Zolpidem Tartrate

Class: Anxiolytics, Sedatives, and Hypnotics; Miscellaneous
VA Class: CN309
Chemical Name: Imidazo(1,2 - a)pyridine - 3 - acetamide,N,N,6 - trimethyl - 2 - (4 - methylphenyl) - ,(R - (R*,R*)) - 2,3 - dihydroxybutanedioate (2:1)
Molecular Formula: C₁₉H₂₁N₃O•½C₄H₆O
CAS Number: 103188-50-7
Brands: Ambien

REMS:

FDA approved a REMS for zolpidem to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of zolpidem and consists of the following: medication guide. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Imidazopyridine-derivative sedative and hypnotic;^{1 2 3 4 89} structurally unrelated to benzodiazepines and other sedatives and hypnotics.^{1 2 3 89}

Uses for Zolpidem Tartrate

Insomnia

Conventional tablets used for short-term management of insomnia characterized by difficulties with sleep initiation.¹ Decreases sleep latency in patients with chronic or transient insomnia;^{1 2 3 22} no substantial evidence of diminished effectiveness during the end of each night’s use (early morning insomnia) despite short half-life.^{1 14 19 20}

Extended-release tablets used for management of insomnia characterized by difficulty with sleep onset or sleep maintenance.⁸⁹

Zolpidem Tartrate Dosage and Administration

General

• 
  

  Use only when able to get 7–8 hours of sleep before being active again.^{1 89}

  
  


• 
  

  Reevaluate patient if zolpidem is to be used for more than 2–3 weeks.^{23 79} (See Adequate Patient Evaluation under Cautions.)

  
  


• 
  

  Avoid abrupt discontinuance after prolonged (e.g., longer than 1–2 weeks) therapy; ²³ consider gradual dosage reduction (e.g., over several nights) when discontinuing short-term therapy.^{77 78}

  
  

Administration

Oral Administration

Administer immediately before going to bed when ready to go to sleep.^{1 89}

Onset of sleep may be facilitated by taking the drug on an empty stomach.^{1 89} Do not administer extended-release tablets with or immediately after a meal.⁸⁹ (See Food under Pharmacokinetics.)

Swallow extended-release tablets whole; do not divide, crush, or chew.⁸⁹

Dosage

Available as zolpidem tartrate; dosage is expressed in terms of the salt.^{1 89}

Individualize dosage; use smallest effective dose.^{1 81 89}

Adults

Insomnia

Oral

10 mg (as conventional tablets) or 12.5 mg (as extended-release tablets).^{1 2 3 4 89}

Prescribing Limits

Adults

Insomnia

Oral

Maximum 10 mg daily as conventional tablets.¹ Higher doses (e.g., 15 or 20 mg) occasionally have been used^{1 2 3 9 10 11 20} but may be associated with increased risk of adverse effects, including abuse potential.^{1 2 3}

Special Populations

Hepatic Impairment

Prolonged elimination.^{81 89} Initially, 5 mg (as conventional tablets) or 6.25 mg (as extended-release tablets).^{1 89}

Renal Impairment

Possible pharmacokinetic alterations. (see Elimination: Special Populations, under Pharmacokinetics.)^{2 3 81} Manufacturer recommends close monitoring but states that dosage reduction is not necessary;^{1 89} some clinicians recommend that dosage reduction be considered.^{2 3 81}

Geriatric or Debilitated Patients

Possible increased sensitivity to sedatives and hypnotics.¹ Initially, 5 mg (as conventional tablets) or 6.25 mg (as extended-release tablets).^{1 2 3 14 89} (See Geriatric Use under Cautions.)

Cautions for Zolpidem Tartrate

Contraindications

• 
  

  Known hypersensitivity to zolpidem or any ingredient in the formulation.^{1 89 90}

  
  

Warnings/Precautions

Warnings

Adequate Patient Evaluation

Insomnia may be a manifestation of an underlying physical and/or psychiatric disorder; carefully evaluate patient before providing symptomatic treatment.^{1 23 79 89}

Failure of insomnia to remit after 7–10 days of treatment, worsening of insomnia, or emergence of new abnormal thinking or behavior may indicate the presence of an underlying psychiatric and/or medical condition that requires evaluation.^{1 89}

Adverse Psychiatric Events

Abnormal thinking and behavioral changes (e.g., aggressiveness, uncharacteristic extroversion, bizarre behavior, agitation, hallucinations, depersonalization, amnesia) may occur unpredictably.^{1 89} Possible worsening of depression (including suicidal thinking) with sedative or hypnotic use in patients with depression.^{1 89} Immediately evaluate any new behavioral sign or symptom.^{1 89}

Some adverse effects appear to be dose related; use the lowest effective dose.^{1 89}

Complex Sleep-related Behaviors

Complex behaviors such as sleep-driving (i.e., driving while not fully awake after ingesting a sedative and hypnotic drug, with no memory of the event), preparing and eating food, making phone calls, or having sex while not fully awake after taking a sedative and hypnotic drug, and usually with no memory of the event, reported.^{1 89 91}

May occur in sedative and hypnotic drug-naive or drug-experienced patients.^{89 91}

Increased risk with concomitant use of alcohol and other CNS depressants or use of the drug at dosages exceeding the maximum recommended dosage; however, may occur with the drug alone at therapeutic dosages.^{1 89 91}

Consider discontinuing drug in patients who report a sleep-driving episode because of the risk to the patient and community.^{1 89 91}

Withdrawal Effects

Rapid dosage reduction or abrupt discontinuance of sedatives or hypnotics has resulted in signs and symptoms of withdrawal.^{1 23 89}

Abuse Potential

Abuse potential similar to that of benzodiazepines and related hypnotics.^{1 89}

Patients with a history of drug or alcohol dependence or abuse are at risk of habituation or dependence; use only with careful surveillance in such patients.^{1 89}

CNS Effects

Rapid onset of CNS effects (sedation, impairment of psychomotor function, impairment of short-term memory); administer only immediately before going to bed.^{1 89}

Performance of activities requiring mental alertness or physical coordination may be impaired the day after ingestion.^{1 89} Some reports of decreased psychomotor and mental performance in adults and geriatric individuals; other studies found no evidence of residual daytime sedative effects.^{1 89} Risk of residual daytime sedation and impaired performance appears to be minimal at usual dosages.^{1 2 3 4 9 10 11 12 13 89}

Concurrent use of other CNS depressants may cause additive or potentiated CNS depression.^{1 89} (See Specific Drugs under Interactions.)

Sensitivity Reactions

Angioedema involving the tongue, glottis, or larynx reported rarely following initial or subsequent doses of sedative and hypnotic drugs, including zolpidem.^{1 89 91} Some patients experienced additional symptoms (e.g., dyspnea, closing of the throat, nausea and vomiting [suggestive of anaphylaxis]).^{1 89 91} Some individuals required medical treatment in an emergency department.^{1 89 91} Angioedema reported during postmarketing surveillance.^{1 89}

Airway obstruction may occur if angioedema involves the throat, glottis, or larynx and can be fatal.^{1 89 91}

Do not rechallenge with the drug if angioedema occurs.^{1 89 91}

Advise patients to immediately discontinue the drug and inform their clinician if signs of an allergic reaction (e.g., rash, hives, dyspnea, swelling of tongue or throat) occur.^{1 89}

General Precautions

Respiratory Effects

No respiratory depressant effects reported at hypnotic doses in healthy individuals or in patients with mild to moderate COPD; ^{1 85 89} however, decreased oxygen saturation reported in patients with mild to moderate sleep apnea.^{1 86 89} Respiratory insufficiency reported, mostly in patients with preexisting respiratory impairment.^{1 89}

Use with caution in patients with compromised respiratory function.^{1 89}

Suicide

Use with caution in depressed patients.^{1 89} Potential for suicidal tendencies; overdosage more frequent in such patients.^{1 89} Prescribe and dispense drug in the smallest feasible quantity.^{1 89}

Concurrent Diseases

Limited experience in patients with concurrent systemic disease.^{1 89} Use with caution in patients with diseases affecting metabolism or hemodynamic response.^{1 89} Use zolpidem tartrate extended-release tablets with caution in patients with sleep apnea syndrome or myasthenia gravis.⁸⁹

Specific Populations

Pregnancy

Category C.^{1 89 90}

Lactation

Distributed into milk in small amounts;^{1 84 89} potential effects on nursing infants are not known.^{1 89} Use is not recommended.^{1 89}

Pediatric Use

Safety and efficacy of zolpidem tartrate conventional tablets not established in children.¹ Dizziness, headache, and hallucinations reported.¹

Safety and efficacy of zolpidem tartrate extended-release tablets not established in children <18 years of age.⁸⁹

Geriatric Use

Pharmacokinetic changes in geriatric patients compared with younger adults.¹ (See Absorption and also Elimination, under Pharmacokinetics.)

Potential increased sensitivity to sedatives and hypnotics.^{1 89} Adverse effects tend to be dose related, ^{1 2 4 9 82 89} particularly in geriatric patients.^{1 2 9} Adverse effect profile in patients ≥65 years of age receiving 6.25-mg dose (as extended-release tablets) similar to that in younger adults receiving 12.5-mg dose.⁸⁹

Use low initial dose and monitor closely.^{1 89} (See Geriatric or Debilitated Patients under Dosage and Administration.)

Hepatic Impairment

Prolonged elimination; reduce initial dose and monitor closely.^{1 81 89} (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Possible pharmacokinetic alterations.^{2 3 81} (See Elimination: Special Populations, under Pharmacokinetics.) Monitor closely.^{1 89} Some clinicians recommend dosage reduction (see Renal Impairment under Dosage and Administration.)^{2 3 81}

Common Adverse Effects

With short-term use at recommended dosages: drowsiness¹ or somnolence,⁸⁹ dizziness,^{1 89} headache,⁸⁹ diarrhea.¹

Interactions for Zolpidem Tartrate

Metabolized principally by CYP3A4 and to a lesser extent by CYP1A2 and CYP2D6.⁸⁸

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction.^{1 89}

Specific Drugs

Drug	Interaction	Comments
CNS depressants (e.g., sedatives, psychotropic drugs, anticonvulsants, antihistamines, alcohol)	Additive depressant effect1 89	Do not use with alcohol; consider dosage reduction if zolpidem is used concomitantly with other CNS depressants1 89
Digoxin	No effect on digoxin pharmacokinetics1 89
Flumazenil	Reversal of sedative/hypnotic effects of zolpidem1 89
Histamine H2-antagonists (cimetidine, ranitidine)	No effect on zolpidem pharmacokinetics1 89
Itraconazole	Increased plasma zolpidem concentrations1 89
Rifampin	Decreased plasma zolpidem concentrations1 89
Warfarin	Pharmacodynamic interaction (effect on PT) unlikely1 89

Zolpidem Tartrate Pharmacokinetics

Absorption

Bioavailability

Conventional tablets: Rapidly absorbed following oral administration, with peak plasma concentrations attained in about 1.6 hours.¹ Absolute bioavailability is about 70%.⁸⁷

Extended-release tablets: Exhibit biphasic absorption characteristics; rapid initial absorption following oral administration (similar to conventional tablets), but with extended plasma concentrations beyond 3 hours after administration.⁸⁹ Peak plasma concentrations are attained in about 1.5 hours.⁸⁹

Food

Conventional tablets: Food decreases AUC by 15%, decreases peak plasma concentration by 25%, and prolongs time to peak plasma concentration by 60%.¹

Extended-release tablets: Food decreases AUC by 23%, decreases peak plasma concentration by 30%, and prolongs time to peak plasma concentration by about 2 hours (from 2 hours to 4 hours).⁸⁹

Special Populations

In geriatric patients receiving zolpidem tartrate as conventional tablets, peak plasma concentration and AUC are increased by 50 and 64%, respectively, compared with younger adults.¹

In patients with chronic hepatic impairment receiving zolpidem tartrate as conventional tablets, peak plasma concentration and AUC are 2 and 5 times higher, respectively, than in healthy individuals.^{1 89} Zolpidem tartrate extended-release tablets not studied to date in patients with hepatic impairment.⁸⁹

Distribution

Extent

Distributed into breast milk in small amounts.^{1 89} Not known whether zolpidem crosses the placenta.¹

Plasma Protein Binding

Approximately 92%.^{1 87 89}

Elimination

Metabolism

Metabolized in the liver via oxidation and hydroxylation, principally by CYP3A4 and to a lesser extent by CYP1A2 and CYP2D6.^{1 88} No active metabolites.^{1 87 89}

Elimination Route

Excreted principally in urine as inactive metabolites.^{1 89}

Half-life

Approximately 2.5 hours (conventional tablets) or 2.8 hours (extended-release tablets).^{1 87 89}

Special Populations

In geriatric patients receiving zolpidem tartrate as conventional tablets, half-life is increased by 32% compared with younger adults.¹ Half-life is 2.9 hours in geriatric patients receiving zolpidem tartrate 6.25 mg as extended-release tablets.⁸⁹

In patients with cirrhosis receiving zolpidem tartrate as conventional tablets, half-life is about 9.9 hours.^{1 89} Extended-release tablets not studied to date in patients with hepatic impairment.⁸⁹

In nondialyzed patients with chronic renal disease and in patients undergoing periodic dialysis, slower elimination rates reported with IV zolpidem (not commercially available in the US).^{2 3 81} No substantial pharmacokinetic alterations reported with oral zolpidem in patients with end-stage renal failure undergoing hemodialysis.^{1 89} Extended-release tablets not studied to date in patients with renal impairment.⁸⁹

Not removed by hemodialysis.^{1 89}

Stability

Storage

Oral

Conventional Tablets

20–25°C.¹

Extended-release Tablets

15–25°C (may be exposed to temperatures up to 30°C).⁸⁹

Actions

• 
  

  Interacts with the CNS GABA_A-receptor-chloride ionophore complex at benzodiazepine (BZ, ο) receptors.^{1 2 3 89}

  
  


• 
  

  Selectivity for the BZ₁ receptor may account for the decreased muscle relaxant, anxiolytic, and anticonvulsant effects compared with benzodiazepines reported in animal studies,^{1 2 3 4 6 7 89} as well as the preservation of deep sleep (stages 3 and 4) reported in human studies.^{1 4 89}

  
  

Advice to Patients

• 
  

  Provide patient with a copy of manufacturer’s patient information.^{1 89}

  
  


• 
  

  Potential risk of complex sleep-related behaviors; importance of immediately informing clinician if sleep-driving events or other complex behaviors occur.^{1 89 91}

  
  


• 
  

  Importance of advising patients to immediately discontinue drug and inform clinician if signs of an allergic reaction (e.g., rash, hives, dyspnea, swelling of tongue or throat) occur.^{1 89}

  
  


• 
  

  Importance of administering immediately before retiring.^{1 89}

  
  


• 
  

  Importance of taking only when able to get a full night’s sleep (i.e., 7–8 hours) before being active again.^{1 89}

  
  


• 
  

  Importance of taking only as prescribed; do not increase dosage or duration of therapy unless otherwise instructed by a clinician.^{1 89}

  
  


• 
  

  Importance of not abruptly discontinuing therapy if drug has been used for more than 1–2 weeks; consult clinician about discontinuing use.^{1 89}

  
  


• 
  

  Potential for drug to impair mental alertness or physical coordination; use caution when operating machinery or performing hazardous tasks until effects on individual are known.^{1 89}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescriptions and OTC drugs, and of concomitant illnesses, particularly depression.^{1 89}

  
  


• 
  

  Importance of avoiding alcohol-containing beverages or products.^{1 89}

  
  


• 
  

  Importance of informing clinicians of any behavioral or mental changes, memory impairment, tolerance, or dependence/withdrawal symptoms.^{1 89}

  
  


• 
  

  Risk of rebound insomnia for 1 or 2 nights after discontinuance.^{1 89}

  
  


• 
  

  Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.^{1 89}

  
  


• 
  

  Importance of informing patients of other important precautionary information. (See Cautions.)^{1 89}

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.^{1 89}

Zolpidem Tartrate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, extended-release, film-coated	6.25 mg	Ambien CR ( C-IV)	Sanofi-Aventis
		12.5 mg	Ambien CR ( C-IV)	Sanofi-Aventis
	Tablets, film-coated	5 mg	Ambien ( C-IV)	Searle
		10 mg	Ambien ( C-IV)	Searle

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Ambien 10MG Tablets (SANOFI-AVENTIS U.S.): 30/$209.98 or 90/$582.91

Ambien 5MG Tablets (SANOFI-AVENTIS U.S.): 30/$203.64 or 90/$582.16

Ambien CR 12.5MG Controlled-release Tablets (SANOFI-AVENTIS U.S.): 30/$190.99 or 90/$549.97

Ambien CR 6.25MG Controlled-release Tablets (SANOFI-AVENTIS U.S.): 30/$191.99 or 90/$545.97

Edluar 10MG Sublingual Tablets (MEDA PHARMACEUTICALS): 30/$163.80 or 90/$457.76

Edluar 5MG Sublingual Tablets (MEDA PHARMACEUTICALS): 30/$160.93 or 90/$452.00

Zolpidem Tartrate 10MG Tablets (MYLAN): 30/$17.99 or 90/$45.97

Zolpidem Tartrate 12.5MG Controlled-release Tablets (WINTHROP): 30/$155.99 or 90/$439.99

Zolpidem Tartrate 5MG Tablets (TORRENT PHARMACEUTICALS): 30/$17.99 or 90/$45.97

Zolpidem Tartrate 6.25MG Controlled-release Tablets (WINTHROP): 30/$155.99 or 60/$299.98

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Sanofi-Aventis. Ambien (zolpidem tartrate) tablet prescribing information. Bridgewater, NJ; 2007 Mar.

2. Langtry HD, Benfield P. Zolpidem: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential. Drugs. 1990; 40:291-313. [PubMed 2226217]

3. Fullerton T, Frost M. Focus on zolpidem: a novel agent for the treatment of insomnia. Hosp Formul. 1992; 27:773-91.

4. Anon. Zolpidem for insomnia. Med Lett Drugs Ther. 1993; 35:35-6. [PubMed 8386301]

5. Cavallaro R, Regazzetti MG, Covelli G et al. Tolerance and withdrawal with zolpidem. Lancet. 1993; 342:374- 5. [IDIS 318718] [PubMed 8101619]

6. Perrault G, Morel E, Sanger DJ et al. Differences in the pharmacological profiles of a new generation of benzodiazepine and non-benzodiazepine hypnotics. Eur J Pharmacol. 1990; 187:487-94. [PubMed 1981555]

7. Perrault G, Morel E, Sanger DJ et al. Lack of tolerance and physical dependence upon repeated treatment with the novel hypnotic zolpidem. J Pharmacol Exp Ther. 1992; 263:298-303. [PubMed 1403792]

8. Griffiths RR, Sannerud CA, Ator NA et al. Zolpidem behavioral pharmacology in baboons: self-injection, discrimination, tolerance and withdrawal. J Pharmacol Exp Ther. 1992; 260:1199-208. [PubMed 1312162]

9. Scharf MB, Mayleben DW, Kaffeman M et al. Dose response effects of zolpidem in normal geriatric subjects. J Clin Psychiatry. 1991; 52:77-83. [IDIS 278622] [PubMed 1993640]

10. Bensimon G, Foret J, Warot D et al. Daytime wakefulness following a bedtime oral dose of zolpidem 20 mg, flunitrazepam 2 mg and placebo. Br J Clin Pharmacol. 1990; 30:463-9. [IDIS 272319] [PubMed 2223425]

11. Fairweather DB, Kerr JS, Hindmarch I. The effects of acute and repeated doses of zolpidem on subjective sleep, psychomotor performance and cognitive function in elderly volunteers. Eur J Clin Pharmacol. 1992; 43:597-601. [IDIS 310281] [PubMed 1493840]

12. Brunner DP, Dijk DJ, Münch M et al. Effect of zolpidem on sleep and sleep EEG spectra in healthy young men. Psychopharmacology (Berl). 1991; 104:1-5. [PubMed 1881993]

13. Sicard BA, Trocherie S, Moreau J et al. Evaluation of zolpidem on alertness and psychomotor abilities among aviation ground personnel and pilots. Aviat Space Environ Med. 1993; 64:371-5. [PubMed 8503809]

14. Roger M, Attali P, Coquelin JP. Multicenter, double- blind, controlled comparison of zolpidem and triazolam in elderly patients with insomnia. Clin Ther. 1993; 15:127-36. [PubMed 8458042]

15. Jonas JM, Coleman BS, Sheridan AQ et al. Comparative clinical profiles of triazolam versus other shorter-acting hypnotics. J Clin Psychiatr. 1992; 53(Suppl):19-31.

16. Byrnes JJ, Greenblatt DJ, Miller LG. Benzodiazepine receptor binding of nonbenzodiazepines in vivo: alpidem, zolpidem and zopiclone. Brain Res Bull. 1992; 29:905- 8. [PubMed 1361878]

17. Benavides J, Peny B, Durand A et al. Comparative in vivo and in vitro regional selectivity of central omega (benzodiazepine) site ligands in inhibiting [3H]flumazenil binding in the rat central nervous system. J Pharmacol Exp Ther. 1992; 263:884-96. [PubMed 1331419]

18. Perrault G, Morel E, Sanger DJ et al. Lack of tolerance and physical dependence upon repeated treatment with the novel hypnotic zolpidem. J Pharmacol Exp Ther. 1992; 263:298-303. [PubMed 1403792]

19. Lader M. Rebound insomnia and newer hypnotics. Psychopharmacology (Berl). 1992; 108:248-55. [PubMed 1523276]

20. Maarek L, Cramer P, Attali P et al. The safety and efficacy of zolpidem in insomniac patients: a long-term open study in general practice. J Int Med Res. 1992; 20:162-70. [PubMed 1521672]

21. Wheatley D. Prescribing short-acting hypnosedatives: current recommendations from a safety perspective. Drug Saf. 1992; 7:106-15. [PubMed 1605897]

22. Kryger MH, Steljes D, Pouliot Z et al. Subjective versus objective evaluation of hypnotic efficacy: experience with zolpidem. Sleep. 1991; 14:399-407. [PubMed 1759092]

23. The Upjohn Company. Halcion (triazolam) tablets prescribing information, dated 1991 Dec. In: Physicians’ desk reference. 46th ed. Montvale, NJ: Medical Economics Company Inc; 1992(Suppl A):A127-30.

24. Greenblatt DJ, Shader RI, Abernethy DR. Drug therapy: current status of benzodiazepines (first of two parts). N Engl J Med. 1983; 309:354-8. [IDIS 173691] [PubMed 6135156]

25. Greenblatt DJ, Shader RI, Abernethy DR. Drug therapy: current status of benzodiazepines (second of two parts). N Engl J Med. 1983; 309:410-6. [IDIS 174051] [PubMed 6135990]

26. Anon. Choice of benzodiazepines. Med Lett Drugs Ther. 1988; 30:26-8. [PubMed 2893246]

27. National Institutes of Health. Drugs and insomnia: the use of medications to promote sleep. Consensus Development Conference. JAMA. 1984; 251:2410-4. [PubMed 6142971]

28. Kales A, Soldatos CR, Kales JD. Sleep disorders: insomnia, sleepwalking, night terrors, nightmares, and enuresis. Ann Intern Med. 1987; 106:582-92. [PubMed 3548525]

29. Greenblatt DJ, Harmatz JS, Zinny MA et al. Effect of gradual withdrawal on the rebound sleep disorder after discontinuation of triazolam. N Engl J Med. 1987; 317:722-8. [IDIS 233512] [PubMed 3306380]

30. Kales A, Soldatos CR, Bixler EO et al. Early morning insomnia with rapidly eliminated benzodiazepines. Science. 1983; 20:95-7.

31. Kales A, Scharf MB, Kales JD et al. Rebound insomnia. Science. 1980; 208:424. [PubMed 17843621]

32. Bixler EO, Kales JD, Kales A et al. Rebound insomnia and elimination half-life: assessment of individual subject response. J Clin Pharmacol. 1985; 25:115-24. [IDIS 197633] [PubMed 2859304]

33. Gillin JC, Spinweber CL, Johnson LC. Rebound insomnia: a critical review. J Clin Psychopharmacol. 1989; 9:161-72. [IDIS 254724] [PubMed 2567741]

34. Kales A, Kales JD. Sleep laboratory studies of hypnotic drugs: efficacy and withdrawal effects. J Clin Psychopharmacol. 1983; 3:140-50. [IDIS 168418] [PubMed 6132933]

35. Kales A, Soldatos CR, Bixler EO et al. Midazolam: dose-response studies of effectiveness and rebound insomnia. Pharmacology. 1983; 26:138-49. [PubMed 6132414]

36. Kales A, Soldatos CR, Bixler EO et al. Rebound insomnia and rebound anxiety: a review. Pharmacology. 1983; 26:121-37. [PubMed 6132413]

37. Kales A, Scharf MB, Kales JD et al. Rebound insomnia: a potential hazard following withdrawal of certain benzodiazepines. JAMA. 1979; 241:1692-5. [IDIS 94542] [PubMed 430730]

38. Kales A, Scharf MB, Kales JD. Rebound insomnia: a new clinical syndrome. Science. 1978; 201:1039-41. [PubMed 684426]

39. Kales A, Bixler EO, Kales JD et al. Comparative effectiveness of nine hypnotic drugs: sleep laboratory studies. J Clin Pharmacol. 1977; 17:207-13. [PubMed 321488]

40. Vogel GW, Barker K, Gibbons P et al. A comparison of the effects of flurazepam 30 mg and triazolam 0.5 mg on the sleep of insomniacs. Psychopharmacologia. 1976; 47:81-6.

41. Murphy P, Hindmarch I, Hyland CM. Aspects of short-term use of two benzodiazepine hypnotics in the elderly. Age Ageing. 1982; 11:222-8. [PubMed 6129788]

42. Ogura C, Nakazawa K, Majima K et al. Residual effects of hypnotics: triazolam, flurazepam, and nitrazepam. Psychopharmacology (Berl). 1980; 68:61-5. [PubMed 6104840]

43. Morgan K, Oswald I. Anxiety caused by a short-life hypnotic. BMJ. 1982; 284:942. [IDIS 148143] [PubMed 6121606]

44. Larson EB, Kukull WA, Buchner D et al. Adverse drug reactions associated with global cognitive impairment in elderly persons. Ann Intern Med. 1987; 107:169-73. [IDIS 233222] [PubMed 2886086]

45. Bixler EO, Kales A, Brubaker BH et al. Adverse reactions to benzodiazepine hypnotics: spontaneous reporting system. Pharmacology. 1987; 35:286-300. [PubMed 2892212]

46. Juhl RP, Daugherty VM, Kroboth PD. Incidence of next-day anterograde amnesia caused by flurazepam hydrochloride and triazolam. Clin Pharm. 1984; 3:622-5. [IDIS 193408] [PubMed 6150782]

47. Kales A, Bixler EO, Vela-Bueno A et al. Comparison of short and long half-life benzodiazepine hypnotics: triazolam and quazepam. Clin Pharmacol Ther. 1986; 40:378-86. [IDIS 222121] [PubMed 3530586]

48. Jerram T. Hypnotics and sedatives. In: Dukes MNG, ed. Meyler’s side effects of drugs. 10th ed. New York: Elsevier; 1984:81-108.

49. Jerram T. Hypnotics and sedatives. In: Dukes MNG, ed. Side effects of drugs. Annual 11. New York: Elsevier; 1987:37-43.

50. Regestein QR, Reich P. Agitation observed during treatment with newer hypnotics. J Clin Psychiatry. 1985; 46:280-3. [IDIS 203334] [PubMed 2861195]

51. Adam K, Oswald I. Can a rapidly-eliminated hypnotic cause daytime anxiety? Pharmacopsychiatry. 1989; 22:115-9.

52. Kales A, Soldatos CR, Bixler EO et al. Diazepam: effects on sleep and withdrawal phenomena. J Clin Psychopharmacol. 1988; 8:340-6. [IDIS 246932] [PubMed 3183072]

53. Baker Cummins Pharmaceuticals, Inc. Doral (quazepam) prescribing information. Miami, FL; 1990 May.

54. Ankier SI, Goa KL. Quazepam: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in insomnia. Drugs. 1988; 35:42-62. [IDIS 238596] [PubMed 2894293]

55. Baker Cummins Pharmaceuticals, Inc. Doral (quazepam) drug reference. Miami, FL; 1989 Jul.

56. Baker Cummins Pharmaceuticals, Inc. Doral (quazepam) receptor-selective benzodiazepine hypnotic monograph. Miami, FL; 1990 Feb.

57. Rall TW. Hypnotics and sedatives; ethanol: benzodiazepines and management of insomnia. In: Gilman AG, Rall TW, Nies AS et al. Goodman and Gilman’s the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press; 1990:346-58,369-70.

58. Kales A, Bixler EO, Soldatos CR et al. Quazepam and flurazepam: long-term use and extended withdrawal. Clin Pharmacol Ther. 1982; 32:781-8. [IDIS 161844] [PubMed 7140142]

59. Kales A, Scharf MB, Soldatos CR et al. Quazepam, a new benzodiazepine hypnotic: intermediate-term sleep laboratory evaluation. J Clin Pharmacol. 1980; 20:184-92. [IDIS 112918] [PubMed 6103903]

60. Anon. Quazepam: a new hypnotic. Med Lett Drugs Ther. 1990; 32:39-40. [PubMed 1970112]

61. Kales A, Bixler EO, Soldatos CR et al. Quazepam and temazepam: effects of short- and intermediate-term use and withdrawal. Clin Pharmacol Ther. 1986; 39:345-52. [IDIS 213997] [PubMed 2868823]

62. Lee A, Lader M. Tolerance and rebound during and after short-term administration of quazepam, triazolam and placebo to healthy human volunteers. Int Clin Psychopharmacol. 1988; 3:31-47. [PubMed 2895786]

63. Mamelak M, Csima A, Price V. A comparative 25-night sleep laboratory study on the effects of quazepam and triazolam on chronic insomniacs. J Clin Pharmacol. 1984; 24:65-75. [IDIS 183605] [PubMed 6143767]

64. Mamelak M, Csima A, Price V. Effects of quazepam and triazolam on the sleep of chronic insomniacs: a comparative 25-night sleep laboratory study. Clin Neuropharmacol. 1985; 8(Suppl 1):S63-73. [PubMed 3837688]

65. Kales A, Scharf MB, Bixler EO et al. Dose-response studies of quazepam. Clin Pharmacol Ther. 1981; 30:194-200. [IDIS 136583] [PubMed 6113910]

66. Bixler EO, Kales JD, Kales A et al. Rebound insomnia and elimination half-life: assessment of individual subject response. J Clin Pharmacol. 1985; 25:115-24. [IDIS 197633] [PubMed 2859304]

67. Aden GC, Thatcher C. Quazepam in the short-term treatment of insomnia in outpatients. J Clin Psychiatry. 1983; 44:454-6. [IDIS 179748] [PubMed 6361006]

68. Kales JD, Kales A, Soldatos CR. Quazepam: sleep laboratory studies of effectiveness and withdrawal. Clin Neuropharmacol. 1985; 8(Suppl 1):S55-62.

69. Mendels J, Stern S. Evaluation of the short-term treatment of insomnia in out-patients with 15 milligrams of quazepam. J Int Med Res. 1983; 11:155-61. [PubMed 6347747]

70. Abbott. ProSom prescribing information. North Chicago, IL; 1990 Dec.

71. Abbott. Product information form for American Hospital Formulary Service on ProSom. North Chicago, IL; 1991 May.

72. Scharf MB, Roth PB, Dominguez RA. Estazolam and flurazepam: a multicenter, placebo-controlled comparative study in outpatients with insomnia. J Clin Pharmacol. 1990; 30:461-7. [IDIS 266288] [PubMed 1971831]

73. Lamphere J, Roehrs T, Zorick F et al. Chronic hypnotic efficacy of estazolam. Drugs Exp Clin Res. 1986; 12:687-91. [PubMed 2875857]

74. Dominguez RA, Goldstein BJ, Jacobson AF et al. Comparative efficacy of estazolam, flurazepam, and placebo in outpatients with insomnia. J Clin Psychiatry. 1986; 47:362-5. [IDIS 218982] [PubMed 2873132]

75. Greenblatt DJ, Miller LG, Shader RI. Neurochemical and pharmacokinetic correlates of the clinical action of benzodiazepine hypnotic drugs. Am J Med. 1990; 88(Suppl 3A):18-24S.

76. Roehrs T. Rebound insomnia: its determinants and significance. Am J Med. 1990; 88(Suppl 3A):39-42S.

77. Greenblatt DJ, Harmatz JS, Zinny MA et al. Effect of gradual withdrawal on the rebound sleep disorder after discontinuation of triazolam. N Engl J Med. 1987; 317:722-8. [IDIS 233512] [PubMed 3306380]

78. Kales A, Manfredi RL, Vgontzas AN et al. Rebound insomnia after only brief and intermittent use of rapidly eliminated benzodiazepines. Clin Pharmacol Ther. 1991; 49:468- 76. [IDIS 281235] [PubMed 2015735]

79. National Institutes of Health. Drugs and insomnia: the use of medications to promote sleep. Consensus Conference. JAMA. 1984; 251:2410-4. [PubMed 6142971]

80. Fillastre JP, Geffroy-Josse S, Etienne I et al. Pharmacokinetics and pharmacodynamics of zolpidem following repeated doses in hemodialyzed uraemic patients. Fundam Clin Pharmacol. 1993; 7:1-9. [PubMed 8458597]

81. Bianchetti G, Dubruc C, Thiercelin JF et al. Clinical pharmacokinetics of zolpidem an various physiological and pathological conditions. In: Sauvenet JP, Langer SZ, Morselli PL, eds. Imidazopyridines in sl