Triazolam

Pronunciation

(trye AY zoe lam)

U.S. Brand Names

Halcion®

Generic Available

Yes

Canadian Brand Names

Apo-Triazo®; Gen-Triazolam; Halcion®

Use

Short-term treatment of insomnia

Use - Dental

Oral premedication before dental procedures

Restrictions

C-IV

Pregnancy Risk Factor

Pregnancy Implications

Other benzodiazepines are known to cross the placenta and accumulate in the fetus. Teratogenic effects have been reported. Use of triazolam is contraindicated in pregnancy.

Lactation

Excretion in breast milk unknown/not recommended

Contraindications

Hypersensitivity to triazolam or any component of the formulation (cross-sensitivity with other benzodiazepines may exist); concurrent therapy with atazanavir, ketoconazole, itraconazole, nefazodone, and ritonavir; pregnancy

Warnings/Precautions

Should be used only after evaluation of potential causes of sleep disturbance. Failure of sleep disturbance to resolve after 7-10 days may indicate psychiatric or medical illness. A worsening of insomnia or the emergence of new abnormalities of thought or behavior may represent unrecognized psychiatric or medical illness and requires immediate and careful evaluation. Prescription should be written for a maximum of 7-10 days and should not be prescribed in quantities exceeding a 1-month supply. Abrupt discontinuation after sustained use (generally >10 days) may cause withdrawal symptoms.

An increase in daytime anxiety may occur after as few as 10 days of continuous use, which may be related to withdrawal reaction in some patients. Anterograde amnesia may occur at a higher rate with triazolam than with other benzodiazepines. Use with caution in elderly or debilitated patients, patients with hepatic disease (including alcoholics), or renal impairment. Use with caution in patients with respiratory disease or impaired gag reflex. Avoid use in patients with sleep apnea.

Causes CNS depression (dose-related) resulting in sedation, dizziness, confusion, or ataxia which may impair physical and mental capabilities. Patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Use with caution in patients receiving other CNS depressants or psychoactive agents. Effects with other sedative drugs or ethanol may be potentiated. Benzodiazepines have been associated with falls and traumatic injury and should be used with extreme caution in patients who are at risk of these events (especially the elderly).

Use caution with potent CYP3A4 inhibitors, as they may significantly decreased the clearance of triazolam. Use caution in patients with depression, particularly if suicidal risk may be present. Use with caution in patients with a history of drug dependence. Benzodiazepines have been associated with dependence and acute withdrawal symptoms on discontinuation or reduction in dose. Acute withdrawal, including seizures, may be precipitated after administration of flumazenil to patients receiving long-term benzodiazepine therapy.

Paradoxical reactions, including hyperactive or aggressive behavior have been reported with benzodiazepines, particularly in adolescent/pediatric or psychiatric patients. Does not have analgesic, antidepressant, or antipsychotic properties.

Adverse Reactions

>10%: Central nervous system: Drowsiness, anteriograde amnesia

1% to 10%:

Central nervous system: Headache, dizziness, nervousness, lightheadedness, ataxia

Gastrointestinal: Nausea, vomiting

<1%: Cramps, confusion, depression, euphoria, fatigue, memory impairment, pain, tachycardia, visual disturbance

Overdosage/Toxicology

Symptoms of overdose include somnolence, confusion, coma, diminished reflexes, dyspnea, and hypotension. Treatment for benzodiazepine overdose is supportive. Flumazenil has been shown to selectively block the binding of benzodiazepines to CNS receptors, resulting in reversal of benzodiazepine-induced CNS depression but not always respiratory depression.

Drug Interactions

Substrate of CYP3A4 (major); Inhibits CYP2C8/9 (weak)

CNS depressants: Sedative effects and/or respiratory depression may be additive with CNS depressants; includes ethanol, barbiturates, narcotic analgesics, and other sedative agents; monitor for increased effect

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of triazolam. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 inhibitors: May increase the levels/effects of triazolam. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

Isoniazid: Isoniazid may increase triazolam levels.

Levodopa: Therapeutic effects may be diminished in some patients following the addition of a benzodiazepine; limited/inconsistent data

Oral contraceptives: May decrease the clearance and increase the half-life of triazolam; monitor for increased triazolam effect

Ranitidine: Ranitidine may increase triazolam levels.

Theophylline: May partially antagonize some of the effects of benzodiazepines; monitor for decreased response; may require higher doses for sedation

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression).

Food: Food may decrease the rate of absorption. Triazolam serum concentration may be increased by grapefruit juice; avoid concurrent use.

Herb/Nutraceutical: St John's wort may decrease levels. Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).

Mechanism of Action

Binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the central nervous system, including the limbic system, reticular formation. Enhancement of the inhibitory effect of GABA on neuronal excitability results by increased neuronal membrane permeability to chloride ions. This shift in chloride ions results in hyperpolarization (a less excitable state) and stabilization.

Pharmacodynamics/Kinetics

Onset of action: Hypnotic: 15-30 minutes

Duration: 6-7 hours

Distribution: Vd: 0.8-1.8 L/kg

Protein binding: 89%

Metabolism: Extensively hepatic

Half-life elimination: 1.7-5 hours

Excretion: Urine as unchanged drug and metabolites

Dosage

Oral (onset of action is rapid, patient should be in bed when taking medication):

Children <18 years: Dosage not established

Adults:

Hypnotic: 0.125-0.25 mg at bedtime (maximum dose: 0.5 mg/day)

Preprocedure sedation (dental): 0.25 mg taken the evening before oral surgery; or 0.25 mg 1 hour before procedure

Elderly: Insomnia (short-term use): 0.0625-0.125 mg at bedtime; maximum dose: 0.25 mg/day (see Geriatric Considerations)

Dosing adjustment/comments in hepatic impairment: Reduce dose or avoid use in cirrhosis

Administration

May take with food. Tablet may be crushed or swallowed whole. Onset of action is rapid, patient should be in bed when taking medication.

Monitoring Parameters

Respiratory and cardiovascular status

Patient Education

Take exactly as directed; do not increase dose or frequency. Drug may cause physical and/or psychological dependence. 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, lightheadedness, impaired coordination, dizziness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea, vomiting, or dry mouth (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); constipation (increased exercise, fluids, fruit, or fiber may help); altered sexual drive or ability (reversible); or photosensitivity (use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight). Report persistent CNS effects (eg, memory impairment, confusion, depression, increased sedation, excitation, headache, agitation, insomnia or nightmares, dizziness, fatigue, impaired coordination, changes in personality, or changes in cognition); changes in urinary pattern; muscle cramping, weakness, tremors, or rigidity; ringing in ears or visual disturbances; chest pain, palpitations, or rapid heartbeat; excessive perspiration; excessive GI symptoms (cramping, constipation, vomiting, anorexia); or worsening of condition. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not get pregnant during or for 1 month following therapy. Consult prescriber for instruction on appropriate contraceptive measures. This drug may cause severe fetal defects. Breast-feeding is not recommended.

Nursing Implications

Patients may require assistance with ambulation; lower doses in the elderly are usually effective; institute safety measures

Anesthesia and Critical Care Concerns/Other Considerations

Chronic use of this agent may increase the perioperative benzodiazepine dose needed to achieve desired effect. Abrupt discontinuation after sustained use (generally >10 days) may cause withdrawal symptoms.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Dental Comment

Triazolam (0.25 mg) 1 hour prior to dental procedure has been used as an oral pre-op sedative

Dosage Forms

Tablet: 0.125 mg, 0.25 mg [contains sodium benzoate]

References

Berthold CW, Dionne RA, and Corey SE, "Comparison of Sublingually and Orally Administered Triazolam for Premedication Before Oral Surgery," Oral Surg Oral Med Oral Pathol Oral Radiol Endod , 1997, 84(2):119-24.

Berthold CW, Schneider A, and Dionne RA, "Using Triazolam to Reduce Dental Anxiety," J Am Dent Assoc , 1993, 124(11):58-64.

Chan TH, Ho SS, and Li PK, "Noncardiogenic Pulmonary Edema Associated With Triazolam," J Toxicol Clin Toxicol , 1995, 33(2):185-7.

Gillin JC and Byerley WF, "Drug Therapy: The Diagnosis and Management of Insomnia," N Engl J Med , 1990, 322(4):239-48.

Greenblatt DJ, Harmatz JS, Shapiro L, et al, "Sensitivity to Triazolam in the Elderly," N Engl J Med , 1991, 324(24):1691-8.

Greenblatt DJ, von Moltke LL, Harmatz JS, et al, "Interaction of Triazolam and Ketoconazole," Lancet , 1995, 345(8943):191.

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(2):127-31.

Kaufman E, Hargreaves KM, and Dionne RA, "Comparison of Oral Triazolam and Nitrous Oxide With Placebo and Intravenous Diazepam for Outpatient Premedication," Oral Surg Oral Med Oral Pathol , 1993, 75(2):156-64.

Kurzrock M, "Triazolam and Dental Anxiety," J Am Dent Assoc , 1994, 125(4):358, 360.

Lieblich SE and Horswell B, "Attenuation of Anxiety in Ambulatory Oral Surgery Patients With Oral Triazolam," J Oral Maxillofac Surg , 1991, 49(8):792-7.

McKinnon NE, "Triazolam Intoxication," Can Med Assoc J , 1982, 126(8):893-4.

Meyer ML, Mourino AP, and Farrington FH, "Comparison of Triazolam to a Chloral Hydrate/Hydroxyzine Combination in the Sedation of Pediatric Dental Patients," Pediatr Dent , 1990, 12(5):283-7.

Milgrom P, Quarnstrom FC, Longley A, et al, "The Efficacy and Memory Effects of Oral Triazolam Premedication in Highly Anxious Dental Patients," Anesth Prog , 1994, 41(3):70-6.

Mokhlesi B, Leikin JB, Murray P, et al, "Adult Toxicology in Critical Care: Part II: Specific Poisonings," Chest , 2003, 123(3):897-922

Neutel CI, Downey W, and Senft D, "Medical Events After a Prescription for a Benzodiazepine," Pharmacoepidemiology and Drug Safety , 1995, 4:63-73.

Olson KR, Yin L, Osterloh J, et al, "Coma Caused by Trivial Triazolam Overdose," Am J Emerg Med , 1985, 3(3):210-1.

Sullivan RJ Jr, "Respiratory Depression Requiring Ventilatory Support Following 0.5 mg of Triazolam," J Am Geriatr Soc , 1989, 37(5):450-2.

Sunter JP, Bal TS, and Cowan WK, "Three Cases of Fatal Triazolam Poisoning," Br Med J (Clin Res Ed) , 1988, 297(6650):719.

Varhe A, Olkkola KT, and Neuvonen PJ, "Oral Triazolam is Potentially Hazardous to Patients Receiving Systemic Antimycotics Ketoconazole or Itraconazole," Clin Pharmacol Ther , 1994, 56(6 Pt 1):601-7.

Votey SR, Bosse GM, Bayer MJ, et al, "Flumazenil: A New Benzodiazepine Antagonist," Ann Emerg Med , 1991, 20(2):181-8.

International Brand Names

Apo-Triazo® (CA); Balidon® (CL); Gen-Triazolam (CA); Halcion® (AT, AU, BE, BG, BR, CA, CH, CR, CZ, DE, DK, ES, FI, FR, GT, HK, HN, ID, IE, IL, IT, LU, MX, NL, NZ, PA, PT, RU, SE, SV, TH, ZA); Hypam® (NZ); Novidorm® (AR); Rilamir® (DK); Somese® (CL, CO); Somniton® (CZ); Songar® (IT); Triazolam "NM"® (DK); Triazolam NM Pharma® (SE); Trilam® (IE); Trycam® (NZ, TH)

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