WARNINGS
Sleep disturbance may be the presenting manifestation of a physical and/or psychiatric disorder. Consequently, a decision to initiate symptomatic treatment of insomnia should only be made after the patient has been carefully evaluated.
The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness.
Worsening of insomnia or the emergence of new abnormalities of thinking or behavior may be the consequence of an unrecognized psychiatric or physical disorder. These have also been reported to occur in association with the use of triazolam.
Because some of the adverse effects of triazolam appear to be dose related (see PRECAUTIONS and DOSAGE AND ADMINISTRATION), it is important to use the smallest possible effective dose. Elderly patients are especially susceptible to dose related adverse effects.
An increase in daytime anxiety has been reported for triazolam after as few as 10 days of continuous use. In some patients this may be a manifestation of interdose withdrawal (see CLINICAL PHARMACOLOGY). If increased daytime anxiety is observed during treatment, discontinuation of treatment may be advisable.
A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of benzodiazepine hypnotics including triazolam. Some of these changes may be characterized by decreased inhibition, e.g., aggressiveness and extroversion that seem excessive, similar to that seen with alcohol and other CNS depressants (e.g., sedative/hypnotics). Other kinds of behavioral changes have also been reported, for example, bizarre behavior, agitation, hallucinations, depersonalization. In primarily depressed patients, the worsening of depression, including suicidal thinking, has been reported in association with the use of benzodiazepines.
It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.
Because of its depressant CNS effects, patients receiving triazolam should be cautioned against engaging in hazardous occupations requiring complete mental alertness such as operating machinery or driving a motor vehicle. For the same reason, patients should be cautioned about the concomitant ingestion of alcohol and other CNS depressant drugs during treatment with triazolam tablets.
As with some, but not all benzodiazepines, anterograde amnesia of varying severity and paradoxical reactions have been reported following therapeutic doses of triazolam. Data from several sources suggest that anterograde amnesia may occur at a higher rate with triazolam than with other benzodiazepine hypnotics.
Triazolam interaction with drugs that inhibit metabolism via cytochrome P450 3A:
The initial step in triazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP 3A). Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of triazolam. Consequently, triazolam should be avoided in patients receiving very potent inhibitors of CYP 3A. With drugs inhibiting CYP 3A to a lesser but still significant degree, triazolam should be used only with caution and consideration of appropriate dosage reduction. For some drugs, an interaction with triazolam has been quantified with clinical data; for other drugs, interactions are predicted from in vitro data and/or experience with similar drugs in the same pharmacologic class.
The following are examples of drugs known to inhibit the metabolism of triazolam and/or related benzodiazepines, presumably through inhibition of CYP 3A.
Potent CYP 3A inhibitors:
Potent inhibitors of CYP 3A that should not be used concomitantly with triazolam include ketoconazole, itraconazole, and nefazodone. Although data concerning the effects of azole-type antifungal agents other than ketoconazole and itraconazole on triazolam metabolism are not available, they should be considered potent CYP 3A inhibitors, and their coadministration with triazolam is not recommended (see CONTRAINDICATIONS).
Drugs demonstrated to be CYP 3A inhibitors on the basis of clinical studies involving triazolam (caution and consideration of dose reduction are recommended during coadministration with triazolam):
Macrolide Antibiotics
Coadministration of erythromycin increased the maximum plasma concentration of triazolam by 46%, decreased clearance by 53%, and increased half-life by 35%; caution and consideration of appropriate triazolam dose reduction are recommended. Similar caution should be observed during coadministration with clarithromycin and other macrolide antibiotics.
Cimetidine
Coadministration of cimetidine increased the maximum plasma concentration of triazolam by 51%, decreased clearance by 55%, and increased half-life by 68%; caution and consideration of appropriate triazolam dose reduction are recommended.
Other drugs possibly affecting triazolam metabolism:
Other drugs possibly affecting triazolam metabolism by inhibition of CYP 3A are discussed in the PRECAUTIONS section (see PRECAUTIONS: Drug interactions).
PRECAUTIONS
General
In elderly and/or debilitated patients it is recommended that treatment with triazolam tablets be initiated at 0.125 mg to decrease the possibility of development of oversedation, dizziness, or impaired coordination.
Some side effects reported in association with the use of triazolam appear to be dose related. These include drowsiness, dizziness. light-headedness, and amnesia.
The relationship between dose and what may be more serious behavioral phenomena is less certain. Specifically, some evidence, based on spontaneous marketing reports, suggests that confusion, bizarre or abnormal behavior, agitation, and hallucinations may also be dose related, but this evidence is inconclusive. In accordance with good medical practice it is recommended that therapy be initiated at the lowest effective dose (see DOSAGE AND ADMINISTRATION).
Cases of “traveler’s amnesia” have been reported by individuals who have taken triazolam to induce sleep while traveling, such as during an airplane flight. In some of these cases, insufficient time was allowed for the sleep period prior to awakening and before beginning activity. Also, the concomitant use of alcohol may have been a factor in some cases.
Caution should be exercised if triazolam is prescribed to patients with signs or symptoms of depression that could be intensified by hypnotic drugs. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional overdosage is more common in these patients, and the least amount of drug that is feasible should be available to the patient at any one time.
The usual precautions should be observed in patients with impaired renal or hepatic function, chronic pulmonary insufficiency, and sleep apnea. In patients with compromised respiratory function, respiratory depression and apnea have been reported infrequently.
Information for patients
The text of a patient package insert is printed at the end of this insert. To assure safe and effective use of triazolam, the information and instructions provided in this patient package insert should be discussed with patients.
Laboratory tests
Laboratory tests are not ordinarily required in otherwise healthy patients.
Drug interactions
Both pharmacodynamic and pharmacokinetic interactions have been reported with benzodiazepines. In particular, triazolam produces additive CNS depressant effects when co-administered with other psychotropic medications, anticonvulsants, antihistamines, ethanol, and other drugs which themselves produce CNS depression.
Drugs that inhibit triazolam metabolism via cytochrome P450 3A (CYP 3A):
The initial step in triazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP 3A). Drugs which inhibit this metabolic pathway may have a profound effect on the clearance of triazolam (see CONTRAINDICATIONS and WARNINGS for additional drugs of this type).
Drugs and other substances demonstrated to be CYP 3A inhibitors of possible clinical significance on the basis of clinical studies involving triazolam (caution is recommended during coadministration with triazolam):
Isoniazid
Coadministration of isoniazid increased the maximum plasma concentration of triazolam by 20%, decreased clearance by 42%, and increased half-life by 31%.
Oral Contraceptives
Coadministration of oral contraceptives increased maximum plasma concentration by 6%, decreased clearance by 32%, and increased half-life by 16%.
Grapefruit juice
Coadministration of grapefruit juice increased the maximum plasma concentration of triazolam by 25%, increased the area under the concentration curve by 48%, and increased half-life by 18%.
Drugs demonstrated to be CYP 3A inhibitors on the basis of clinical studies involving benzodiazepines metabolized similarly to triazolam or on the basis of in vitro studies with triazolam or other benzodiazepines (caution is recommended during coadministration with triazolam):
Available data from clinical studies of benzodiazepines other than triazolam suggest a possible drug interaction with triazolam for the following: fluvoxamine, diltiazem, and verapamil. Data from in vitro studies of triazolam suggest a possible drug interaction with triazolam for the following: sertraline and paroxetine. Data from in vitro studies of benzodiazepines other than triazolam suggest a possible drug interaction with triazolam for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine. Caution is recommended during coadministration of any of these drugs with triazolam (see WARNINGS).
Drugs that affect triazolam pharmacokinetics by other mechanisms:
Ranitidine
Coadministration of ranitidine increased the maximum plasma concentration of triazolam by 30%, increased the area under the concentration curve by 27%, and increased half-life by 3.3%. Caution is recommended during coadministration with triazolam.
Carcinogenesis, mutagenesis, impairment of fertility:
No evidence of carcinogenic potential was observed in mice during a 24-month study with triazolam in doses up to 4,000 times the human dose.
Pregnancy
- Teratogenic effects: Pregnancy category X (see CONTRAINDICATIONS).
- Non-teratogenic effects: It is to be considered that the child born of a mother who is on benzodiazepines may be at some risk for withdrawal symptoms from the drug, during the postnatal period. Also, neonatal flaccidity has been reported in an infant born of a mother who had been receiving benzodiazepines.
Nursing mothers
Human studies have not been performed; however, studies in rats have indicated that triazolam and its metabolites are secreted in milk. Therefore, administration of triazolam to nursing mothers is not recommended.
Pediatric use
Safety and effectiveness of triazolam in pediatric patients below the age of 18 have not been established.
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