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Restoril

Generic Name: Temazepam
Class: Benzodiazepines
VA Class: CN302
Chemical Name: 7-Chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one
Molecular Formula: C16H13ClN2O2
CAS Number: 846-50-4

Medically reviewed on Dec 11, 2017

Warning

    Concomitant Use with Opiates
  • Concomitant use of benzodiazepines and opiates may result in profound sedation, respiratory depression, coma, and death.700 701 703 705 706 707

  • Reserve concomitant use for patients in whom alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy and monitor closely for respiratory depression and sedation.700 703 (See Specific Drugs under Interactions.)

Introduction

Benzodiazepine; sedative and hypnotic.a c

Uses for Restoril

Insomnia

Short-term (generally 7–10 days) management of insomnia.a c

Decreases sleep latency, reduces early morning awakening, and improves sleep maintenance in patients with chronic insomnia; similar effects in patients with transient insomnia.a

Restoril Dosage and Administration

General

  • Use only when able to get 7–8 hours of sleep before being active again.a

  • Generally limit hypnotic therapy to 7–10 days.a

  • Avoid abrupt discontinuance; after extended therapy at doses >15 mg, taper dosage gradually.a

Administration

Oral Administration

Administer at bedtime.a c

Dosage

Adults

Insomnia
Oral

7.5–30 mg; 15 mg is the usual recommended dose.a c In patients with transient insomnia, 7.5 mg may be sufficient.a

Special Populations

Geriatric or Debilitated Patients

Possible increased sensitivity to benzodiazepines.a b Initially, 7.5 mg.a c

Cautions for Restoril

Contraindications

  • Pregnancy.a b

  • Known hypersensitivity to benzodiazepines.b

Warnings/Precautions

Warnings

Concomitant Use with Opiates

Concomitant use of benzodiazepines, including temazepam, and opiates may result in profound sedation, respiratory depression, coma, and death.700 701 703 705 706 707 Substantial proportion of fatal opiate overdoses involve concurrent benzodiazepine use.700 701 705 706 707 711

Reserve concomitant use of temazepam and opiates for patients in whom alternative treatment options are inadequate.700 703 (See Specific Drugs under Interactions.)

Adequate Patient Evaluation

Insomnia may be a manifestation of an underlying physical and/or psychiatric disorder; carefully evaluate patient before providing symptomatic treatment.a

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.a

Immediately evaluate any new behavioral sign or symptom.a

Adverse Psychiatric Events

Abnormal thinking and behavioral changes (e.g., aggressiveness, uncharacteristic extroversion, bizarre behavior, agitation, hallucinations, depersonalization, amnesia) may occur unpredictably in patients receiving benzodiazepines.a

Some adverse effects appear to be dose related; use the lowest effective dose.a

Complex Sleep-related Behaviors

Potential risk of complex sleep-related behaviors such as sleep-driving (i.e., driving while not fully awake after ingesting a sedative-hypnotic drug, with no memory of the event), making phone calls, or preparing and eating food while asleep.629

Abuse Potential

Psychologic and physical dependence may occur following prolonged use.a

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.a

Withdrawal Effects

Rapid dosage reduction or abrupt discontinuance may result in signs and symptoms of withdrawal (similar to barbiturates or alcohol).a c

Sensitivity Reactions

Potential risk of anaphylaxis and angioedema; may occur as early as with the first dose of drug.629

General Precautions

Suicide

Use with caution in depressed patients; potential for suicidal tendencies.a Prescribe and dispense drug in the smallest feasible quantity.a b

CNS Effects

Performance of activities requiring mental alertness and physical coordination may be impaired.a b In clinical studies, risk of residual daytime sedation and impaired psychomotor and mental performance appeared to be minimal.a

Concurrent use of other CNS depressants may potentiate CNS depression.a b (See Concomitant Use with Opiates under Cautions and also see Specific Drugs under Interactions.)

Respiratory Effects

Use with caution in patients with compromised respiratory function.a

Specific Populations

Pregnancy

Category X.a

Lactation

Benzodiazepines generally are distributed into milk; not known whether temazepam is distributed into milk.a

Caution advised if used in nursing women.a

Pediatric Use

Safety and efficacy not established in children <18 years of age.a c

Geriatric Use

Potential increased sensitivity (increased risk of oversedation, dizziness, confusion, and/or ataxia); use low initial dose and monitor closely.a (See Geriatric or Debilitated Patients under Dosage and Administration.)

Common Adverse Effects

Drowsiness, fatigue, lethargy, dizziness, hangover, anxiety, diarrhea, euphoria, weakness, confusion, vertigo.a

Interactions for Restoril

Specific Drugs

Drug

Interaction

Comments

CNS depressants (e.g., sedatives, psychotropic drugs, anticonvulsants, antihistamines, alcohol)

Additive depressant effecta b

Do not use with alcohol; consider dosage reduction if temazepam is administered concomitantly with other CNS depressantsa b

Diphenhydramine

Possible synergistic effecta b

Concomitant use in a pregnant woman at term was associated with stillbirth 8 hours after administration; causal relationship not establisheda b

Opiate agonists and partial agonists

Risk of profound sedation, respiratory depression, coma, or death700 701 703 705 706 707

Whenever possible, avoid concomitant use708 709 710 711

Opiate analgesics: Use concomitantly only if alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy; monitor closely for respiratory depression and sedation700 703

In patients receiving temazepam, initiate opiate analgesic, if required, at reduced dosage and titrate based on clinical response700

In patients receiving an opiate analgesic, initiate temazepam, if required, at lower dosage than indicated in the absence of opiate therapy and titrate based on clinical response700

Opiate antitussives: Avoid concomitant use700 704

Consider offering naloxone to patients receiving benzodiazepines and opiates concomitantly709 712

Restoril Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration,a b with peak plasma concentrations achieved in about 1.2–1.6 hours.a

Distribution

Extent

Benzodiazepines are widely distributed into body tissues and cross the blood-brain barrier.b

Benzodiazepines generally cross the placenta and are distributed into milk;b not known whether temazepam distributes into milk.a

Plasma Protein Binding

96%.a

Elimination

Metabolism

Conjugated in the liver to form inactive metabolites.a

Elimination Route

Excreted in urine as inactive metabolites.a b

Half-life

About 8 hours.a b

Stability

Storage

Oral

Capsules

Tight, light-resistant containers at 20–25°C.a

Actions

  • Effects appear to be mediated through the inhibitory neurotransmitter GABA; the sites and mechanisms of action within the CNS appear to involve a macromolecular complex (GABAA-receptor-chloride ionophore complex) that includes GABAA receptors, high-affinity benzodiazepine receptors, and chloride channels.320 358 359 360 361 362 363 364 365 366 367 368 369 370

Advice to Patients

  • Provide patient with a copy of manufacturer’s patient information.a

  • Importance of taking only as prescribed; do not increase dosage or duration of therapy unless otherwise instructed by a clinician.a

  • Risk of potentially fatal additive effects (e.g., profound sedation, respiratory depression, coma) if used concomitantly with opiates either therapeutically or illicitly.700 703 Avoid concomitant use of opiate antitussives;700 704 also avoid concomitant use of opiate analgesics unless use is supervised by clinician.700 703

  • Importance of informing clinicians of any behavioral or mental changes, memory impairment, tolerance, or dependence/withdrawal symptoms.a

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

  • 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.a

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescriptions and OTC drugs, and of concomitant illnesses, particularly depression.a

  • Importance of not consuming alcoholic beverages.a

  • Risk of rebound insomnia for 1 or 2 nights after discontinuance.a

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.b

  • Importance of informing patients of other important precautionary information. (See Cautions.)a

Preparations

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Temazepam

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

7.5 mg*

Restoril ( C-IV)

Mallinckrodt

Temazepam Capsules (C-IV)

15 mg*

Restoril ( C-IV)

Mallinckrodt

Temazepam Capsules (C-IV)

22.5 mg*

Restoril ( C-IV)

Mallinckrodt

Temazepam Capsules (C-IV)

30 mg*

Restoril ( C-IV)

Mallinckrodt

Temazepam Capsules (C-IV)

AHFS DI Essentials. © Copyright 2018, Selected Revisions December 11, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

320. 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.

358. Bloom FE. Neurohumoral transmission and the central nervous system: amino acids. In: Gilman AG, Rall TW, Nies AS et al, eds. Goodman and Gilman’s the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press; 1990:256-8.

359. Haefely W. The GABA-benzodiazepine interaction fifteen years later. Neurochem Res. 1990; 15:169-74. http://www.ncbi.nlm.nih.gov/pubmed/2159122?dopt=AbstractPlus

360. De Feudis FV. Overview—GABAa receptors. Ann NY Acad Sci. 1990; 585:231-40. http://www.ncbi.nlm.nih.gov/pubmed/2162643?dopt=AbstractPlus

361. Mohler H, Malherbe P, Draguhn A et al. GABAa-receptors: structural requirements and sites of gene expression in mammalian brain. Neurochem Res. 1990; 15:199-207. http://www.ncbi.nlm.nih.gov/pubmed/2159125?dopt=AbstractPlus

362. Farrant M, Gibbs TT, Farb DH. Molecular and cellular mechanisms of GABA/benzodiazepine-receptor regulation: electrophysiological and biochemical studies. Neurochem Res. 1990; 15:175-91. http://www.ncbi.nlm.nih.gov/pubmed/2159123?dopt=AbstractPlus

363. Sieghart W. Benzodiazepine receptor subtypes and their possible clinical significance. Psychopharmacol Ser. 1989; 7:131-7. http://www.ncbi.nlm.nih.gov/pubmed/2574448?dopt=AbstractPlus

364. Knapp RJ, Malatynska E, Yamamura HI. From binding studies to the molecular biology of GABA receptors. Neurochem Res. 1990; 15:105-12. http://www.ncbi.nlm.nih.gov/pubmed/2159117?dopt=AbstractPlus

365. Williams M. Anxioselective anxiolytics. J Med Chem. 1983; 26:619-28. http://www.ncbi.nlm.nih.gov/pubmed/6132997?dopt=AbstractPlus

366. Rogawski MA, Porter RJ. Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol Rev. 1990; 42:223-86. http://www.ncbi.nlm.nih.gov/pubmed/2217531?dopt=AbstractPlus

367. Haefely WE. Pharmacology of the benzodiazepine receptor. Eur Arch Psychiatry Neurol Sci. 1989; 238:294-301. http://www.ncbi.nlm.nih.gov/pubmed/2569974?dopt=AbstractPlus

368. Haefely WE. Benzodiazepines. Int Anesthesiol Clin. 1988; 26:262-72. http://www.ncbi.nlm.nih.gov/pubmed/2461909?dopt=AbstractPlus

369. Schoch P, Richards JG, Haring P et al. Co-localization of GABA receptors and benzodiazepine receptors in the brain shown by monoclonal antibodies. Nature. 1985; 314:168-71. http://www.ncbi.nlm.nih.gov/pubmed/2983231?dopt=AbstractPlus

370. Haefely W. Endogenous ligands of the benzodiazepine receptor. Pharmacopsychiatry. 1988; 21:43-6. http://www.ncbi.nlm.nih.gov/pubmed/2834760?dopt=AbstractPlus

629. Food and Drug Administration. Sedative-hypnotic drug products. [March 14, 2007] MedWatch drug labeling changes. Rockville, MD; April 2007. From FDA website. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm150441.htm

700. US Food and Drug Administration. Drug safety communication: FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines; requires its strongest warning. Silver Spring, MD; 2016 Aug 31. From FDA website. https://www.fda.gov/drugs/drugsafety/ucm518473.htm

701. Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United States, 2010. JAMA. 2013; 309:657-9. http://www.ncbi.nlm.nih.gov/pubmed/23423407?dopt=AbstractPlus

703. Hughes A. Letter to manufacturers of benzodiazepines: safety labeling change notification. Silver Spring, MD: US Food and Drug Administration. Accessed 2017 Mar 20. https://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM518615.pdf

704. Seymour S. Letter to manufacturers of opioid antitussives: safety labeling change notification. Silver Spring, MD: US Food and Drug Administration. Accessed 2017 Mar 20. https://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM518612.pdf

705. Park TW, Saitz R, Ganoczy D et al. Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics: case-cohort study. BMJ. 2015; 350:h2698. http://www.ncbi.nlm.nih.gov/pubmed/26063215?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4462713&blobtype=pdf

706. Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths From Combined Use of Opioids and Benzodiazepines. Am J Prev Med. 2015; 49:493-501. http://www.ncbi.nlm.nih.gov/pubmed/26143953?dopt=AbstractPlus

707. Dasgupta N, Funk MJ, Proescholdbell S et al. Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose Mortality. Pain Med. 2016; 17:85-98. http://www.ncbi.nlm.nih.gov/pubmed/26333030?dopt=AbstractPlus

708. Nuckols TK, Anderson L, Popescu I et al. Opioid prescribing: a systematic review and critical appraisal of guidelines for chronic pain. Ann Intern Med. 2014; 160:38-47. http://www.ncbi.nlm.nih.gov/pubmed/24217469?dopt=AbstractPlus

709. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016. MMWR Recomm Rep. 2016; 65:1-49. http://www.ncbi.nlm.nih.gov/pubmed/26987082?dopt=AbstractPlus

710. Manchikanti L, Abdi S, Atluri S et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part 2--guidance. Pain Physician. 2012; 15(3 Suppl):S67-116.

711. New York City Department of Health and Mental Hygiene. New York City emergency department discharge opioid prescribing guidelines. From NYC Health website. 2013 Jan. http://www1.nyc.gov/assets/doh/downloads/pdf/basas/opioid-prescribing-guidelines.pdf

712. Washington State Agency Medical Directors' Group (AMDG). Interagency guideline on prescribing opioids for pain, 3rd ed. From Washington State AMDG website. 2015 Jun. http://www.agencymeddirectors.wa.gov/Files/2015AMDGOpioidGuideline.pdf

a. Mallinckrodt. Restoril (temazepam) capsules prescribing information. St. Louis, MO. 2006 May 24.

b. AHFS drug information 2003. McEvoy GK, ed. Benzodiazepine general statement. Bethesda, MD: American Society of Hospital Pharmacists; 2003:2353-60.

c. AHFS drug information 2003. McEvoy GK, ed. Temazepam. Bethesda, MD: American Society of Hospital Pharmacists; 2003:2380.

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