Generic Name: Triazolam
Class: Benzodiazepines
VA Class: CN302
CAS Number: 28911-01-5

Introduction

Benzodiazepine; sedative and hypnotic.a b c

Uses for Halcion

Insomnia

Short-term (generally 7–10 days) management of insomnia.100 121

Decreases sleep latency, increases the duration of sleep, and decreases the number of nocturnal awakenings.a

Slideshow: View Frightful (But Dead Serious) Drug Side Effects

Has been used for the prevention or short-term treatment of transient insomnia associated with sleep-wake schedule changes (e.g., rapid travel across time zones [“jet lag”], rotating shift work). May be useful for this purpose in some patients; however, consider the possibility of transient impairment of cognitive function (e.g., anterograde amnesia [“traveler’s amnesia”]). (See Amnesia under Cautions.)

Halcion Dosage and Administration

General

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

  • Avoid prolonged administration.100 Generally limit hypnotic therapy to 7–10 days.100 121

  • Write prescriptions for short-term (7–10 days) use only; the quantity dispensed to the patient should not exceed a 1-month supply.100 121 a

  • Reevaluate patient if triazolam is to be used for more than 2–3 weeks.100 121 a

  • Avoid abrupt discontinuance in patients who have received prolonged therapy (because of potential for precipitating withdrawal manifestations);100 after therapy with more than the lowest dose for longer than a few weeks, taper dosage gradually, particularly in patients with a seizure history.100

  • Consider gradual dosage reduction (e.g., over several nights) when discontinuing short-term triazolam therapy (because of potential for rebound insomnia).100 101 120

Administration

Oral Administration

Administer at bedtime.a b

Avoid concomitant oral administration with grapefruit juice.

Dosage

Individualize dosage; use the smallest effective dose.a

Some adverse effects (e.g., amnesia, dizziness, drowsiness, lightheadedness) appear to be dose related.a Inconclusive whether other effects (e.g., confusion, bizarre or abnormal behavior, agitation, hallucinations) are dose related.a

Adults

Insomnia
Oral

Usual dose is 0.25 mg.100

In some patients (e.g., those with low body weight), 0.125 mg may be adequate.100

Reserve 0.5-mg dose for exceptional cases in which the patient does not respond adequately to a lower dose.100 121

Prescribing Limits

Adults

Insomnia
Oral

Maximum 0.5 mg daily.100 121

Special Populations

Hepatic Impairment

No specific dosage recommendations.a

Renal Impairment

No specific dosage recommendations.a

Geriatric or Debilitated Patients

Usual dosages in healthy geriatric patients should be approximately half those in younger adults.102 103 122 123 124 125 126 127 128

Initially, 0.125 mg daily.100 Increased risk of adverse (e.g., behavioral) effects if therapy is initiated at doses >0.125 mg.106

Reserve 0.25-mg dose for exceptional cases in which the patient does not respond adequately to a lower dose.100 121

Cautions for Halcion

Contraindications

  • Concomitant use of itraconazole,a ketoconazole,a nefazodone,a delavirdine,139 141 efavirenz,140 141 or HIV protease inhibitors.130 131 132 133 134 135 136 137 138 141

  • Pregnancy.a

  • Known hypersensitivity to benzodiazepines or any ingredient in the formulation.a

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; avoid use of benzodiazepines as hypnotics during pregnancy.a c If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.a c

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

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.

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 evidence suggests that some such behavioral effects may occur more frequently with triazolam than with other hypnotic benzodiazepines.b

Immediately evaluate any new behavioral sign or symptom.a

Amnesia

Anterograde amnesia of varying degrees of severity reported following therapeutic doses.a Frequency may be greater with triazolam than with other benzodiazepines.a May be particularly disturbing with triazolam, especially when high doses (e.g., 0.5 mg) are used.

Anterograde amnesia (“traveler’s amnesia”) that occurred upon awakening and persisted for several hours has been reported by individuals who took triazolam to induce sleep while traveling (e.g., during airplane flights).a Concomitant use of alcohol may have been a contributory factor in some cases.a

Bizarre behavior has been associated with the period of amnesia in some patients.

Consider the risk of anterograde amnesia in patients receiving triazolam, particularly when relatively high doses are considered (e.g., for transient insomnia associated with sleep-wake schedule changes) or when the duration of drug effect is likely to exceed the intended period of sleep (e.g., when taken to induce sleep while traveling).

CNS Depression

Performance of activities requiring mental alertness and physical coordination may be impaired.a b

Concurrent use of other CNS depressants may potentiate CNS depression.a b (See Specific Drugs and Foods under Interactions.)

Dependence and Abuse Potential

Psychologic and physical dependence may occur following prolonged use.a c

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

Tolerance and Withdrawal Effects

Tolerance and adaptation to the hypnotic effect may occur after several weeks of therapy, resulting in diminished effectiveness during the end of each night’s use (early morning insomnia) and, possibly, increased daytime anxiety.

Increase in daytime anxiety reported after as few as 10 days of continuous use; daytime anxiety also may occur between nightly doses as a manifestation of interdose withdrawal.a If increased daytime anxiety occurs, discontinuance may be advisable.a

Potential for rebound insomnia for 1 or 2 nights after drug discontinuance.a

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

Interactions

Concomitant use with drugs that are potent inhibitors of CYP3A (e.g., itraconazole, ketoconazole, nefazodone, delavirdine, efavirenz, HIV protease inhibitors) is contraindicated.130 131 132 133 134 135 136 137 138 139 140 141 a Less potent inhibitors of CYP3A should be used concomitantly with caution; consider possible need for reduction of triazolam dosage.a (See Interactions.)

Sensitivity Reactions

Potential risk of anaphylaxis and angioedema; may occur even with the first dose of drug.

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

Respiratory Effects

Use with caution in patients with compromised respiratory function (e.g., chronic pulmonary insufficiency, sleep apnea).a Respiratory depression and apnea reported infrequently in these patients.a

Specific Populations

Pregnancy

Category X.a (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

If used during the last weeks of pregnancy, potential for neonatal CNS depression.a

Lactation

Distributed into milk in rats; not known whether distributed into human milk.a Use not recommended.a

Pediatric Use

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

Geriatric Use

Increased sensitivity to dose-related adverse effects.100 121 Clearance is reduced and plasma concentrations are increased by about 50%.a Use reduced dosages (see Geriatric or Debilitated Patients under Dosage and Administration); use the smallest effective dose.a

Hepatic Impairment

Use with caution.a

Renal Impairment

Use with caution.a

Common Adverse Effects

Drowsiness, headache, dizziness, nervousness, lightheadedness, coordination disorders or ataxia, nausea or vomiting.a

Interactions for Halcion

Metabolized by CYP3A.a b c

Drugs Affecting Hepatic Microsomal Enzymes

Pharmacokinetic interaction (increased plasma triazolam concentrations) with inhibitors of CYP3A.a b Concomitant use with potent CYP3A inhibitors is contraindicated.a b Use less potent CYP3A inhibitors with caution; triazolam dosage reduction may be indicated (see table).a b

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Amiodarone

Possible increased plasma concentrations of triazolama

Use with cautiona

Antidepressants, SSRIs (fluvoxamine, paroxetine, sertraline)

Possible increased plasma concentrations of triazolama

Use with cautiona

Antifungals, azoles (itraconazole, ketoconazole)

Increased plasma concentrations and decreased clearance of triazolama

Concomitant use of itraconazole or ketoconazole is contraindicated; avoid concomitant use of other azole antifungals that are potent CYP3A inhibitorsa

Calcium-channel blocking agents (diltiazem, nicardipine, nifedipine, verapamil)

Possible increased plasma concentrations of triazolama

Use with cautiona

Cimetidine

Increased plasma concentrations and decreased clearance of triazolama

Use with caution; consider triazolam dosage reductiona

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

Additive CNS depressant effectsa c

Avoid concomitant use of alcohol;a use other CNS depressants with cautionc

Cyclosporine

Possible increased plasma concentrations of triazolama

Use with cautiona

Delavirdine

Decreased metabolism and clearance of triazolam; potential for intense and prolonged sedation and respiratory depression139 141

Concomitant use contraindicated139 141

Efavirenz

Decreased metabolism and clearance of triazolam; potential for intense and prolonged sedation and respiratory depression140 141

Concomitant use contraindicated140 141

Ergotamine

Possible increased plasma concentrations of triazolama

Use with cautiona

Grapefruit juice

Increased triazolam bioavailability with concomitant oral administration129 a

Avoid concomitant administration129

HIV protease inhibitors (amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, tipranavir)

Decreased metabolism and clearance of triazolam; potential for intense and prolonged sedation and respiratory depression130 131 132 133 134 135 136 137 138 141

Concomitant use contraindicated130 131 132 133 134 135 136 137 138 141

Isoniazid

Increased plasma concentrations and decreased clearance of triazolama

Use with cautiona

Macrolide antibiotics (clarithromycin, erythromycin)

Increased plasma concentrations and decreased clearance of triazolama

Use with caution; consider triazolam dosage reductiona

Nefazodone

Increased plasma concentrations and decreased clearance of triazolama

Concomitant use contraindicateda

Oral contraceptives

Increased plasma concentrations and decreased clearance of triazolama

Use with cautiona

Ranitidine

Increased plasma concentrations of triazolama

Use with cautiona

Warfarin

Effect on warfarin pharmacokinetics or PT unlikelya

Halcion Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentration usually attained within 2 hours after oral administration.a

Special Populations

In healthy geriatric patients, peak plasma concentration and AUC are increased by about 50% compared with younger adults.

Distribution

Extent

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

Benzodiazepines generally cross the placenta and are distributed into milk; not known whether triazolam distributes into milk.c

Elimination

Metabolism

Extensively metabolized in the liver.a b c Hydroxylated by CYP3A and subsequently conjugated to form inactive metabolites.a b c

Elimination Route

Excreted principally in urine as inactive glucuronide conjugates.a c

Half-life

1.5–5.5 hours.a c

Special Populations

In healthy geriatric patients, clearance is decreased by about 50% compared with younger adults.

Stability

Storage

Oral

Tablets

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.

Advice to Patients

  • Provide patient with a copy of the 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

  • 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 prescription 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 to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy.a

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

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.

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

Triazolam

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

0.125 mg*

Halcion (C-IV)

Pfizer

0.25 mg*

Halcion (C-IV; scored)

Pfizer

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Halcion 0.25MG Tablets (PFIZER U.S.): 30/$79.56 or 60/$144.94

Triazolam 0.13MG Tablets (ROXANE): 30/$18.99 or 90/$42.99

Triazolam 0.25MG Tablets (GREENSTONE): 30/$18.99 or 90/$48.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

100. Pharmacia & Upjohn. Halcion (triazolam) tablets prescribing information. Kalamazoo, MI; 1999 May.

101. 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]

102. Greenblatt DJ, Harmatz JS, Shapiro L et al. Sensitivity to triazolam in the elderly. N Engl J Med. 1991; 324:1691-8. [IDIS 281764] [PubMed 2034245]

103. Gillin JC. The long and the short of sleeping pills. N Engl J Med. 1991; 324:1735-7. [IDIS 281768] [PubMed 2034252]

104. Roehrs T, Zorick F, Wittig R et al. Efficacy of a reduced triazolam dose in elderly insomniacs. Neurobiol Aging. 1985; 6:293-6. [PubMed 4088425]

105. Kanba S, Miyaoka H, Terada H et al. Triazolam accumulation in the elderly after prolonged use. Am J Psychiatry. 1991; 148:1264-5. [IDIS 287958] [PubMed 1652900]

106. Wysowski DK, Barash D. Adverse behavioral reactions attributed to triazolam in the Food and Drug Administration’s spontaneous reporting system. Arch Intern Med. 1991; 151:2003-8. [IDIS 289254] [PubMed 1929688]

107. Ayd FJ Jr. Next-day memory impairment/amnesia associated with triazolam. Int Drug Ther Newsl. 1991; 26:21-4.

108. Ayd FJ Jr. An overview of safety problems of triazolam. Int Drug Ther Newsl. 1991; 26:25-8.

109. Hellander I, Wolfe SM. Dear doctor letter regarding appropriate use of triazolam. Washington, DC: Public Citizen Health Research Group; 1990 Apr. (Pub. No. 1196.)

110. Wolfe SM, Hellander I. Dear doctor letter regarding appropriate use of Halcion. Washington, DC: Public Citizen Health Research Group; 1991 Oct. (Pub. No. 1240.)

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

112. Bixler EO, Kales A, Manfredi RL et al. Next-day memory impairment with triazolam use. Lancet. 1991; 337:827-31. [IDIS 279627] [PubMed 1672921]

113. Bixler EO, Kales A, Manfredi RL et al. Triazolam. Lancet. 1991; 337:1612. [IDIS 282592] [PubMed 1675742]

114. Anon. Upjohn to meet with EC’s CPMP to discuss halcion safety following withdrawal in U.K.; British regulators cite inadequate safety data after review. FDC Rep. 1991 (Oct 7):11-2.

115. Food and Drug Administration. Halcion update. Talk Paper. 1991 Oct 3.

116. van der Kroef C. Triazolam. Lancet. 1991; 338:56. [PubMed 1676109]

117. Oswald I. Triazolam syndrome 10 years old. Lancet. 1989; 2:451-2. [IDIS 258083] [PubMed 2569633]

118. van der Kroef C. Reactions to triazolam. Lancet. 1979; 2:526. [IDIS 103109] [PubMed 90240]

119. Ayd FJ Jr, Barclay WR, Callan JP et al. Behavioural reactions to triazolam. Lancet. 1979; 2:1018. [IDIS 105023] [PubMed 91745]

120. 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]

121. Nightingale SL. From the Food and Drug Administration: new labeling and patient package insert for triazolam. JAMA. 1992; 267:787. [PubMed 1732641]

122. Silverman MS. Triazolam in the elderly. N Engl J Med. 1991; 325:1742. [IDIS 288973] [PubMed 1944477]

123. Kales A. Triazolam in the elderly. N Engl J Med. 1991; 325:1742-3. [IDIS 288973] [PubMed 1944477]

124. Ayd FJ. Triazolam in the elderly. N Engl J Med. 1991; 325:1743.

125. Thompson JF, Robinson CA. Triazolam in the elderly. N Engl J Med. 1991; 325:1743-4.

126. Kurt TL. Triazolam in the elderly. N Engl J Med. 1991; 325:1744.

127. Greenblatt DJ, Shader RI, Harmatz JS. Triazolam in the elderly. N Engl J Med. 1991; 325:1744.

128. Gillin JC. Triazolam in the elderly. N Engl J Med. 1991; 325:1745. [IDIS 288978] [PubMed 1944478]

129. Hukkinen SK, Varhe A, Olkkola KT et al. Plasma concentrations of triazolam are increased by concomitant ingestion of grapefruit juice. Clin Pharmacol Ther. 1995; 58:127-31. [IDIS 352452] [PubMed 7648762]

130. Roche Laboratories. Invirase (saquinavir mesylate) capsules prescribing information. Nutley, NJ; 2005 Sep.

131. GlaxoSmithKline. Agenerase (amprenavir) capsules prescribing information. Research Triangle Park, NC; 2005 May.

132. Bristol-Myers Squibb. Reyataz(atazanavir sulfate) prescribing information. Princeton, NJ; 2006 Feb

133. Merck & Company Inc. Crixivan (indinavir sulfate) capsules prescribing information. West Point, PA;2006 Apr.

134. Abbott Laboratories. Kaletra (lopinavir/ritonavir) oral tablets and solution prescribing information. North Chicago, IL; 2005 Oct.

135. Agouron Pharmaceuticals. Viracept (nelfinavir mesylate) tablets and oral powder prescribing information. La Jolla, CA; 2006 Apr

136. Abbott Laboratories. Norvir (ritonavir) soft gelatin capsules and oral solution prescribing information. North Chicago, IL; 2006 Jan.

137. Boehringer Ingelheim. Aptivus (tipranavir) capsules prescribing information. Ridgefield, CT; 2006 Jun 27.

138. GlaxoSmithKline. Lexiva (fosamprenavir calcium) tablets prescribing information. Research Triangle Park, NC; 2006 June.

139. Pfizer. Rescriptor (delavirdine mesylate) tablets prescribing information. La Jolla, CA; 2006 Feb.

140. Bristol-Myers Squibb Company. Sustiva (efavirenz) capsules and tablets prescribing information. Princeton, NJ; 2006 Mar

141. Panel on Clinical Practices for Treatment of HIV Infection of the Department of Health and Human Services (DHHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (October 10, 2006). From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website ().

a. Pharmacia & Upjohn. Halcion (triazolam) tablets prescribing information. Kalamazoo, MI; 2003 Jan.

b. AHFS drug information 2007. McEvoy GK, ed. Triazolam. Bethesda, MD: American Society of Hospital Pharmacists; 2007: 2540.

c. AHFS drug information 2007. McEvoy GK, ed. Benzodiazepines general statement. Bethesda, MD: American Society of Hospital Pharmacists; 2007: 2508-18.

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