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zolpidem (Ambien, Zolpimist, Edluar, Intermezzo)

Tradename: Ambien. DEA-controlled substance: class 4. Indications: 1) treatment of insomnia - delayed sleep onset or sleep maintenance in elderly 2) Ambien CR, but not Ambien is FDA approved for long-termuse 3) Intermezzo FDA-approved for early awakening Contraindications: Caution: - may increase apnea in patients with obstructive sleep apnea Dosage: 1) 10 mg PO QHS (immediate release); 12.5 mg PO QHS (Ambien CR) - recommendations for women [13] - 5 mg PO QHS (immediate release) - 6.25 mg PO QHS (Ambien CR) 2) 5 mg QHS (immediate release) in the elderly 3) limit therapy to 7-10 days 4) Intermezzo 1.75 mg (women) 3.5 mg (men) QHS Tabs: 5 & 10 mg. Ambien CR 6.25 & 12.5 mg. - 5 or 10 mg immediate release component & 1.25 or 2.5 mg of extended release component Zolpimist oral spray Edluar sublingual formulation Intermezzo sublingual formulation Pharmacokinetics: 1) rapidly absorbed; absorption decreased by food 2) onset of effect 30 minutes-1 hour 3) bioavailability 70% 4) protein-binding 92% 5) metabolized in liver by cyt P450 3A4 -> no active metabolites 6) elimination 1/2life 2.5-5 hours, 10 hours with cirrhosis 7) women clear zolpidem slower than men [10] 8) Ambien CR has 5 or 10 mg immediate release component & 1.25 or 2.5 mg of extended release component Adverse effects: (infrequent) 1) central nervous system a) anxiety b) dizziness c) drowsiness [8] d) fatigue e) headache f) irritability g) diplopia 2) neuromuscular a) muscle tremors b) myalgia 3) gastrointestinal a) nausea b) diarrhea 4) report of hypotension & falls in the elderly [5] - 6-fold increased risk of falls in elderly inpatients [12] - 2 fold increased risk of hip fracture [15] 5) sleepwalking & other parasomnias (rare) [7] 6) a single dose may impair driving the next morning in women & people > 55 years of age [9,13] 7) drug interactions involved in 50% of emergency department visits for zolpidem-related adverse drug effects [14] * Boxed warning: - rare risks for sleepwalking, sleepdriving, & other unusual behaviors (i.e., using a stove while sleeping) [17] Drug interactions: 1) any drug that inhibits cyt P450 3A4 may increase levels of zolpidem 2) any drug that induces cyt P450 3A4 may diminish levels of zolpidem Laboratory: -> therapeutic range: 80-150 ng/mL Mechanism of action: 1) imidazopyridine 2) non-benzodiazepine GABA receptor agonist 3) selective binding to benzodiazepine omega-1 receptor 4) retains anxiolytic effects 5) inactive as muscle relaxant & anticonvulsant 6) minimal next day sedation 7) mild rebound insomnia after discontinuation Notes: - higher than recommended doses in the elderly & prolonged use common [16]

Interactions

drug adverse effects (more general classes)

Related

cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)

General

sedative/hypnotic (tranquilizer)

Properties

MISC-INFO: elimination route LIVER 1/2life 2.5-5 HOURS elimination by hemodialysis - protein-binding 92% pregnancy-category B safety in lactation -

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Medical Knowledge Self Assessment Program (MKSAP) 11, American College of Physicians, Philadelphia 1998
  3. Drugdex(R) Drug Evaluation
  4. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  5. Geriatric Dosage Handbook, 6th edition, Selma et al eds, Lexi-Comp, Cleveland, 2001
  6. Prescriber's Letter 12(9): 2005 Comparison of Insomnia Treatments Detail-Document#: 211015 (subscription needed) http://www.prescribersletter.com
  7. Prescriber's Letter 13(4): 2006 Ambien-Induced Parasomnias (Sleep Disorders) Detail-Document#: 220402 (subscription needed) http://www.prescribersletter.com
  8. Frey DJ et al. Influence of zolpidem and sleep inertia on balance and cognition during nighttime awakening: A randomized placebo- controlled trial. J Am Geriatr Soc 2011 Jan; 59:73 PMID: 21226678
  9. Bocca M-L et al. Zolpidem and zopiclone impair similarly monotonous driving performance after a single nighttime intake in aged subjects. Psychopharmacology (Berl) 2011 Apr; 214:699 PMID: 21086117
  10. Jeffrey S Medscape Oncology FDA Approves Intermezzo, First Drug for Early Wakening http://www.medscape.com/viewarticle/754201?sssdmh=dm1.736760&src=nl_newsalert
  11. Department of Veterans Affairs, VA National Formulary
  12. Kolla BP et al Zolpidem is independently associated with increased risk of inpatient falls. Journal of Hospital Medicine, Nov 19, 2012 PMID: 23165956 http://onlinelibrary.wiley.com/doi/10.1002/jhm.1985/abstract
  13. FDA MedWatch: Jan 10, 2013 Zolpidem Containing Products: Drug Safety Communication - FDA Requires Lower Recommended Doses Including Ambien, Ambien CR, Edluar, and Zolpimist http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm334738.htm
  14. SAMHSA. May 1, 2013 The DAWN Report. Drug Abuse Reporting Network. Emergency Department Visits for Adverse Reactions Involving the Insomnia Medication Zolpidem. http://www.samhsa.gov/data/2k13/DAWN079/sr079-Zolpidem.htm
  15. Lin F-Y et al. Retrospective population cohort study on hip fracture risk associated with zolpidem medication. Sleep 2014 Apr; 37:673 http://www.journalsleep.org/ViewAbstract.aspx?pid=29396
  16. Moore TJ, Mattison DR. Assessment of patterns of potentially unsafe use of zolpidem. JAMA Intern Med 2018 Jul 16; PMID: 30014137 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2687525
  17. FDA News Release. April 30, 2019 FDA requires stronger warnings about rare but serious incidents related to certain prescription insomnia medicines. Updated warnings for eszopiclone, zaleplon and zolpidem. https://www.fda.gov/news-events/press-announcements/fda-requires-stronger-warnings-about-rare-serious-incidents-related-certain-prescription-insomnia
  18. Marbin A et al Zaleplon Versus Zolpidem Use in Older Adults Being Treated for Insomnia: A Review. Am J Geriatr Psychiatr. 2023. 31(3)S68-S69 Not indexed in PubMed https://www.sciencedirect.com/science/article/abs/pii/S1064748123000544