Triazolam

Boxed Warning 2/2021 Dosage and Administration ( 2.3 ) 2/2021 Warnings and Precautions ( 5.2 , 5.3 ) 2/2021

INDICATIONS AND USAGE Triazolam is indicated for the short-term treatment of insomnia (generally 7–10 days). Use for more than 2–3 weeks requires complete reevaluation of the patient (see WARNINGS ). Prescriptions for triazolam should be written for short-term use (7–10 days) and it should not be prescribed in quantities exceeding a 1-month supply.

2 DOSAGE AND ADMINISTRATION • Adults: Recommended dosage is 0.25 mg once daily before bedtime. Maximum recommended dosage is 0.5 mg once daily ( 2.1 ) • Geriatric patients: Reduce starting dosage to 0.125 mg once daily. May increase to 0.25 mg if no response. Geriatric patients should not exceed 0.25 mg once daily ( 2.2 , 8.5 ) • Triazolam tablets should not be prescribed in quantities exceeding a 1-month supply ( 2.1 ) 2.1 Dosing Information The recommended dosage is 0.25 mg once daily before bedtime. A dosage of 0.125 mg once daily may be sufficient for some patients (e.g., patients with low body weight). A dosage of 0.5 mg should be used only for patients who do not respond adequately to a trial of a lower dose. The maximum recommended dosage is 0.5 mg once daily. Use the lowest effective dose for the patient as there are significant dose related adverse reactions. Use of triazolam tablets for more than 3 weeks requires evaluation of the patient for a primary psychiatric or medical condition [see Warnings and Precautions ( 5.4 , 5.6 )]. Prescriptions for triazolam tablets should be written for short-term use (7 to 10 days) and it should not be prescribed in quantities exceeding a 1-month supply. 2.2 Use in Geriatric Patients In geriatric patients, the recommended dosage is 0.125 mg to 0.25 mg once daily. Initiate therapy at 0.125 mg once daily. The 0.25 mg dose should be used only for patients who do not respond to a trial of the lower dose. The maximum recommended dosage is 0.25 mg once daily. Elderly patients have an increased risk of dose related adverse reactions [see Use in Specific Populations ( 8.5 )]. 2.3 Discontinuation or Dosage Reduction of Triazolam Tablets To reduce the risk of withdrawal reactions, use a gradual taper to discontinue triazolam or reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly [see Warnings and Precautions ( 5.3 ), Drug Abuse and Dependence ( 9.3 )] .

3 DOSAGE FORMS AND STRENGTHS Triazolam Tablets, USP are available as 0.125 mg and 0.25 mg tablets. 0.125 mg tablets are supplied as a white to off-white, elliptical shaped tablets with “ING645” debossed on one side and plain on other side and 0.25 mg tablets are supplied as a blue colored, elliptical shaped tablets with “ING646” debossed on one side and scored on other side. Unscored Tablets: 0.125 mg and Scored Tablets: 0.25 mg ( 3 )

CONTRAINDICATIONS Triazolam tablets are contraindicated in patients with known hypersensitivity to this drug or other benzodiazepines. Benzodiazepines may cause fetal damage when administered during pregnancy. An increased risk of congenital malformations associated with the use of diazepam and chlordiazepoxide during the first trimester of pregnancy has been suggested in several studies. Transplacental distribution has resulted in neonatal CNS depression following the ingestion of therapeutic doses of a benzodiazepine hypnotic during the last weeks of pregnancy. Triazolam is contraindicated in pregnant women. If there is a likelihood of the patient becoming pregnant while receiving triazolam, she should be warned of the potential risk to the fetus. Patients should be instructed to discontinue the drug prior to becoming pregnant. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Triazolam is contraindicated with medications that significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP 3A) including ketoconazole, itraconazole, nefazodone, and several HIV protease inhibitors, (see WARNINGS and PRECAUTIONS–Drug Interactions ).

ADVERSE REACTIONS During placebo-controlled clinical studies in which 1,003 patients received triazolam tablets, the most troublesome side effects were extensions of the pharmacologic activity of triazolam, eg, drowsiness, dizziness, or light-headedness. The figures cited below are estimates of untoward clinical event incidence among subjects who participated in the relatively short duration (i.e., 1 to 42 days) placebo-controlled clinical trials of triazolam. The figures cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice where patient characteristics and other factors often differ from those in clinical trials. These figures cannot be compared with those obtained from other clinical studies involving related drug products and placebo, as each group of drug trials is conducted under a different set of conditions. Comparison of the cited figures, however, can provide the prescriber with some basis for estimating the relative contributions of drug and nondrug factors to the untoward event incidence rate in the population studied. Even this use must be approached cautiously, as a drug may relieve a symptom in one patient while inducing it in others. (For example, an anticholinergic, anxiolytic drug may relieve dry mouth [a sign of anxiety] in some subjects but induce it [an untoward event] in others.) Triazolam PLACEBO Number of Patients 1003 997 % Patients Reporting: Central Nervous System Drowsiness 14.0 6.4 Headache 9.7 8.4 Dizziness 7.8 3.1 Nervousness 5.2 4.5 Light-headedness 4.9 0.9 Coordination disorders/ataxia 4.6 0.8 Gastrointestinal Nausea/vomiting 4.6 3.7 In addition to the relatively common (i.e., 1% or greater) untoward events enumerated above, the following adverse events have been reported less frequently (i.e., 0.9% to0.5%): euphoria, tachycardia, tiredness, confusional states/memory impairment, cramps/pain, depression, visual disturbances. Rare (i.e., less than 0.5%) adverse reactions included constipation, taste alterations, diarrhea, dry mouth, dermatitis/allergy, dreaming/nightmares, insomnia, paresthesia, tinnitus, dysesthesia, weakness, congestion, death from hepatic failure in a patient also receiving diuretic drugs. In addition to these untoward events for which estimates of incidence are available, the following adverse events have been reported in association with the use of triazolam and other benzodiazepines: amnestic symptoms (anterograde amnesia with appropriate or inappropriate behavior), confusional states (disorientation, derealization, depersonalization, and/or clouding of consciousness), dystonia, anorexia, fatigue, sedation, slurred speech, jaundice, pruritus, dysarthria, changes in libido, menstrual irregularities, incontinence, and urinary retention. Other factors may contribute to some of these reactions, eg, concomitant intake of alcohol or other drugs, sleep deprivation, an abnormal premorbid state, etc. Other events reported include: paradoxical reactions such as stimulation, mania, an agitational state (restlessness, irritability, and excitation), increased muscle spasticity, sleep disturbances, hallucinations, delusions, aggressiveness, falling, somnambulism, syncope, inappropriate behavior and other adverse behavioral effects. Should these occur, use of the drug should be discontinued. The following events have also been reported: chest pain, burning tongue/glossitis/stomatitis. Laboratory analyses were performed on all patients participating in the clinical program for triazolam. The following incidences of abnormalities were observed in patients receiving triazolam and the corresponding placebo group. None of these changes were considered to be of physiological significance. Triazolam PLACEBO Number of Patients 380 361 % of Patients Reporting: Low High Low High Hematology Hematocrit Less than 1% Hemoglobin Total WBC count 1.7 2.1 1.3 Neutrophil count 1.5 1.5 3.3 1.0 Lymphocyte count 2.3 4.0 3.1 3.8 Monocyte count 3.6 4.4 1.5 E …

Drug interactions The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABA A sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation. Both pharmacodynamic and pharmacokinetic interactions have been reported with benzodiazepines. In particular, triazolam produces additive CNS depressant effects when coadministered with other psychotropic medications, anticonvulsants, antihistamines, ethanol, and other drugs which themselves produce CNS depression. Drugs that inhibit triazolam metabolism via cytochrome P450 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). Triazolam is contraindicated with ketoconzaole, itraconazole, nefazodone, and several HIV protease inhibitors. 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.

8 USE IN SPECIFIC POPULATIONS Lactation: A lactating woman may pump and discard breast milk during treatment and for 28 hours after triazolam administration ( 8.2 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to triazolam during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Other Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/othermedications/. Risk Summary Infants born to mothers using benzodiazepines during the later stages of pregnancy have been reported to experience symptoms of sedation and neonatal withdrawal (see Clinical Considerations) [ see Warnings and Precautions ( 5.1 0) ] . At this time, there is no clear evidence that triazolam exposure in early pregnancy can cause major birth defects (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression and sedation in neonates. Monitor neonates exposed to triazolam during pregnancy and labor for signs of sedation, respiratory depression, withdrawal, and feeding problems and manage accordingly [ see Warnings and Precautions ( 5.1 0) ] . Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings. At this time, there is no clear evidence that triazolam exposure in early pregnancy can cause major birth defects. Infants exposed to benzodiazepines during the late third trimester of pregnancy or during labor have been reported to exhibit sedation and neonatal withdrawal symptoms. Animal Data Oral administration of triazolam to pregnant rats and rabbits during the period of organogenesis caused skeletal developmental changes (variations and malformations) at maternally toxic doses in rats and at doses in rats and rabbits which are approximately equal to or greater than 200 times the maximum recommended human dose (MRHD) of 0.5 mg/day based on mg/m 2 body surface area. Oral administration of triazolam to male and female rats before mating, and continuing during gestation and lactation did not result in embryotoxicity at doses up to approximately 100 times the MRHD based on mg/m 2 body surface area, but did cause an increase in the number of stillbirths and postnatal pup mortalities at doses greater than or equal to approximately 40 times the MRHD based mg/m 2 body surface area. 14 C-triazolam was administered orally to pregnant mice. Drug-related material appeared uniformly distributed in the fetus with 14 C concentrations approximately the same as in the brain of the mother. 8.2 Lactation Risk Summary There are no data on the presence of triazolam in human milk or the effects on milk production. There are reports of central nervous system depression (sedation, respiratory depression), withdrawal symptoms, and feeding problems in infants who are breastfed by mothers taking benzodiazepines (see Clinical Considerations) . Triazolam and its metabolites are present in the milk o …

12.1 Mechanism of Action Triazolam is a benzodiazepine. Triazolam exerts its effect for the short-term treatment of insomnia through binding to the benzodiazepine site of the gamma-aminobutyric acid-A (GABA A ) receptors in the brain and enhances GABA-mediated synaptic inhibition.

11 DESCRIPTION Triazolam Tablets, USP contains triazolam, a triazolobenzodiazepine. Triazolam, USP is a white crystalline powder, soluble in alcohol and poorly soluble in water. It has a molecular weight of 343.21. The chemical name for triazolam is 8-chloro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo-[4,3-α] [1,4] benzodiazepine. The structural formula is represented below: Each triazolam tablet, for oral administration, contains 0.125 mg or 0.25 mg of Triazolam, USP. Inactive ingredients: 0.125 mg- lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, docusate sodium with sodium benzoate, colloidal silicon dioxide and magnesium stearate; 0.25 mg - lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, FD&C Blue No. 1, docusate sodium with sodium benzoate, colloidal silicon dioxide and magnesium stearate. structure

OVERDOSAGE Because of the potency of triazolam, some manifestations of overdosage may occur at 2 mg, four times the maximum recommended therapeutic dose (0.5 mg). Manifestations of overdosage with triazolam tablets include somnolence, confusion, impaired coordination, slurred speech, and ultimately, coma. Respiratory depression and apnea have been reported with overdosages of triazolam. Seizures have occasionally been reported after overdosages. Death has been reported in association with overdoses of triazolam by itself, as it has with other benzodiazepines. In addition, fatalities have been reported in patients who have overdosed with a combination of a single benzodiazepine, including triazolam, and alcohol; benzodiazepine and alcohol levels seen in some of these cases have been lower than those usually associated with reports of fatality with either substance alone. As in all cases of drug overdosage, respiration, pulse, and blood pressure should be monitored and supported by general measures when necessary. Immediate gastric lavage should be performed. An adequate airway should be maintained. Intravenous fluids may be administered. Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including CONTRAINDICATIONS, WARNINGS and PRECAUTIONS should be consulted prior to use. Experiments in animals have indicated that cardiopulmonary collapse can occur with massive intravenous doses of triazolam. This could be reversed with positive mechanical respiration and the intravenous infusion of norepinephrine bitartrate or metaraminol bitartrate. Hemodialysis and forced diuresis are probably of little value. As with the management of intentional overdosage with any drug, the physician should bear in mind that multiple agents may have been ingested by the patient. The oral LD 50 in mice is greater than 1,000 mg/kg and in rats is greater than 5,000 mg/kg.

16 HOW SUPPLIED/STORAGE AND HANDLING Triazolam Tablets USP, 0.125 mg are white to off-white, elliptical tablet, plain on one side and debossed with "1521" on other side of tablet and are supplied as follows: NDC 70710-1521-8 in bottles of 10 tablets with child-resistant closure NDC 70710-1521-1 in bottles of 100 tablets with child-resistant closure NDC 70710-1521-5 in bottles of 500 tablets Triazolam Tablets USP, 0.25 mg are light-grayish blue, elliptical, mottled, scored tablet, plain on one side and debossed with "12" and "89" on either side of scoreline and are supplied as follows: NDC 70710-1289-8 in bottles of 10 tablets with child-resistant closure NDC 70710-1289-1 in bottles of 100 tablets with child-resistant closure NDC 70710-1289-5 in bottles of 500 tablets Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP.