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Triazolam

Pronunciation

Pronunciation

(trye AY zoe lam)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Halcion: 0.25 mg [scored]

Generic: 0.125 mg, 0.25 mg

Brand Names: U.S.

  • Halcion

Pharmacologic Category

  • Benzodiazepine

Pharmacology

Binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the central nervous system, including the limbic system and 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. Benzodiazepine receptors and effects appear to be linked to the GABA-A receptors. Benzodiazepines do not bind to GABA-B receptors (Vinkers, 2012).

Distribution

Vd: 0.6 to 1.7 L/kg (Pakes, 1981)

Metabolism

Extensively hepatic; hydroxylation via CYP3A4 (initial step in metabolism) with subsequent glucuronide conjugation to 6 metabolites, including a short-acting active metabolite, alpha-hydroxytriazolam (Pakes, 1981)

Excretion

Urine (~80% as metabolites; small amounts as unchanged drug)

Onset of Action

Hypnotic: 15 to 30 minutes (Pakes, 1981)

Time to Peak

Oral: Within 2 hours

Half-Life Elimination

1.5 to 5.5 hours

Protein Binding

89% (Pakes, 1981)

Special Populations: Elderly

Cmax and AUC are increased; clearance is decreased (Greenblatt, 1991)

Use: Labeled Indications

Insomnia: Short-term (generally 7 to 10 days) treatment of insomnia

Use: Unlabeled

Oral sedation prior to outpatient dental procedures

Contraindications

Hypersensitivity to triazolam, other benzodiazepines, or any component of the formulation; concurrent therapy with cytochrome P450 3A (CYP 3A) inhibitors including itraconazole, ketoconazole, nefazodone, and several HIV protease inhibitors; pregnancy

Dosage

Insomnia (short-term use): Oral:

Adults: Usual dose: 0.25 mg at bedtime; 0.125 mg at bedtime may be sufficient in some patients, such as those with low body weight; maximum dose: 0.5 mg daily

Elderly and/or debilitated patients: Initial: 0.125 mg at bedtime; maximum dose: 0.25 mg daily

Dental preprocedure oral sedation (off-label use): Adults: 0.25 mg 1 hour before procedure; 0.125 mg used for elderly patients or patients sensitive to sedative effects (Dionne, 2006)

Dosage adjustment in renal impairment: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Dosage adjustment in hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Administration

Administer on an empty stomach; do not take with a meal or immediately after a meal. Tablet may be crushed or swallowed whole. Onset of action is rapid; patient should take immediately before bedtime.

Storage

Store at 20°C to 25°C (68°F to 77°F).

Drug Interactions

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Antihepaciviral Combination Products: May increase the serum concentration of Triazolam. Avoid combination

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Boceprevir: May increase the serum concentration of Triazolam. Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

CloZAPine: Benzodiazepines may enhance the adverse/toxic effect of CloZAPine. Management: Consider decreasing the dose of (or possibly discontinuing) benzodiazepines prior to initiating clozapine. Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Monitor therapy

Cobicistat: May increase the serum concentration of Triazolam. Avoid combination

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Dexamethasone (Systemic): May decrease the serum concentration of Triazolam. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Hydrocodone: CNS Depressants may enhance the CNS depressant effect of Hydrocodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Itraconazole: May increase the serum concentration of Triazolam. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Ketoconazole (Systemic): May increase the serum concentration of Triazolam. Avoid combination

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Macrolide Antibiotics: May increase the serum concentration of Triazolam. Management: Consider an alternative less likely to interact. Azithromycin is likely a lower-risk macrolide, and benzodiazepines less dependent on CYP3A metabolism (e.g., lorazepam, oxazepam) are similarly less likely to interact. Exceptions: Azithromycin (Systemic); Fidaxomicin; Roxithromycin; Spiramycin. Consider therapy modification

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Methadone: Benzodiazepines may enhance the CNS depressant effect of Methadone. Avoid combination

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

Metyrosine: CNS Depressants may enhance the sedative effect of Metyrosine. Monitor therapy

Mifepristone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

OLANZapine: May enhance the adverse/toxic effect of Benzodiazepines. Management: Avoid concomitant use of parenteral benzodiazepines and IM olanzapine due to risks of additive adverse events (e.g., cardiorespiratory depression). Olanzapine prescribing information provides no specific recommendations regarding oral administration. Avoid combination

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Protease Inhibitors: May increase the serum concentration of Triazolam. Avoid combination

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of Triazolam. Monitor therapy

Sodium Oxybate: Benzodiazepines may enhance the CNS depressant effect of Sodium Oxybate. Avoid combination

St Johns Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

Teduglutide: May increase the serum concentration of Benzodiazepines. Monitor therapy

Telaprevir: May increase the serum concentration of Triazolam. Avoid combination

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Adverse Reactions

>10%: Central nervous system: Drowsiness (14%)

1% to 10%:

Central nervous system: Headache (10%), dizziness (8%), ataxia (5%), lightheadedness (5%), nervousness (5%)

Gastrointestinal: Nausea (5%), vomiting (5%)

<1% (Limited to important or life-threatening): Anaphylaxis, angioedema, anterograde amnesia; complex sleep-related behavior (sleep-driving, cooking or eating food, making phone calls); confusion, cramps, depression, dermatitis, dreaming/nightmares, dysesthesia, euphoria, fatigue, hepatic failure (fulminant), memory impairment, pain, paresthesia, tachycardia, violent acts, visual disturbance, weakness, xerostomia

In addition, the following have been reported in association with triazolam and other benzodiazepines: Burning tongue/glossitis/stomatitis, chest pain, dysarthria, libido changes, menstrual irregularities; paradoxical reactions (eg, aggressiveness, agitational state, delusions, falling, hallucination, mania, sleep disturbances, syncope); pruritus, sedation, slurred speech, urinary retention

Warnings/Precautions

Concerns related to adverse effects:

• Anterograde amnesia: Benzodiazepines have been associated with anterograde amnesia, particularly benzodiazepines with short half-lives such as triazolam.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• CNS effects: Abnormal thinking and behavior changes including symptoms of decreased inhibition (eg, excessive aggressiveness and extroversion), bizarre behavior, agitation, hallucinations, and depersonalization have been reported with the use of benzodiazepine hypnotics. Some evidence suggests symptoms may be dose-related.

• Hypersensitivity reactions: Reports of hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with triazolam. Patients who develop angioedema should not be rechallenged with triazolam.

• Paradoxical reactions: Paradoxical reactions, including hyperactive or aggressive behavior, have been reported with benzodiazepines, particularly in adolescent/pediatric or psychiatric patients. Evaluate any new or unusual changes in behavior.

• Sleep-related activities: An increased risk for hazardous sleep-related activities such as sleep-driving, cooking and eating food, having sex, and making phone calls while asleep have also been noted. Concurrent use of alcohol and other CNS depressants as well as exceeding the maximum recommended dose may increase the risk of these behaviors. Patients will often not remember doing these activities. Consider discontinuation of therapy for patients who report sleep-driving episodes.

Disease-related concerns:

• Depression: Use caution in patients with depression, particularly if suicidal risk may be present. Minimize risks of overdose by prescribing the least amount of drug that is feasible in suicidal patients. Worsening of depressive symptoms has also been reported with use of benzodiazepines.

• Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use.

• Hepatic impairment: Use with caution in patients with hepatic impairment; undergoes extensive hepatic metabolism.

• Renal impairment: Use with caution in patients with renal impairment.

• Respiratory disease: Use with caution in patients with respiratory compromise, COPD or sleep apnea.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Debilitated patients: Use with caution in debilitated patients; potential for oversedation, impaired coordination, and dizziness with use.

• Elderly: In older adults, benzodiazepines increase the risk of impaired cognition, delirium, falls, fractures, and motor vehicle accidents. Due to increased sensitivity in this age group, avoid use for treatment of insomnia, agitation, or delirium. (Beers Criteria). Elderly patients also experience greater sedation and increased psychomotor impairment (Greenblatt, 1991).

• Fall risk: Use with extreme caution in patients who are at risk of falls; benzodiazepines have been associated with falls and traumatic injury.

Other warnings/precautions:

• Appropriate use: Does not have analgesic, antidepressant, or antipsychotic properties. Should be used only after evaluation of potential causes of sleep disturbance. Failure of sleep disturbance to resolve after 7 to 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 to 10 days and should not be prescribed in quantities exceeding a 1-month supply.

• Tolerance: Triazolam is a short half-life benzodiazepine. Duration of action after a single dose is determined by redistribution rather than metabolism. Tolerance develops to the hypnotic effects (Vinkers, 2012). Chronic use of this agent may increase the perioperative benzodiazepine dose needed to achieve desired effect.

• Withdrawal: Rebound insomnia or withdrawal symptoms may occur following abrupt discontinuation or large decreases in dose. Use caution when reducing dose or withdrawing therapy; decrease slowly and monitor for withdrawal symptoms. Flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy. 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.

Monitoring Parameters

Daytime alertness; respiratory rate; behavior profile

Pregnancy Risk Factor

X

Pregnancy Considerations

A case report describes placental transfer of triazolam following a maternal overdose. Teratogenic effects have been observed with some benzodiazepines; however, additional studies are needed. The incidence of premature birth and low birth weights may be increased following maternal use of benzodiazepines; hypoglycemia and respiratory problems in the neonate may occur following exposure late in pregnancy. Neonatal withdrawal symptoms may occur within days to weeks after birth and “floppy infant syndrome” (which also includes withdrawal symptoms) have been reported with some benzodiazepines (Bergman, 1992; Iqbal, 2002; Sakai, 1996; Wikner, 2007). Use of triazolam is contraindicated in pregnant women.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache or fatigue. Have patient report immediately to prescriber signs of depression (ie, suicidal ideation, anxiety, emotional instability, illogical thinking), hallucinations, memory impairment, severe dizziness, change in balance, or considerable asthenia (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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