VA Class:CN302

AHFS Class:

• Benzodiazepines 28:24.08

Generic Name(s):

• Triazolam

Associated Monographs

• Benzodiazepines General Statement

Triazolam is a benzodiazepine.

Triazolam shares the actions of other benzodiazepines and is used as a hypnotic agent in the short-term treatment of insomnia generally for periods not exceeding 7-10 days in duration.100,121 The failure of insomnia to remit after 7-10 days of triazolam therapy may indicate the presence of an underlying psychiatric and/or medical condition.100,121 Continued use of the drug for longer than 2-3 weeks usually is not indicated and should be undertaken only upon further evaluation of the patient.100,121 The possibility that insomnia may be a symptom of an underlying condition for which there may be a more specific treatment should be considered.

Administration

Triazolam is administered orally at bedtime.

Concomitant oral administration of triazolam with grapefruit juice should be avoided since grapefruit juice has been reported to increase bioavailability of triazolam.129 (See Drug Interactions: Grapefruit Juice in the Benzodiazepines General Statement 28:24.08.)

Dosage

Dosage of triazolam must be individualized, and the smallest effective dosage should be used (especially in geriatric and/or debilitated patients or in those with liver disease or low serum albumin). Prolonged administration of triazolam should be avoided.

Because of the risk associated with prolonged triazolam therapy and the need for periodic reevaluation of the patient's condition, prescriptions for the drug should be written only for short-term (7-10 days) use and the quantity dispensed to the patient should not exceed a 1-month supply.100,121 In addition, to ensure safe and effective use of triazolam, patients should be given a copy of the patient information provided by the manufacturers and the contents of this information should be discussed with them.100,121 To aid in complying with these recommendations, triazolam is commercially available in unit-of-use packaging that contains a supply of only 10 tablets of the drug and the patient information.100,121

The usual adult dose of triazolam is 0.25 mg; a dose of 0.125 mg may be adequate for some patients (e.g., those with low body weight).100 A dose of 0.5 mg should be reserved for exceptional cases in which the patient does not respond adequately to a lower dose, since the risk of some adverse effects increases with increasing dose; a 0.5-mg dose should not be exceeded.100,121

In geriatric and/or debilitated patients, an initial triazolam dose of 0.125 mg should be used.100 While the usual dose in patients generally ranges from 0.125-0.25 mg, a dose of 0.25 mg should be reserved for exceptional cases in which the patient does not respond adequately to a lower dose, since geriatric patients are particularly susceptible to dose-related adverse effects of the drug.100,121 The pharmacokinetics (peak plasma concentration, area under the plasma concentration-time curve, clearance) and dose-related effects (sedation, psychomotor performance) of single doses of triazolam suggest that usual dosages in otherwise healthy geriatric patients should be approximately half those in younger adults.102,103,122,123,124,125,126,127,128 (See Pharmacokinetics: Elimination, in the Benzodiazepines General Statement 28:24.08.) In addition, epidemiologic evidence suggests that the risk of adverse (e.g., behavioral) effects is increased when therapy is initiated in geriatric patients at doses exceeding 0.125 mg.106

In patients who have received prolonged triazolam therapy, abrupt discontinuance of the drug should be avoided since manifestations of withdrawal can be precipitated.100 While the risk and severity of withdrawal manifestations are increased as the duration and dose increase, such manifestations can occur at usual doses given for relatively short periods (e.g., 1-2 weeks) and occasionally between nightly doses.100 Therefore, if the drug is to be discontinued in any patient receiving more than the lowest dose for longer than a few weeks, it is recommended that dosage be tapered gradually.100 Gradual tapering is particularly important in patients with a seizure history.100 There also is evidence that abrupt discontinuance of triazolam after relatively short periods of therapy (e.g., 1 week) can result in rebound insomnia, which generally persists for one or two nights.100,101,120 Therefore, some clinicians suggest that gradual dosage reduction (e.g., over several nights) also be considered when discontinuing short-term triazolam therapy, since the development of rebound insomnia can perpetuate continued use of hypnotics in patients with insomnia.101,120

Precautions

A boxed warning has been included in the prescribing information for all benzodiazepines describing the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions associated with all drugs in this class.900 Abuse and misuse can result in overdose or death, especially when benzodiazepines are combined with other medicines, such as opioid pain relievers, alcohol, or illicit drugs.900 Frequent follow-up with patients receiving benzodiazepines is important.900 Reassess patients regularly to manage their medical conditions and any withdrawal symptoms.900 Clinicians should assess a patient's risk of abuse, misuse, and addiction. 900 Standardized screening tools are available ([Web]).900 To reduce the risk of acute withdrawal reactions, use a gradual dose taper when reducing the dosage or discontinuing benzodiazepines.900 Take precautions when benzodiazepines are used in combination with opioid medications.900

Triazolam shares the toxic potentials of the benzodiazepines, and the usual precautions of benzodiazepine administration should be observed. (See Cautions in the Benzodiazepines General Statement 28:24.08.) Some evidence suggests that anterograde amnesia and possibly other behavioral effects (e.g., confusion, bizarre or abnormal behavior, agitation, hallucinations) may occur more frequently with triazolam than with other hypnotic benzodiazepines, particularly at triazolam doses exceeding 0.25 mg and/or in geriatric patients. (See Cautions: CNS Effects, in the Benzodiazepines General Statement 28:24.08.) The manufacturers recommend that patients be advised not to use triazolam in circumstances where a full night's sleep and clearance of the drug from the body are not possible before they would again need to be active and functional (e.g., an overnight flight of less than 7-8 hours) since amnesic episodes have been reported in such circumstances.

The initial step in triazolam metabolism is hydroxylation catalyzed by the hepatic cytochrome P-450 (CYP) 3A isoenzyme.100 Concomitant use of triazolam with drugs (e.g., some azole antifungal agents, HIV protease inhibitors, nefazodone, some macrolide antibiotics, some calcium-channel blocking agents) or foods (e.g., grapefruit juice) that inhibit CYP3A isoenzymes may result in decreased triazolam metabolism and clearance and increased plasma triazolam concentrations.100,130,132,133,134,135,136,137,138 The manufacturer states that caution should be exercised and triazolam dosage adjustment considered during concomitant use of the drug with some inhibitors of CYP3A isoenzymes (e.g., some macrolide antibiotics, cimetidine).100 Other CYP3A inhibitors (e.g., isoniazid, grapefruit juice, fluvoxamine, sertraline, paroxetine, diltiazem, verapamil, amiodarone) may cause clinically important decreases in triazolam metabolism and clearance and should be used with caution in patients receiving the drug.100 Because itraconazole, ketoconazole, and nefazodone are very potent CYP3A isoenzyme inhibitors that can markedly decrease the metabolism and clearance of triazolam, the manufacturer states that concomitant use of these drugs with triazolam is contraindicated.100 In addition, concomitant use of triazolam with other azole antifungal agents that are potent inhibitors of CYP3A isoenzymes should be avoided.100 Concomitant use with some other drugs (oral contraceptives, ergotamine, cyclosporine, nicardipine, nifedipine) may result in decreases in triazolam metabolism and clearance; caution is advised if triazolam is administered with one of these agents.100 In addition, concomitant use of triazolam with HIV protease inhibitors or with the nonnucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine and efavirenz is contraindicated because these antiretroviral agents may interfere with metabolism of triazolam and increase the potential for prolonged sedation.130,132,133,134,135,136,137,138,139,140,141 For further information about potential interactions between benzodiazepines and drugs and foods affecting hepatic microsomal enzymes, see Drug Interactions in the Benzodiazepines General Statement 28:24.08.

Pediatric Precautions

Safety and efficacy of triazolam in children younger than 18 years of age have not been established.

Carcinogenicity

No evidence of carcinogenic potential was observed in mice receiving triazolam doses up to 4000 times the human dose for 24 months.

Lactation

It is not known whether triazolam is distributed into milk in humans; however, the drug and its metabolites are distributed into milk in rats. It is recommended that triazolam not be administered to nursing women.

Chemistry and Stability

Chemistry

Triazolam is a benzodiazepine. Triazolam occurs as a white, crystalline powder. The drug is poorly soluble in water and soluble in alcohol.

Stability

Triazolam tablets should be stored in tight, light-resistant containers at a controlled room temperature of 20-25°C.100

Additional Information

For further information on chemistry, pharmacology, pharmacokinetics, uses, cautions, chronic toxicity, acute toxicity, drug interactions, laboratory test interferences, and dosage and administration of triazolam, see the Benzodiazepines General Statement 28:24.08.

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

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