another 3-week trial involving 205 elderly patients who received either zolpidem tartrate extended-release 6.25 mg or placebo, dizziness was reported in 8% compared with 3% in the placebo group (Prod Info AMBIEN CR oral extended-release tablets, 2007).
    3) In an 8-week controlled study involving 201 pediatric patients (aged 6 to 17 years) with insomnia associated with ADHD, 23.5% patients receiving oral solution of zolpidem (n=136) compared with 1.5% of patients receiving placebo (n=65) experienced dizziness (Prod Info AMBIEN CR oral extended-release tablets, 2007).
    4) During short-term trials (up to 10 nights), dizziness was reported in 1% of patients receiving immediate-release zolpidem tartrate 10 mg or less per night (n=685) compared with 0% of patients receiving placebo (n=473) (Prod Info AMBIEN(R) oral tablets, 2008).
    5) CONTROLLED STUDY: 5.2% of patients in a controlled study (n=1028) reported dizziness or lightheadedness after 10- to 30-mg zolpidem ingestion (Langtry & Benfield, 1990a).
    2) WITH POISONING/EXPOSURE
    a) In a series of 204 zolpidem ingestions by young children (0 to 5 years of age), dizziness was reported in 4 (2%) patients; the mean dose ingested by children who developed dizziness was 27.5 mg, the range was 10 to 40 mg (Forrester, 2009).
    b) In a retrospective study of 897 zolpidem ingestions, dizziness/vertigo was reported in 26 (3.5%) of 734 patients after ingesting immediate-release tablets (mean dose, 31.9 mg) and 7 (4.3%) of 163 patients after ingesting controlled-release tablets (mean dose, 57.1 mg) (Forrester, 2009a).
    G) HEADACHE
    1) WITH THERAPEUTIC USE
    a) ZOLPIDEM
    1) During short-term trials (up to 10 nights), headache was reported in 7% of patients receiving immediate-release zolpidem tartrate 10 mg or less per night (n=685) compared with 6% of patients receiving placebo (n=473) (Prod Info AMBIEN(R) oral tablets, 2008).
    2) During a 3-week clinical trial, headache occurred in 19% of patients who received extended-release zolpidem 12.5 mg; this adverse effect occurred in 16% of patients in the placebo group. In another 3-week trial involving 205 elderly patients who received either zolpidem tartrate extended-release 6.25 mg or placebo, headache was reported in 14% compared with 11% in the placebo group (Prod Info AMBIEN CR oral extended-release tablets, 2007).
    3) In an 8-week controlled study involving 201 pediatric patients (aged 6 to 17 years) with insomnia associated with ADHD, 12.5% patients receiving oral solution of zolpidem (n=136) compared with 9.2% of patients receiving placebo (n=65) experienced headache (Prod Info AMBIEN CR oral extended-release tablets, 2007).
    4) CASE SERIES: 3% of patients taking therapeutic doses of zolpidem in a controlled study (n=1028) experienced headache (Langtry & Benfield, 1990a).
    H) AMNESIA
    1) WITH THERAPEUTIC USE
    a) ZOLPIDEM: 5 of 24 patients in a controlled study experienced anterograde amnesia while taking 10 or 20 mg of zolpidem nightly (Maarek et al, 1992).
    b) ZALEPLON: Amnesia was reported in 4% of patients treated with zaleplon 20 mg (n=297), 2% of patients treated with zaleplon 5 mg or 10 mg (n=569), and 1% of those treated with placebo (n=344) in a pooled analysis of three 28-night and one 35-night placebo-controlled trials (Prod Info SONATA(R) oral capsules, 2007a).
    I) CLOUDED CONSCIOUSNESS
    1) WITH THERAPEUTIC USE
    a) ZOLPIDEM
    1) SUMMARY: Confusion and agitation have occurred following single 10 mg and 20 mg doses of zolpidem both in adults and the elderly (Langtry & Benfield, 1990a; Freudenreich & Menza, 2000).
    2) CASE SERIES: 96% of elderly patients reporting falls were taking 20 to 30 mg of zolpidem; no falls were reported among elderly patients taking 5 mg of zolpidem (Langtry & Benfield, 1990a). Ninety-six percent of elderly patients reporting falls while taking 20 to 30 mg of zolpidem were greater than or equal to 70 years of age.
    J) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) ZALEPLON: Asthenia was reported in 7% of patients treated with zaleplon 20 mg (n=297), 5% of patients treated with zaleplon 5 mg or 10 mg (n=569), and 5% of those treated with placebo (n=344) in a pooled analysis of three 28-night and one 35-night placebo-controlled trials (Prod Info SONATA(R) oral capsules, 2007a).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) ZOLPIDEM
    1) During a three-week clinical trial, nausea was reported in 7% of patients who received extended-release zolpidem (12.5 mg); this adverse effect occurred in 4% of patients in the placebo group (Prod Info AMBIEN CR(TM) oral tablets , 2005).
    2) Nausea was reported in at least 1% of 3660 patients receiving zolpidem tartrate at any dose during pre-approval clinical trials conducted in the United States, Europe, and Canada. Adverse event causality could not be determined (Prod Info AMBIEN(R) oral tablets, 2008).
    3) Nausea, vomiting, or abdominal pain occurred in 3.6% of patients in a controlled study (n=1028) (Langtry & Benfield, 1990a).
    2) WITH POISONING/EXPOSURE
    a) ZOLPIDEM
    1) INCIDENCE: In a series of 2918 patients reported to a poison center with exposure to zolpidem only, 33 (1.4%) developed nausea and 94 (3.9%) vomited (Forrester, 2006).
    2) In a series of 204 zolpidem ingestions by young children (0 to 5 years of age), vomiting was reported in 14 (6.9%) patients; in children who developed vomiting, the mean dose was 41.8 mg with a range of 5 to 200 mg (Forrester, 2009).
    3) In a retrospective study of 897 zolpidem ingestions, vomiting was reported in 37 (5%) of 734 patients after ingesting immediate-release tablets (mean dose, 74.9 mg) and 9 (5.5%) of 163 patients after ingesting controlled-release tablets (mean dose, 61.1 mg) (Forrester, 2009a).
    4) In a retrospective study which included 105 patients with acute zolpidem overdoses (no mixed ingestions), 8 developed nausea or vomiting (Garnier et al, 1994).
    b) ZALEPLON
    1) CASE REPORT: A 24-year-old woman vomited dark blue-green stomach contents after ingesting up to 28 zaleplon tablets. It is believed that the dark blue-green color is from an additive (indigo carmine) in the zaleplon capsules used in Europe (Louis et al, 2008; Hojer et al, 2002).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ABNORMAL LIVER FUNCTION
    1) WITH THERAPEUTIC USE
    a) ZOLPIDEM: Elevated liver enzymes, jaundice, and abdominal pain were reported in a 53-year-old woman following administration of zolpidem as a single agent (Karsenti et al, 1999). Unintentional rechallenge (9 months later) resulted in similar signs and symptoms.

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) URINE COLOR ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) ZALEPLON: Bluish-green urine was found in two comatose patients following zaleplon overdose (Hojer et al, 2002). This was felt to be from an additive (indigo carmine) used in Europe to prevent surreptitious administration of the drug and is not currently being added to zaleplon in the United States (Hojer et al, 2002). In another case report, blue-green urine was observed in a 24-year-old woman who ingested up to 28 zaleplon tablets (Louis et al, 2008).

Summary Of Exposure

    A) USES: Zolpidem and zaleplon are sedative hypnotics used for the treatment of insomnia. They have surpassed benzodiazepines as most frequently prescribed sleep aids. They are thought to have less addiction potential than benzodiazepines. Zolpidem is available as a controlled-release formulation. Zolpidem oral spray has a sweet cherry flavor, high concentration (50 mg/mL), and faster onset of action than immediate-release zolpidem. It may be more likely than zolpidem tablets to be used in excess.
    B) PHARMACOLOGY: Although classified as a non-benzodiazepine drug due to different chemical structure, the hypothesized mechanism of action is similar to benzodiazepines; interaction with GABA-benzodiazepine receptor complexes (specifically GABA(A) alpha-1 subunit), enhancing the function of GABA-mediated chloride channels.
    C) TOXICOLOGY: Toxicology is the extension of the pharmacology. CNS depression is the primary effect and is exacerbated by co-ingestion of other sedatives.
    D) EPIDEMIOLOGY: Overdose is common, but serious toxicity is rare.
    E) WITH THERAPEUTIC USE
    1) Gastrointestinal effects of therapeutic doses of zolpidem included nausea, vomiting, and abdominal pain. Dizziness, confusion, impaired coordination, delusions or psychotic reactions, daytime drowsiness, headache, and sleep-eating or sleep-driving, may develop in some patients. Taking the medication immediately prior to bedtime may minimize some of these effects. Toxic psychosis occurred in two adults after the initial intake of zolpidem at therapeutic doses. Withdrawal from these medications has been reported but is likely to be mild.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Somnolence, slurred speech, confusion, and ataxia may occur.
    2) SEVERE TOXICITY: Severe effects are very rare but may occur after co-ingestion with other sedatives and may include hypotension, coma and respiratory depression. Death is extremely rare but may be caused by respiratory depression. Patients that present with coma are at risk for aspiration pneumonia, rhabdomyolysis, and renal failure. Severe ischemia and gangrene were seen following intraarterial injection of a crushed zolpidem tablet.

Vital Signs

    3.3.2) RESPIRATIONS
    A) WITH POISONING/EXPOSURE
    1) ZOLPIDEM: Respiratory depression requiring ventilation occurred in one case of mixed overdose with 300 mg zolpidem, ethanol, and 600 mg prothipendyl in an adult (Lheureux et al, 1990).
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) ZOLPIDEM: Hypotension occurred in one case of mixed overdose with 300 mg zolpidem, ethanol, and 600 mg prothipendyl in an adult (Lheureux et al, 1990).

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) ZOLPIDEM
    a) MIOSIS: Miosis occurred in one case of mixed overdose with 300 mg zolpidem, ethanol, and 600 mg prothipendyl in an adult (Lheureux et al, 1990).
    b) DIPLOPIA: Diplopia occurred infrequently after therapeutic doses of zolpidem (Cashman et al, 1987).
    c) MYDRIASIS: Mydriasis was reported in 3 of 344 cases of zolpidem overdose (Garnier et al, 1994).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOCYTOSIS
    1) WITH POISONING/EXPOSURE
    a) ZOLPIDEM: In a retrospective study of acute zolpidem intoxications, 7 patients out of 344 were noted to have abnormal hematologic studies. Hematological effects were attributed to factors other than zolpidem exposure in six of the cases. The remaining case had leucocytosis and moderate polynucleosis which persisted for several days. The medical history of this patient was not documented (Garnier et al, 1994).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN NECROSIS
    1) WITH POISONING/EXPOSURE
    a) ZOLPIDEM: Severe ischemia and gangrene in the first 4 digits of the right hand occurred following intraarterial injection of zolpidem. To maximize the effects of the drug, a 24-year-old female with severe insomnia mixed a crushed 10 mg zolpidem tablet and 2 mL of water, then inadvertently injected it into her radial artery. Immediate severe pain in the right hand occurred followed by mottling, cyanosis, and tenderness. The fingers eventually turned black. Emergent right arm angiography revealed patent ulnar and radial arteries; duplex scan showed reduced blood flow to the interphalangeal arteries. Treatment included continuous heparin infusion, nifedipine, parenteral oxacillin, prostacyclin infusion, one hyperbaric oxygen treatment, and arm elevation. Her condition failed to improve and she discharged herself against medical advice. The effects were thought to be caused by microcrystalline cellulose used as a filler in the pill. Microcrystalline cellulose is an embolic agent used in animals (Chang & Lin, 2003).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) ZOLPIDEM
    1) During a three-week clinical trial, myalgia occurred in 4% of patients who received extended-release zolpidem (12.5 mg); the incidence was 0% in the placebo group (Prod Info AMBIEN CR oral extended-release tablets, 2007).
    2) Myalgia was reported in at least 1% of 3660 patients receiving zolpidem tartrate at any dose during pre-approval clinical trials conducted in the United States, Europe, and Canada. Adverse event causality could not be determined (Prod Info AMBIEN(R) oral tablets, 2008).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANGIOEDEMA
    1) WITH THERAPEUTIC USE
    a) ZOLPIDEM: Cases of angioedema involving the tongue, glottis, or larynx, some fatal, have been reported rarely in patients following the first or subsequent doses of sedative-hypnotics, including zolpidem. Additional symptoms suggestive of anaphylaxis, including dyspnea, throat closing, or nausea and vomiting, have been reported. Some patients with these symptoms have presented to the emergency department (Prod Info AMBIEN(R) oral tablets, 2008; Prod Info AMBIEN CR oral extended-release tablets, 2007).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) ZOLPIDEM
    1) In a series of 2918 patients reported to a poison center with exposure to zolpidem only, 54 (2.3%) developed hypertension (Forrester, 2006).
    2) In a retrospective study of 897 zolpidem ingestions, hypertension was reported in 27 (3.7%) of 734 patients after ingesting immediate-release tablets (mean dose, 164.6 mg) and 9 (5.5%) of 163 patients after ingesting controlled-release tablets (mean dose, 172.2 mg) (Forrester, 2009a).
    B) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) ZOLPIDEM
    1) In a retrospective study of 897 zolpidem ingestions, hypotension was reported in 11 (1.5%) of 734 patients after ingesting immediate-release tablets (mean dose, 130.9 mg) and 3 (1.8%) of 163 patients after ingesting controlled-release tablets (mean dose, 170.8 mg) (Forrester, 2009a).
    2) CASE REPORT: A 50-year-old man ingested 300 mg zolpidem, 600 mg prothipendyl (a phenothiazine), and ethanol in an intentional overdose. He was found in deep coma with obstructed airway and systolic arterial pressure of 70 mmHg (Lheureux et al, 1990).
    3) CASE REPORT: Hypotension developed in one patient after ingesting 60 mg of zolpidem (Garnier et al, 1994).
    C) TACHYARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) ZOLPIDEM
    1) INCIDENCE: In a series of 2918 patients reported to a poison center with exposure to zolpidem only, 161 (6.7%) developed tachycardia (Forrester, 2006).
    2) In a review of pediatric exposures, a 14-year-old woman developed sinus tachycardia along with drowsiness and slurred speech after ingesting 100 mg of zolpidem (Kurta et al, 1997).
    3) In a retrospective study of 897 zolpidem ingestions, tachycardia was reported in 78 (10.6%) of 734 patients after ingesting immediate-release tablets (mean dose, 199.3 mg) and 19 (11.7%) of 163 patients after ingesting controlled-release tablets (mean dose, 196.7 mg) (Forrester, 2009a).
    b) ZALEPLON
    1) CASE REPORT: Sinus tachycardia developed in a 24-year-old woman after ingesting up to 28 zaleplon tablets (Louis et al, 2008).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH POISONING/EXPOSURE
    a) ZOLPIDEM
    1) CASE REPORT: Intentional poisoning with zolpidem (300 mg) in combination with prothipendyl (600 mg) and ethanol by a 50-year-old male resulted in respiratory depression requiring ventilation (Lheureux et al, 1990).
    2) CASE REPORT: In a retrospective survey of acute zolpidem overdoses, hypoxia and hypercapnia were observed in an adult with a history of chronic respiratory insufficiency. Tachypnea was noted after intoxication with 170 mg of zolpidem (Garnier et al, 1994).
    3) CASE REPORT: A 57-year-old woman developed coma (responding to only painful stimuli) and respiratory depression following an intentional ingestion of 125 mg of zolpidem and alcohol (blood alcohol was 209 mg/dL on admission) (Burton et al, 1998). Despite continuous oxygen (O2) at 12 L/min via a nonrebreather, oxygen saturation fell below 85%. Symptoms of respiratory and CNS depression were successfully treated with a flumazenil infusion.
    B) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) ZOLPIDEM: Evidence of pulmonary edema was present at autopsy in two adult females following zolpidem overdose (Gock et al, 1999).

Reproductive

    3.20.1) SUMMARY
    A) Zolpidem is classified as FDA pregnancy category C. Adequate and well-controlled studies with zolpidem have not been conducted in pregnant women. One study of women who received zolpidem during pregnancy found significant risks for preterm, cesarean, low birth weight, small for gestational age births, but not congenital abnormalities, compared with controls. Animal studies note maternal effects of reduced weight gain and sedation in rabbits, and maternal lethargy and ataxia in rats. Adverse fetal effects include postimplantation fetal loss and underossification of sternebrae in rabbits, and incomplete skull bone ossification, decreased offspring growth, and decreased survival in rats. Limited data indicate small amounts of zolpidem are excreted in human breast milk, and caution is advised in nursing women. No impairment of fertility was noted in animal studies, but irregular estrus cycles and prolonged precoital intervals are reported for rats.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent (Prod Info Ambien(R) oral tablets, 2009; Prod Info Edluar(TM) sublingual tablets, 2009).
    B) LACK OF EFFECT
    1) A series of observational cohort studies suggested that zolpidem did not increase the rate of congenital anomalies when used during pregnancy. Of 45 pregnant women who took the drug, 24 discontinued the drug before the last menstrual period, 18 were exposed during the first trimester, and one during the second or third trimester; exposure for two was unknown. Of the 18 exposed during the first trimester, there were 10 births without congenital anomalies, two spontaneous abortions, and six intentionally terminated pregnancies (Wilton et al, 1998).
    2) Zolpidem was measured in the cord blood of a neonate born to a 30-year-old woman who was exposed to zolpidem during pregnancy. The female neonate was delivered at 38 weeks (weight 3.95 kg, Apgar score 8 to 9) with no complications or withdrawal symptoms within 48 hours after delivery. The cord blood zolpidem level was 41 ng/mL at approximately 20 minutes after delivery, indicating zolpidem may have been used up until the delivery. The time from the last dose and the amount of zolpidem taken were unknown (Askew, 2007).
    3) In an adjusted analysis, a retrospective Taiwanese study of women (mean age 29.7 years) who received zolpidem during pregnancy (n=2497) found significant risks for preterm, cesarean, low birth weight (LBW), small for gestational age (SGA) births, but not congenital abnormalities, compared with controls (n=12,485). Zolpidem treatment between 30 and more than 180 days significantly increased risks of low birth weight, preterm, small for gestational age, and cesarean births, but not congenital abnormalities, compared with controls (Wang et al, 2010).
    C) ANIMAL STUDIES
    1) RATS: A dose-related decrease in fetal skull ossification was demonstrated when pregnant rats were given oral zolpidem base in doses of 20 or 100 mg/kg (approximately 24 and 120 times the maximum recommended human dose (MRHD) on a mg/m(2) basis, respectively) during organogenesis; no adverse effects were seen with 4 mg/kg (approximately 5 times the MRHD on a mg/m(2) basis) (Prod Info Ambien(R) oral tablets, 2009; Prod Info Edluar(TM) sublingual tablets, 2009).
    2) RABBITS: An increase in embryo-fetal death and incomplete fetal skeletal (sternebrae) ossification occurred when pregnant rabbits were dosed with 16 mg/kg of oral zolpidem base (approximately 40 times the maximum recommended human dose (MRHD) on a mg/m(2) basis); no adverse effects were seen with 1 or 4 mg/kg doses (approximately 2.5 and 10 times the MRHD on a mg/m(2) basis, respectively) (Prod Info Ambien(R) oral tablets, 2009; Prod Info Edluar(TM) sublingual tablets, 2009)
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info Ambien(R) oral tablets, 2009; Prod Info Edluar(TM) sublingual tablets, 2009).
    B) PREGNANCY CATEGORY
    1) Pregnancy Category C (Prod Info Ambien(R) oral tablets, 2009; Prod Info Edluar(TM) sublingual tablets, 2009)
    C) STUDIES
    1) In an adjusted analysis, a retrospective Taiwanese study of women (mean age 29.7 years) who received zolpidem during pregnancy (n=2497) found significant risks for preterm, cesarean, low birth weight (LBW), small for gestational age (SGA) births, but not congenital abnormalities, compared with controls (n=12,485). Overall incidence of LBW (7.61%; odds ratio (OR) 1.39 (95% confidence interval (CI), 1.17 to 1.64); p less than 0.001), preterm birth (10.01%; OR 1.49 (95% CI, 1.28 to 1.74); p less than 0.001), SGA (19.94%; OR 1.34 (95% CI, 1.2 to 1.49); p less than 0.001), and cesarean births (46.86%; OR 1.74 (95% CI, 1.59 to 1.9); p less than 0.001) was higher in women who received zolpidem compared with 5.19%, 6.3%, 15.06%, and 33.46%, respectively, of controls tracked across all trimesters (n=12,485). The risk of low birth weight with first-trimester zolpidem exposure (n=535) was not significant, but preterm birth (10.28%), SGA (20.19%), and cesarean births (47.66%) were all higher than controls (OR 1.48 (95% CI, 1.1 to 1.98), p less than 0.01; OR 1.36 (95% CI, 1.09 to 1.69) p less than 0.01; and OR 1.73 (95% CI, 1.45 to 2.06), p less than 0.001, respectively). Risks of second- or third-trimester zolpidem exposure (n=1962) remained significantly higher than controls for LBW (7.75%; OR 1.42 (95% CI, 1.18 to 1.71), p less than 0.001), preterm birth (9.94%; OR 1.49 (95% CI, 1.26 to 1.77), p less than 0.001), SGA (19.88%; OR 1.33 (95% CI, 1.18 to 1.5), p less than 0.001), and cesarean births (46.64%; OR 1.75 (95% CI, 1.58 to 1.93), p less than 0.001) (Wang et al, 2010).
    2) Zolpidem treatment between 30 and more than 180 days significantly increased risks of low birth weight (LBW), preterm, small for gestational age (SGA), and cesarean births, but not congenital abnormalities, compared with controls (n=12,485). Significantly increased risks of LBW (7.19%; adjusted odds ratio (AOR) 1.3 (95% confidence interval (CI), 1.05 to 1.62), p less than 0.05), preterm (9.65%; AOR 1.46 (95% CI, 1.2 to 1.76), p less than 0.001), SGA (18.48%; AOR 1.21 (95% CI, 1.05 to 1.4), p less than 0.01), and cesarean births (46%; AOR 1.72 (95% CI, 1.52 to 1.92), p less than 0.001) were reported for zolpidem therapy between 30 and 90 days (n=1461) compared with 5.19%, 6.3%, 15.06%, and 33.46%, respectively, of controls (n=12,485). Significant risks of LBW (8.29%; AOR 1.52 (95% CI, 1.1 to 2.11), p less than 0.05), SGA (22.6%; AOR 1.57 (95% CI, 1.27 to 1.94), p less than 0.001), and cesarean births (45.57%; AOR 1.66 (95% CI, 1.34 to 1.98), p less than 0.001) were reported for zolpidem therapy between 90 to 180 days (n=531), but with no significantly increased risk of preterm birth. Significantly increased risks of LBW (8.12%; AOR 1.48 (95% CI, 1.06 to 2.07), p less than 0.05), preterm (11.68%; AOR 1.74 (95% CI, 1.31 to 2.32), p less than 0.001), SGA (21.39%; AOR 1.48 (95% CI, 1.19 to 1.85), p less than 0.001), and cesarean births (50.69%; AOR 1.9 (95% CI, 1.31 to 2.62), p less than 0.001) were reported with more than 180 days of zolpidem therapy (n=505) (Wang et al, 2010).
    D) ANIMAL STUDIES
    1) RATS: Maternal dose-related lethargy and ataxia, and a decrease in offspring growth and survival, were noted when pregnant Sprague-Dawley rats were given oral zolpidem base in doses of 20 or 100 mg/kg/day; no maternal or offspring effects were seen with 4 mg/kg (approximately 4 to 5 times the maximum recommended human dose (MRHD) on a mg/m(2) basis) (Prod Info AMBIEN(R) oral tablets, 2007).
    2) RABBITS: Maternal dose-related sedation and decreased weight gain were noted when pregnant Himalayan Albino rabbits were given 1, 4, or 16 mg/kg/day of oral zolpidem base (approximately 2, 10, and over 35 times the maximum recommended human dose (MRHD) on a mg/m(2) basis, respectively); no maternal effects occurred with doses below 1 mg/kg/day (Prod Info AMBIEN(R) oral tablets, 2007).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Excreted in human breast milk in small amounts (Pons et al, 1989).
    2) Caution advised if zolpidem administered to nursing mothers (Prod Info Ambien(R) oral tablets, 2009; Prod Info Edluar(TM) sublingual tablets, 2009).
    3) CASE REPORT: Three hours after a single oral dose of zolpidem 20 mg, the breast milk contained 0.76 to 3.88 mcg (0.004% to 0.019% of the dose), with a milk-to-plasma (M/P) ratio of 0.13. The amount in samples taken 13 and 16 hours after the dose was less than the detectable limit of 0.5 mcg/L (Pons et al, 1989).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent (Prod Info Ambien(R) oral tablets, 2009; Prod Info Edluar(TM) sublingual tablets, 2009).
    B) ANIMAL STUDIES
    1) RATS: Irregular estrus cycles and prolonged precoital intervals were noted after daily oral doses of zolpidem base 100 mg/kg (approximately 120 times the maximum recommended human dose (MRHD) on a mg/m(2) basis) were given to male and female rats prior to and during mating, with the females continuing through postpartum day 25. No adverse effects were seen with 4 or 20 mg/kg doses (approximately 5 and 24 times the MRHD on a mg/m(2) basis, respectively). No impairment of fertility was noted at all doses tested (Prod Info Ambien(R) oral tablets, 2009; Prod Info Edluar(TM) sublingual tablets, 2009).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) No evidence of carcinogenic potential was observed in mice.
    3.21.3) HUMAN STUDIES
    A) LACK OF EFFECT
    1) No evidence of carcinogenic potential was observed in mice (Prod Info Ambien(R), zolpidem tartrate, 1993).

Genotoxicity

    A) No evidence of genotoxic potential was observed in animal tests.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Serum drug concentrations are not readily available and not clinically helpful. These medications are not detected on routine urine drug screens.
    C) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity.
    D) Monitor creatinine phosphokinase in patients with prolonged immobilization from coma; monitor renal function and urine output in patients with rhabdomyolysis.
    E) Routine monitoring of electrolytes, renal function, glucose, pulse oximetry and blood gases may be helpful. Other causes of coma should be ruled out if the diagnosis is not clear.
    4.1.2) SERUM/BLOOD
    A) Blood cell count and chemistry were within normal parameters on admission and 24 hours later in one case of acute zolpidem poisoning (Lheureux et al, 1990).

Methods

    A) CHROMATOGRAPHY
    1) High performance liquid chromatography with UV detection has been used for emergency toxicological determination. It is not suitable for metabolite detection (Debailleul & Abi Khalil, 1991).
    2) Column-switching high performance liquid chromatography (Ascalone & Flaminio, 1992) has been used for urine testing in overdose situations.
    3) High performance liquid chromatography with fluorometric detection has also been used.
    B) LC/MS
    1) Liquid chromatography/mass spectrometry (LC/MS) was used successfully to detect zolpidem in blood and urine, which was used in a drug-related assault of a 23-year-old female. Because of a 6-day delay by the victim in reporting the event, concentrations were low at 16 and 32 picograms/mL in blood and urine, respectively. The presence of zolpidem was confirmed by hair segmentation (Kintz et al, 2005).
    C) GC/MS
    1) Keller et al (1999) described a rapid method of analyzing and determining zolpidem concentration in postmortem specimens. Quantitation of zolpidem was performed by ethyl acetate extraction from alkalinized body fluids before the use of gas-chromatography/mass spectrometry analysis. This method required no complex steps and only required a small sample of material (Keller et al, 1999).
    2) Levine & Smialek (1999) described the use of alkaline extraction and a full scan gas-chromatography/mass spectrometry method to determine the distribution of zolpidem in eight postmortem cases. Quantification of all samples was performed by gas-chromatography-nitrogen-phosphorus (GC-NPD) detection (Levine & Smialek, 1999).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with significant persistent central nervous system toxicity (CNS depression, confusion or ataxia), should be admitted. Patients with coma or respiratory depression should be admitted to an intensive care setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic patients (other than mild drowsiness) with inadvertent ingestions may be monitored at home. Children inadvertently ingesting 1 or 2 tablets may be monitored at home.
    B) In one study, the following triage guidelines for the management of unintentional pediatric (0 to 5 years of age) zolpidem ingestions were suggested (Forrester, 2009):
    1) Children in whom the maximum total amount possibly ingested is equal or less than 1 mg/kg, or if weight unknown, equal to or less than 20 mg, may be managed at home if a responsible adult is present.
    2) Children in whom the maximum amount ingested cannot be estimated, or those in whom the maximum amount is more than 1 mg/kg (or more than 20 mg if weight is unknown) should be referred to a healthcare facility.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (coma, respiratory depression), or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate ingestions and symptomatic patients should be sent to a health care facility for observation for at least 4 to 6 hours and/or until symptomatically improved. Consider longer observation periods for patients with ingestion of controlled release formulations.

Monitoring

    A) Monitor vital signs and mental status.
    B) Serum drug concentrations are not readily available and not clinically helpful. These medications are not detected on routine urine drug screens.
    C) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity.
    D) Monitor creatinine phosphokinase in patients with prolonged immobilization from coma; monitor renal function and urine output in patients with rhabdomyolysis.
    E) Routine monitoring of electrolytes, renal function, glucose, pulse oximetry and blood gases may be helpful. Other causes of coma should be ruled out if the diagnosis is not clear.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital decontamination is not recommended because of potential for somnolence and loss of airway protection.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY: In general, decontamination is not indicated for this overdose, but may be considered for large overdoses that present early. Activated charcoal could be considered if the patient is awake and cooperative and if the ingestion was large and relatively recent. There is no evidence for the use of whole bowel irrigation or multiple doses of charcoal. Gastric lavage is not indicated as overdose is not life-threatening.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) Serum drug concentrations are not readily available and not clinically helpful. These medications are not detected on routine urine drug screens.
    3) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity.
    4) Monitor creatinine phosphokinase in patients with prolonged immobilization from coma; monitor renal function and urine output in patients with rhabdomyolysis.
    5) Routine monitoring of electrolytes, renal function, glucose, pulse oximetry and blood gases may be helpful. Other causes of coma should be ruled out if the diagnosis is not clear.
    B) FLUMAZENIL
    1) SUMMARY: Flumazenil has been used with varying success but has not been well-studied. Routine use of flumazenil is NOT recommended. Flumazenil may be useful in establishing a diagnosis in a patient with CNS depression and possibly in preventing the need for respiratory support. Flumazenil should not be administered to patients with cardiac arrhythmias, seizures or a history of seizures, signs/symptoms of a cyclic antidepressant intoxication, or a suspected multidrug ingestion (Prod Info ROMAZICON(R) IV injection, 2004; Thomson et al, 2006).
    2) Flumazenil is a benzodiazepine agonist/antagonist which has been effective in reversing the clinical effects of zolpidem and zaleplon. Zolpidem binds selectively at the benzodiazepine w-1 receptor (Naef et al, 1989; Lheureux et al, 1990; Patat et al, 1994; Burton et al, 1998; Lheureux, 1998; Hojer et al, 2002).
    3) INFUSION RATES: A continuous infusion of flumazenil has been suggested to avoid cyclic changes of alertness associated with repeated administration of flumazenil (Lheureux, 1998). The optimal infusion rate is unknown, titrate to effect. A rate of 0.3 to 1 milligram/hour has been suggested (Lheureux, 1998).
    4) ADULT DOSE/ZOLPIDEM OVERDOSE
    a) CONTROLLED STUDY: 0.04 milligram/kilogram flumazenil has been used to reverse the clinical effects of 0.21 milligram/kilogram zolpidem in healthy volunteers (Naef et al, 1989).
    b) CASE REPORT: Flumazenil 1 milligram intravenously completely reversed coma and respiratory depression in an adult following mixed ingestion of 300 milligrams zolpidem, ethanol, and 600 milligrams prothipendyl (Lheureux et al, 1990).
    5) ADULT DOSE/BENZODIAZEPINE OVERDOSE
    a) Recommended initial intravenous dose is 0.2 mg (2 mL), administered over 30 seconds. If adequate consciousness is not obtained within 30 seconds, a further dose of 0.3 mg (3 mL) may be administered over 30 seconds (Prod Info ROMAZICON(R) injection, 2007).
    b) Further doses of 0.5 mg (5 mL) may be administered at 1 minute intervals up to a maximum total dose of 3 mg (30 mL). Most patients will respond to 1 to 3 mg; doses beyond 3 mg do not usually produce additional effects (Prod Info ROMAZICON(R) injection, 2007).
    c) Occasionally, patients with partial response at 3 mg may require a 5 mg total dose for full response. If a patient has not responded within 5 minutes of administration of a 5-mg total dose, the major cause of sedation is not likely to be benzodiazepines (Prod Info ROMAZICON(R) injection, 2007).
    d) ADULT DOSE/ZOLPIDEM AND ALCOHOL OVERDOSE
    1) A 57-year-old woman in a coma with respiratory depression following an intentional ingestion of 125 milligrams of zolpidem and alcohol (blood alcohol was 209 mg/dL on admission) was treated with flumazenil 0.3 milligram IV (Burton et al, 1998). An immediate improvement in level of consciousness and decreased oxygen demands were observed. A continuous infusion (0.3 mg/hour) was required for an additional 6 hours to maintain oxygen saturation.
    6) PEDIATRIC DOSE/BENZODIAZEPINE OVERDOSE
    a) CHILDREN: Administer an initial dose of 0.01 mg/kg (up to 0.2 mg) in children 1-year-old or older; repeat as necessary at 60-second intervals, up to a maximum total dose of 0.05 mg/kg or 1 mg, whichever is less (Prod Info ROMAZICON(R) injection, 2007).
    b) Flumazenil has also been used in children aged 4, 7, and 13 years who overdosed on benzodiazepines in doses of 10 micrograms/kilogram intravenously for 2 doses (Wood et al, 1988).
    c) NEONATES: Flumazenil administration consisted of 0.02 milligram/kilogram intravenous loading dose followed by 0.05 milligram/kilogram/hour maintenance infusion over 6 hours in a neonate following maternal benzodiazepine ingestion (Richard et al, 1991).
    d) FETAL: Administration of flumazenil (0.3 milligram), to a 22-year-old primipara (36 weeks gestation) who overdosed on diazepam, restored the normal beat-to-beat variation and periodic oscillations of amplitude of fetal heart rate. No adverse effects or withdrawal symptoms were reported (Stahl et al, 1993).
    7) ADMINISTRATION
    a) Administer flumazenil intravenously. Can be diluted in D5W, normal saline, or lactated Ringer's solution. Secure the airway and have venous access prior to flumazenil administration (Prod Info ROMAZICON(R) IV injection, 2004).
    8) CONTRAINDICATIONS
    a) Flumazenil is contraindicated in patients with known hypersensitivity to benzodiazepines or flumazenil, patients suspected of tricyclic antidepressant overdose, and in those who have been given benzodiazepines for control of a life-threatening condition. Flumazenil should not be used until the effects of neuromuscular blocking agents have worn off (Prod Info ROMAZICON(R) IV injection, 2004).
    b) Precipitation of seizures may occur in epileptic patients or in those ingesting epileptogenic coingestants (Bismuth et al, 1985).
    c) TRICYCLIC ANTIDEPRESSANTS: Flumazenil is NOT recommended for use when patients show signs of tricyclic toxicity; the patient should be allowed to remain sedated (with respiratory and other support) until the tricyclic signs abate. Concurrent ingestion of large doses of tricyclics may predispose patients to seizures upon flumazenil administration.
    1) Deaths have occurred after flumazenil treatment in mixed overdose patients who have ingested large doses of tricyclics.
    9) ADVERSE REACTIONS
    a) Adverse reactions have included fatigue, nausea and vomiting, agitation, confusion, and rarely seizures and cardiac arrhythmias. Heart block has been reported in one elderly patient given flumazenil following possible benzodiazepine and acetaminophen overdose (Herd & Clarke, 1991). Panic attacks may occur in patients under psychiatric care; signs associated with head trauma may be exacerbated in some patients.
    b) Be prepared to treat any of these signs; most seizures have responded to treatment with benzodiazepines, phenytoin, or barbiturates.
    c) Deaths have occurred in patients treated with flumazenil; most of these occurred with severe underlying disease states or overdoses of large amounts of non-benzodiazepines.
    C) DRUG WITHDRAWAL
    1) DIAZEPAM
    a) ZOLPIDEM: Currently there are no approved medications or protocols for zolpidem detoxification. In one case, diazepam was used successfully for detoxification without incident using the following schedule (Rappa et al, 2004):
    SEVEN DAY DETOXIFICATION SCHEDULE
    DAYORAL DIAZEPAM REGIMEN
    110 mg every 4 hours for 24 hours
    210 mg every 6 hours for 24 hours
    35 mg every 6 hours for 24 hours
    42 mg every 6 hours for 24 hours
    52 mg every 8 hours for 24 hours
    62 mg every 12 hours for 24 hours
    72 mg every 24 hours for 24 hours

    2) PREGABALIN
    a) ZOLPIDEM: One case described successful treatment of zolpidem withdrawal seizures and dependence with pregabalin. A 49-year-old woman dependent on 1500 mg/day of zolpidem developed partial epileptic seizures of the right upper arm after missing 1 day of dosing. She was treated with pregabalin (PGB) titrated up to 600 mg/day over a 3-day period and discharged 4 days later in good condition on PGB monotherapy tapered down to 300 mg/day over 6 months. She relapsed about 1 year later again taking zolpidem 1500 mg/day and PGB therapy was again effective for withdrawing zolpidem without symptoms (Oulis et al, 2011).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is unlikely to be of benefit because of the high degree of protein binding of zolpidem and zaleplon.

Abstracts

Case Reports

    A) ADULT
    1) ZOLPIDEM
    a) CASE REPORT: A 40-year-old woman with a history of depression being treated with zolpidem 10 mg (frequency not given) became unconscious on her way to the hospital. Reportedly, she was seeking emergency care for labor and delivery despite the absence of a uterus or ovaries detected on ultrasound and a negative beta hcG. Upon arrival she had a heart rate of 94, a Glasgow Coma Score of 3, pupils dilated to 5 mm and unresponsive to light, and absent corneal and vestibulo-ocular reflexes. Laboratory analysis was normal. Urine toxicology, alcohol, acetaminophen, and salicylates were negative. Prenatal vitamins were the only other medication that she was taking. Brain CT was also normal. She was admitted and intubated. On day 2 minimal pupil response was noted and ECG revealed a moderate degree of diffuse, nonspecific slow-wave abnormalities with no epileptiform activity. On day 3 she experienced a spontaneous, full recovery and was extubated. She was transferred to a psychiatric ward on day 4 (Kuzniar et al, 2010).
    b) A 50-year-old man ingested 300 mg of zolpidem, 600 mg of prothipendyl, and ethanol. Paramedics found the patient in deep coma with respiratory depression and systolic arterial pressure of 70 mmHg. The patient was intubated and ventilated because of apneic episodes. Treatment included gastric lavage with activated charcoal administration. Naloxone 0.8 mg was administered intravenously, without effect. Flumazenil 1 mg was administered intravenously and resulted in arousal of the patient and reversal of the respiratory depression (Lheureux et al, 1990).

Range Of Toxicity

Summary

    A) TOXICITY: Patients that co-ingest these medications with other sedatives may manifest symptoms at much lower amounts than those ingesting these medications alone. In adults, ingestion of 70 to 600 mg zolpidem resulted in mild toxicity and ingestion of 2 g resulted in coma. Children with inadvertent zolpidem ingestions ranging from 2.5 to 30 mg developed mild toxicity (drowsiness) which resolved in 4 hours.
    B) THERAPEUTIC DOSE: ZALEPLON: 5 to 20 mg; ZOLPIDEM: 5 to 12.5 mg.

Therapeutic Dose

    7.2.1) ADULT
    A) ZALEPLON
    1) ORAL CAPSULES: The usual dose is 10 mg orally at bedtime; the dose range is 5 to 20 mg/day. The safety of doses exceeding 20 mg/day has not been evaluated (Prod Info SONATA(R) oral capsules, 2007).
    B) ZOLPIDEM
    1) IMMEDIATE-RELEASE TABLETS: The recommended dose for men is 5 or 10 mg orally immediately before bedtime; use the lowest dose possible. The recommended dose for women is 5 mg orally immediately before bedtime. MAXIMUM dose: 10 mg/day (Prod Info Ambien(R) oral tablets, 2013; U.S. Food and Drug Administration (FDA), 2013).
    2) EXTENDED-RELEASE TABLETS: The recommended dose for men is 6.25 or 12.5 mg orally immediately before bedtime; use the lowest dose possible. The recommended starting dose for women is 6.25 mg orally immediately before bedtime. Do not re-administer the drug during the same night (Prod Info AMBIEN CR(R) oral extended-release tablets, 2016; U.S. Food and Drug Administration (FDA), 2013). MAXIMUM dose: 12.5 mg/day (Prod Info AMBIEN CR(R) oral extended-release tablets, 2016).
    3) ORAL SPRAY: The recommended dose for men is 5 or 10 mg (1 or 2 sprays directly into mouth over the tongue) orally immediately before bedtime. MAXIMUM DOSE: Should not exceed 10 mg/day (Prod Info ZOLPIMIST(R) oral spray, 2008). Use the lowest dose possible. The recommended dose for women is 5 mg (1 spray directly into mouth over the tongue) orally immediately before bedtime (U.S. Food and Drug Administration (FDA), 2013).
    4) SUBLINGUAL TABLET (EDLUAR(TM)): The recommended dose for men is 5 or 10 mg SL immediately before bedtime (Prod Info Edluar(TM) sublingual tablets, 2009); use lowest dose possible (U.S. Food and Drug Administration (FDA), 2013). MAXIMUM DOSE: Should not exceed 10 mg/day (Prod Info Edluar(TM) sublingual tablets, 2009). The recommended dose for women is 5 mg SL immediately before bedtime (U.S. Food and Drug Administration (FDA), 2013).
    5) SUBLINGUAL TABLET (INTERMEZZO(R)): The usual dose is 1.75 mg sublingually for women and 3.5 mg sublingually for men taken only once per night as needed if a middle-of-the-night awakening is followed by difficulty returning to sleep and at least 4 hours of bedtime remain. MAXIMUM DOSE: 1.75 mg for women and 3.5 mg for men once nightly (Prod Info INTERMEZZO(R) sublingual tablets, 2011).
    7.2.2) PEDIATRIC
    A) Zolpidem is not recommended for use in children (Prod Info AMBIEN CR(R) oral extended-release tablets, 2016).
    B) Safety and effectiveness in children below the age of 18 have not been established for zaleplon or zolpidem (Prod Info AMBIEN CR(R) oral extended-release tablets, 2016; Prod Info Ambien(R) oral tablets, 2013; Prod Info SONATA(R) oral capsules, 2007).

Maximum Tolerated Exposure

    A) ZOLPIDEM
    1) CASE REPORT: A 68-year-old man was found comatose following the ingestion of 2 g (two hundred 10 mg zolpidem tablets). Upon admission, his Glasgow Coma score (GCS) was 3. Following supportive care, the patient became more alert and had a GCS of 10 approximately 24 hours after admission. At 72 hours, the patient was transferred to psychiatric care with no sequelae (Jung, 2007).
    2) Mild symptoms of toxicity (somnolence) were reported following up to 0.6 grams zolpidem; only one patient, with anorexia, became comatose at this dose (Wyss et al, 1996).
    3) In a series of 204 zolpidem ingestions (mean 13.3 mg; range 0.5 to 300 mg) by young children (0 to 5 years of age), drowsiness (29.4%), ataxia (10.3%), vomiting (6.9%), hallucinations (4.9%), agitation (3.9%), and dizziness (2%) were reported. Overall, most patients did not experience any adverse effects following zolpidem doses of 20 mg or lower or 1 mg/kg or lower (Forrester, 2009).
    4) In a retrospective study of 897 zolpidem ingestions (734 immediate-release (IR) tablets, mean dose 92.9 mg; 163 controlled-release (CR) tablets, mean dose, 104.6 mg), the following adverse effects were reported: Drowsiness/lethargy (54.4% IR vs 42.3% CR); tachycardia (10.6% IR vs 11.7% CR), ataxia (6.3% IR vs 11.7% CR); slurred speech (6.3% IR vs 6.7% CR); vomiting (5% IR vs 5.5% CR); hallucinations/delusions (4.9% IR vs 3.1% CR); confusion (4.1% IR vs 1.8% CR); hypertension (3.7% IR vs 5.5% CR); dizziness/vertigo (3.5% IR vs 4.3% CR) ; agitation/irritability (2.9% IR vs 3.7% CR) ; hypotension (1.5% IR vs 1.8% CR) (Forrester, 2009a).
    5) Intentional ingestion of 70 to 390 mg of zolpidem resulted in somnolence (20), dizziness (1), amnesia (1), and vomiting (1) with full recovery over several hours in 22 adult cases (Meram & Descotes, 1989).
    6) PEDIATRIC: A small pediatric case series reviewed accidental and intentional pediatric zolpidem exposures. Of the accidental cases (age 20 months to 5 years), zolpidem exposure ranged from 2.5 mg to 30 mg. Drowsiness (5) was most frequently reported along with ataxia (2) and visual hallucinations (1). Symptoms resolved within 4 hours. Intentional adolescent (12 to 16 years) ingestion of 12.5 to 150 mg of zolpidem resulted in drowsiness (3), hallucinations (1), ataxia (1), slurred speech (1), and sinus tachycardia (1). Two cases involved co-ingestants. All symptoms resolved within 6 to 10 hours. Flumazenil was NOT given to any patient in this case series (Kurta et al, 1997).
    7) MIXED INGESTION: A 57-year-old woman survived an intentional ingestion of zolpidem 125 mg and alcohol (blood alcohol 209 mg/dL) (Burton et al, 1998). Symptoms of central nervous system and respiratory depression were successfully treated with flumazenil.
    8) DRUG DEPENDENCE: A 49-year-old woman became dependent on zolpidem 1500 mg/day over a 4-year period and developed partial epileptic seizures of the right upper arm after missing 1 day of dosing. Her seizures and dependence were successfully treated with pregabalin (Oulis et al, 2011).
    9) DRUG DEPENDENCE: A 46-year-old man reported increasing his total dosage of zolpidem to 400 mg/day in divided doses over a period of 2 years before seeking treatment for detoxification. He presented with tremors, sweats, chills, shakiness, and headache (Rappa et al, 2004).
    B) ZALEPLON
    1) CASE REPORT: A 24-year-old woman presented confused and somnolent with blue-green discoloration of lips and mouth after ingesting up to 28 zaleplon tablets. She became restless and confused and experienced visual hallucinations and intermittent myoclonia. Following supportive care, she recovered completely (Louis et al, 2008).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) SUMMARY
    a) THERAPEUTIC DOSE: A single oral dose of 20 mg in a healthy volunteer produced peak blood levels of 200 ng/mL after 30 minutes (Guinebault et al, 1986).
    2) OVERDOSE CONCENTRATIONS WITH SURVIVAL
    a) CASE REPORT: A 68-year-old man was found comatose, and had an initial blood zolpidem concentration of 8.4 micrograms (mcg)/milliliter (mL) following the ingestion of 2 g (two hundred 10-mg zolpidem tablets). Zolpidem concentration decreased to 0.11 mcg/mL 24 hours after admission, and he recovered without sequelae (Jung, 2007).
    b) CASE REPORT: Initial plasma level of greater than 500 ng/mL occurred with acute ingestion of 300 mg zolpidem. The patient was intubated, ventilated, treated with flumazenil, and recovered (Lheureux et al, 1990).
    3) POSTMORTEM BLOOD CONCENTRATIONS
    a) The postmortem blood concentration in two separate fatal overdoses of zolpidem in adult females was 1.6 to 7.7 mg/L (Gock et al, 1999).
    b) ZALEPLON: Postmortem zaleplon levels in a woman who died from multiple drug intoxication (zaleplon, promethazine, butalbital, alprazolam) were: blood, 2.2 milligrams (mg)/liter (L); bile, 8.6 mg/L; and urine, 1.4 mg/L(Moore et al, 2003).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) HUMAN DATA

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Zolpidem is a hypnotic agent unrelated to benzodiazepines or barbiturates. It binds the benzodiazepine (BZ) receptor subunit of the GABA-A receptor complex, which is hypothesized to be responsible for sedative, anticonvulsant, anxiolytic, and myorelaxant properties. The preferential binding of zolpidem to the BZ1 receptor may explain the relative absence of myorelaxant and anticonvulsant effects as well as the preservation of deep sleep (stages 3 and 4) of zolpidem at hypnotic doses (Prod Info INTERMEZZO(R) sublingual tablets, 2011; Prod Info AMBIEN CR(R) extended-release oral tablets, 2009; Prod Info Ambien(R) oral tablets, 2009; Prod Info Edluar(TM) sublingual tablets, 2009; Prod Info ZOLPIMIST(R) oral spray, 2008).
    B) Zaleplon interacts with the gamma-aminobutyric acid type A-benzodiazepine (GABA-BZ) receptor complex. Modulation of the GABA-BZ receptor chloride channel macromolecular complex appears to be responsible for the pharmacological properties of the benzodiazepines including sedative, anxiolytic, muscle relaxant, and anticonvulsant effects. Zaleplon binds selectively to the brain alpha subunit of the GABA-A omega-1 receptor (Prod Info SONATA(R) oral capsules, 2007).

Physicochemical

Physical Characteristics

    A) White to off-white crystalline powder (Prod Info Ambien(R) oral tablets, 2009)

Ph

    A) Weak base

Molecular Weight

    A) ZOLPIDEM TARTRATE: 764.88 (Prod Info Ambien(R) oral tablets, 2009)

References

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    60) Product Information: AMBIEN CR oral extended-release tablets, zolpidem tartrate oral extended-release tablets. Sanofi-Aventis US LLC, Bridgewater, NJ, 2007.
    61) Product Information: AMBIEN CR(R) extended-release oral tablets, zolpidem tartrate extended-release oral tablets. Sanofi-Aventis U.S. LLC, Bridgewater, NJ, 2009.
    62) Product Information: AMBIEN CR(R) oral extended-release tablets, zolpidem tartrate oral extended-release tablets. sanofi-aventis U.S. LLC (per FDA), Bridgewater, NJ, 2016.
    63) Product Information: AMBIEN CR(TM) oral tablets , zolpidem tartrate oral extended-release tablets. Sanofi-Synthelabo Inc, New York, NY, 2005.
    64) Product Information: AMBIEN(R) oral tablets, zolpidem tartrate oral tablets. Sanofi-Aventis US,LLC, Bridgewater, NJ, 2007.
    65) Product Information: AMBIEN(R) oral tablets, zolpidem tartrate oral tablets. Sanofi-Aventis US,LLC, Bridgewater, NJ, 2008.
    66) Product Information: Ambien CR(R) oral extended release tablets, zolpidem tartrate oral extended release tablets. Sanofi-Aventis U.S. LLC (per FDA), Bridgewater, NJ, 2013.
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