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Medication Safety Issues
Sound-alike/look-alike issues:
Ambien® may be confused with Ambi 10®
Pronunciation
(zole PI dem)
U.S. Brand Names
Index Terms
Generic Available
Yes: Excludes extended release
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Ambien®: Short-term treatment of insomnia (with difficulty of sleep onset)
Ambien CR™: Treatment of insomnia (with difficulty of sleep onset and/or sleep maintenance)
Use: Dental
Has not been established
Restrictions
C-IV
An FDA-approved patient medication guide is available and must be distributed when dispensing an outpatient prescription (new or refill) where this medication is to be used without direct supervision of a healthcare provider. The guide provides information about the appropriate use of zolpidem, and discusses concerns relating to "sleep-driving" and other activities of which the patient may have no recollection.
Pregnancy Risk Factor
C
Pregnancy Considerations
Teratogenic effects were not observed in animal studies. Children born of mothers taking sedative/hypnotics may be at risk for withdrawal; neonatal flaccidity has been reported in infants following maternal use of sedative/hypnotics during pregnancy.
Lactation
Enters breast milk/not recommended (AAP rates “compatible”)
Breast-Feeding Considerations
0.004% to 0.019% of the maternal dose is found in breast milk.
Contraindications
Hypersensitivity to zolpidem or any component of the formulation
Warnings/Precautions
Concerns related to adverse effects:
• Abnormal thinking/behavioral changes: Hypnotics/sedatives have been associated with abnormal thinking and behavior changes including decreased inhibition, aggression, bizarre behavior, agitation, hallucinations, and depersonalization. These changes may occur unpredictably and may indicate previously unrecognized psychiatric disorders; evaluate appropriately.
• CNS depression: May cause CNS depression impairing physical and mental capabilities; patients must be cautioned about performing tasks which require mental alertness (operating machinery or driving). Zolpidem should only be administered when the patient is able to stay in bed a full night (7-8 hours) before being active again.
• Hypersensitivity reactions: Postmarketing studies have indicated that the use of hypnotic/sedative agents for sleep has been associated with hypersensitivity reactions including anaphylaxis as well as angioedema.
• Sleep-related activities: An increased risk for hazardous sleep-related activities such as sleep-driving; cooking and eating food, and making phone calls while asleep have also been noted; amnesia may also occur. Discontinue treatment in patients who report a sleep-driving episode.
Disease-related concerns:
• Depression: Use with caution in patients with depression; worsening of depression, including suicide or suicidal ideation has been reported with the use of hypnotics. Intentional overdose may be an issue in this population. The minimum dose that will effectively treat the individual patient should be used. Prescriptions should be written for the smallest quantity consistent with good patient care.
• Drug abuse: Use with caution in patients with a history of drug dependence.
• Hepatic impairment: Use with caution in patients with hepatic impairment; dose adjustment recommended.
• Myasthenia gravis: Use with caution in patients with myasthenia gravis.
• Respiratory disease: Use with caution in patients with respiratory compromise, COPD, or sleep apnea.
Concurrent drug therapy issues:
• CNS depressants/psychoactive medications: Use with caution in patients receiving other CNS depressants or psychoactive medication; effects with other sedative drugs or ethanol may be potentiated.
Special populations:
• Elderly: Use with caution in the elderly; dose adjustment recommended. Closely monitor elderly or debilitated patients for impaired cognitive or motor performance.
• Pediatrics: Safety and efficacy have not been established in children.
Other warnings/precautions:
• Appropriate use: Symptomatic treatment of insomnia should be initiated only after careful evaluation of potential causes of sleep disturbance. Failure of sleep disturbance to resolve after 7-10 days may indicate psychiatric and/or medical illness.
• Rapid onset: Because of the rapid onset of action, administer immediately prior to bedtime or after the patient has gone to bed and is having difficulty falling asleep.
• Withdrawal: Abrupt discontinuance may lead to withdrawal symptoms.
Adverse Reactions
Actual frequency may be dosage form, dose, and/or age dependent
>10%: Central nervous system: Dizziness, headache, somnolence
1% to 10%:
Cardiovascular: Blood pressure increased, chest discomfort/pain, palpitation
Central nervous system: Abnormal dreams, anxiety, apathy, amnesia, ataxia, attention disturbance, body temperature increased, confusion, depersonalization, depression, disinhibition, disorientation, drowsiness, drugged feeling, euphoria, fatigue, fever, hallucinations, hypoesthesia, insomnia, memory disorder, lethargy, lightheadedness, mood swings, sleep disorder, stress
Dermatologic: Rash, urticaria, wrinkling
Endocrine & metabolic: Menorrhagia
Gastrointestinal: Abdominal discomfort, abdominal pain, abdominal tenderness, appetite disorder, constipation, diarrhea, dyspepsia, flatulence, gastroenteritis, gastroesophageal reflux, hiccup, nausea, vomiting, xerostomia
Genitourinary: Urinary tract infection
Neuromuscular & skeletal: Arthralgia, back pain, balance disorder, myalgia, neck pain, paresthesia, psychomotor retardation, tremor, weakness
Ocular: Asthenopia, blurred vision, depth perception altered, diplopia, visual disturbance, red eye
Otic: Labyrinthitis, tinnitus, vertigo
Renal: Dysuria
Respiratory: Pharyngitis, sinusitis, upper respiratory tract infection, throat irritation
Miscellaneous: Allergy, binge eating, flu-like syndrome
<1% (Limited to important or life-threatening): Agitation, anorexia, arthritis, bronchitis, cerebrovascular disorder, cognition decreased, concentrating difficulty, constipation, cough, cystitis, diaphoresis, dysarthria, dysphagia, dyspnea, edema, emotional lability, eye irritation, falling, hepatic function abnormalities, hyperglycemia, hyper-/hypotension, illusion, leg cramps, menstrual disorder, nervousness, pallor, postural hypotension, pruritus, rhinitis, scleritis, somnambulism (sleepwalking), speech disorder, stupor, syncope, tachycardia, taste perversion, thirst, urinary incontinence, vaginitis
Postmarketing and/or case reports: Anaphylaxis, angioedema, complex sleep-related behavior (sleep-driving, cooking or eating food, making phone calls)
Metabolism/Transport Effects
Substrate of CYP1A2 (minor), 2C9 (minor), 2C19 (minor), 2D6 (minor), 3A4 (major)
Drug Interactions
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Zolpidem. Exceptions: Miconazole. Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Flumazenil: May diminish the sedative effect of Hypnotics (Nonbenzodiazepine). Risk C: Monitor therapy
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Rifamycin Derivatives: May increase the metabolism of Zolpidem. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: May enhance the adverse/toxic effects of zolpidem; avoid use.
Food: Maximum plasma concentration and bioavailability are decreased with food; time to peak plasma concentration is increased; half-life remains unchanged. Grapefruit juice may decrease the metabolism of zolpidem.
Herb/Nutraceutical: St John's wort may decrease the levels/effects of zolpidem; avoid concomitant use. In addition, concomitant use of valerian, kava kava, and gotu kola should be avoided due to the risk of increased CNS depression.
Storage
Store Ambien® at controlled room temperature of 20°C to 25°C (68°F to 77°F). Store Ambien CR™ at controlled room temperature of 15°C to 25°C (59°F to 77°F).
Mechanism of Action
Zolpidem, an imidazopyridine hypnotic that is structurally dissimilar to benzodiazepines, enhances the activity of the inhibitory neurotransmitter, ?-aminobutyric acid (GABA), via selective agonism at the benzodiazepine-1 (BZ1) receptor; the result is increased chloride conductance, neuronal hyperpolarization, inhibition of the action potential, and a decrease in neuronal excitability leading to sedative and hypotic effects. Because of its selectivity for the BZ1 receptor site over the BZ2 receptor site, zolpidem exhibits minimal anxiolytic, myorelaxant, and anticonvulsant properties (effects largely attributed to agonism at the BZ2 receptor site).
Pharmacodynamics/Kinetics
Onset of action: 30 minutes
Duration: 6-8 hours
Absorption: Rapid
Distribution: Vd: 0.54 L/kg
Protein binding: ~93%
Metabolism: Hepatic methylation and hydroxylation via CYP3A4 (~60%), CYP2C9 (~22%), CYP1A2 (~14%), CYP2D6 (~3%), and CYP2C19 (~3%) to three inactive metabolites
Bioavailability: 70%
Half-life elimination: ~2.5 hours (range 1.4-4.5 hours); Cirrhosis: Up to 9.9 hours; Elderly: prolonged up to 32%
Time to peak, plasma: 1.6 hours; 2.2 hours with food
Excretion: Urine (48% to 67%, primarily as metabolites); feces (29% to 42%, primarily as metabolites)
Dosage
Oral:
Adults:
Ambien®: 10 mg immediately before bedtime; maximum dose: 10 mg
Ambien CR™: 12.5 mg immediately before bedtime
Elderly:
Ambien®: 5 mg immediately before bedtime
Ambien CR™: 6.25 mg immediately before bedtime
Dosing adjustment in renal impairment: Dose adjustment not required; monitor closely
Hemodialysis: Not dialyzable
Dosing adjustment in hepatic impairment:
Ambien®: 5 mg
Ambien CR™: 6.25 mg
Administration: Oral
Ingest immediately before bedtime due to rapid onset of action. Ambien CR™ tablets should be swallowed whole; do not divide, crush, or chew.
Monitoring Parameters
Daytime alertness; respiratory rate; behavior profile
Reference Range
80-150 ng/mL
Dietary Considerations
For faster sleep onset, do not administer with (or immediately after) a meal.
Patient Education
Use exactly as directed; do not increase dose or frequency or discontinue without consulting prescriber. Take immediately before going to bed. Only use this medication if you can get a full night's sleep (at least 7-8 hours). Drug may cause physical and/or psychological dependence. While using this medication, do not use alcohol or other prescription or OTC medications (especially, pain medications, sedatives, antihistamines, or hypnotics) without consulting prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You may experience drowsiness, dizziness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); or diarrhea (buttermilk, boiled milk, yogurt may help). Report CNS changes (confusion, memory problems, depression, increased sedation, excitation, headache, abnormal thinking or behavior, insomnia, or nightmares); muscle pain or weakness; respiratory difficulty; unusual swelling, especially on face or neck; chest pain or palpitations; or ineffectiveness of medication. Report episodes of "sleep driving" or other complex behaviors such as driving a vehicle, preparing food, or other activities which you have no memory of performing. Pregnancy/breast-feeding precaution: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.
Geriatric Considerations
In doses >5 mg, there was subjective evidence of impaired sleep on the first post-treatment night. There have been few reports of increased hypotension and/or falls in the elderly with this drug. Can be considered a drug of choice in the elderly when a hypnotic is indicated. With Ambien CR™, the adverse event profile of 6.25 mg in elderly patients was similar to the 12.5 mg dose in younger adults. Until there is more experience with this dosage form, use with caution in the elderly.
Additional Information
Causes fewer disturbances in sleep stages as compared to benzodiazepines. Time spent in sleep stages 3 and 4 are maintained; zolpidem decreases sleep latency; should not be prescribed in quantities exceeding a 1-month supply.
Anesthesia and Critical Care Concerns/Other Considerations
Causes fewer disturbances in sleep stages as compared to benzodiazepines. Time spent in sleep stages 3 and 4 are maintained; zolpidem decreases sleep latency; should not be prescribed in quantities exceeding a 1-month supply.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation).
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Comment
In 2007, the FDA requested that all manufacturers of sedative-hypnotic drug products revise labeling to include a greater emphasis on the risks of adverse effects. These risks include severe allergic reactions (anaphylaxis, angioedema) and complex sleep-related behaviors, which may include sleep-driving (driving while not fully awake and with no memory of the event), making phone calls, and preparing and eating food while asleep.
Nursing: Physical Assessment/Monitoring
For short-term use. Assess effectiveness and interactions of other medications patient may be taking. Assess for history of addiction; long-term use can result in dependence, abuse, or tolerance; periodically evaluate need for continued use. After long-term use, taper dosage slowly when discontinuing. Be alert to possibility of anaphylaxis any time during therapy. Monitor for CNS depression. For inpatient use, institute safety measures and monitor effectiveness and adverse reactions. For outpatients, monitor for effectiveness of therapy and adverse reactions at beginning of therapy and periodically with long-term use. Assess knowledge/teach patient appropriate use, interventions to reduce side effects, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, as tartrate: 5 mg, 10 mg
Ambien®: 5 mg, 10 mg
Tablet, extended release, as tartrate:
Ambien CR™: 6.25 mg, 12.5 mg
Pricing: U.S. (www.drugstore.com)
Tablet, controlled release (Ambien CR)
6.25 mg (30): $124.99
12.5 mg (30): $125.99
Tablets (Ambien)
5 mg (30): $134.12
10 mg (30): $135.99
Tablets (Zolpidem Tartrate)
5 mg (30): $17.99
10 mg (30): $17.99
References
Garnier R, Guerault E, Muzard D, et al, “Acute Zolpidem Poisoning - Analysis of 344 Cases,” J Toxicol Clin Toxicol, 1994, 32(4):391-404.
Holm KJ and Goa KL, “Zolpidem: An Update of Its Pharmacology, Therapeutic Efficacy and Tolerability in the Treatment of Insomnia,” Drugs, 2000, 59(4):865-89.
Lange CL, “Medication-Associated Somnambulism,” J Am Acad Child Adolesc Psychiatry, 2005, 44(3):211-2.
Langtry HD and Benfield P, “Zolpidem: A Review of Its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Potential,” Drugs, 1990, 40(2):291-313.
Lheureux P, Debailleul G, De Witte O, et al, “Zolpidem Intoxication Mimicking Narcotic Overdose: Response to Flumazenil,” Hum Exp Toxicol, 1990, 9(2):105-7.
Meram D and Descotes J, “Acute Poisoning By Zolpidem,” Rev Med Interne, 1989, 10(5):466.
Mercurio M, De Roos F, and Hoffman RS, “Zolpidem (Ambien®): Exposure Assessment of a New Nonbenzodiazepine GABA Agonist,” Vet Hum Toxicol, 1994, 36:371.
Pacifici GM, Viani A, Rizzo G, et al, “Plasma Protein Binding of Zolpidem in Liver and Renal Insufficiency,” Int J Clin Pharmacol Ther Toxicol, 1988, 26(9):439-43.
Queneau PE, Koch S, Hrusovsky S, et al, “Cytolytic Hepatitis Related to Zolpidem,” 1st International Symposium on Hepatology and Clinical Pharmacology Liver and Drugs, Abstract, 1994, 39.
Salva P and Costa J, “Clinical Pharmacokinetics and Pharmacodynamics of Zolpidem. Therapeutic Implications,” Clin Pharmacokinet, 1995, 29(3):142-53.
Sanger DJ, “The Pharmacology and Mechanisms of Action of New Generation, Non-Benzodiazepine Hypnotic Agents,” CNS Drugs, 2004, 18 (Suppl 1):9-15.
Simcox DA, “Zolpidem-Associated Falls,” Consult Pharm, 1995, 10:1378-80.
International Brand Names
Lexi-Comp.com
Last full review/revision August 2008
Content last modified August 2008
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