Triazolam

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections: Risks from Concomitant Use with Opioids [see Warnings and Precautions ( 5.1 )] Abuse, Misuse, and Addiction [see Warnings and Precautions ( 5.2 )] Dependence and Withdrawal Reactions [see Warnings and Precautions ( 5.3 )] Persistent or Worsening Insomnia [see Warnings and Precautions ( 5.4 )] “Sleep-driving” and Other Complex Behaviors [see Warnings and Precautions ( 5.5 )] Central Nervous System Manifestations [see Warnings and Precautions ( 5.6 )] Effects on Driving and Operating Heavy Machinery [see Warnings and Precautions ( 5.7 )] Patients with Depression [see Warnings and Precautions ( 5.9 )] Neonatal Sedation and Withdrawal Syndrom e [see Warnings and Precautions ( 5.10 )] Compromised Respiratory Function [see Warnings and Precautions ( 5.11 )] Most common adverse reactions (incidence ≥4% and twice placebo) are drowsiness, dizziness, light-headedness, and coordination disorder/ataxia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ingenus Pharmaceuticals, LLC at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The incidences cited below are estimates of clinical reactions among 1003 subjects who participated in the short term (duration of 1 to 42 days) placebo-controlled clinical trials of triazolam. Adverse reactions leading to discontinuation in two multi-dose placebo controlled clinical trials include coordination disorders, drowsiness, grogginess, somnolence, depression, restlessness, dizziness, lightheadedness, headache, nausea, visual disturbance, nervousness, abdominal distress, bladder trouble, aching limbs, backache, and blepharitis. Table 1: Common Adverse Drug Reactions in 1% or More of Triazolam-Treated Subjects (and Greater than Placebo) Reported in Placebo-Controlled Clinical Trials Event Triazolam (N=1003) % Patients Reporting Placebo (N=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 common reactions enumerated above in Table 1, the following adverse reactions have been reported at an incidence of 0.9% to 0.5%: euphoria, tachycardia, tiredness, confusional states/memory impairment, cramps/pain, depression, and visual disturbances. Adverse reactions reported at an incidence less than 0.5% include: constipation, taste alterations, diarrhea, dry mouth, dermatitis/allergy, dreaming/nightmares, insomnia, paresthesia, tinnitus, dysesthesia, weakness, congestion, and death from hepatic failure in a patient also receiving diuretic drugs. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of triazolam. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. General disorders and administration site conditions : Paradoxical drug reaction, chest pain and fatigue Gastrointestinal disorders : Tongue discomfort, glossitis, stomatitis Hepatobiliary disorders : Jaundice Injury, poisoning and procedural complication s : Fall Metabolism and nutrition disorders : Anorexia Nervous system disorders : Anterograde amnesia, altered state of consciousness, dystonia, sedation, syncope, dysarthria and muscle spasticity Psychiatric disorders : Confusional state (disorientation, derealisation, depersonalization), mania, agitation, restlessness, irritability, sleep disorder and libido disorder, hallucination, delusion, aggression, somnambulism, and abnormal behavior Renal and urinary disorders : Urinary retention and urinary incontinence Reproductive system and breast disorders : Menstruation irregular Skin and subcutaneous tissue disorders : Pruritis

4 CONTRAINDICATIONS Triazolam is contraindicated in: Patients with known hypersensitivity to triazolam, any of component of triazolam tablets, or other benzodiazepines. Reactions consistent with angioedema (involving the tongue, glottis, or larynx), dyspnea, and throat closing have been reported and may be fatal. Concomitant administration of strong cytochrome P450 (CYP 3A) enzyme inhibitors (e.g., ketoconazole, itraconazole, nefazodone, lopinavir, ritonavir) [ see Warnings and Precautions ( 5.8 ), Drug Interactions ( 7.1 ) ] . Known hypersensitivity to triazolam or other benzodiazepines ( 4 ) Concomitant use with medications that significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP 3A) including ketoconazole, itraconazole, nefazodone, and several human immunodeficiency virus (HIV) protease inhibitors ( 4 , 5.8 , 17 )

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: structure 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.

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 )] .

1 INDICATIONS AND USAGE Triazolam is indicated for the short-term treatment of insomnia (generally 7 to 10 days) in adults. Triazolam is a benzodiazepine indicated for the short-term treatment of insomnia (generally 7 to 10 days) in adults.

9.2 Abuse Triazolam is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see Warnings and Precautions ( 5.2 )] . The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo. The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).

9.1 Controlled Substance Triazolam Tablets, USP contains triazolam, a Schedule IV controlled substance.

9.3 Dependence Physical Dependence Triazolam may produce physical dependence from continued therapy. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions ( 5.3 )] . To reduce the risk of withdrawal reactions, use a gradual taper to discontinue triazolam or reduce the dosage [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.3 )] . Acute Withdrawal Signs and Symptoms Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality. Protracted Withdrawal Syndrome Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used. Tolerance Tolerance to triazolam may develop from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of triazolam may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Triazolam Tablets, USP contains triazolam, a Schedule IV controlled substance. 9.2 Abuse Triazolam is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see Warnings and Precautions ( 5.2 )] . The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo. The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol). 9.3 Dependence Physical Dependence Triazolam may produce physical dependence from continued therapy. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions ( 5.3 )] . To reduce the risk of withdrawal reactions, use a gradual taper to discontinue triazolam or reduce the dosage [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.3 )] . Acute Withdrawal Signs and Symptoms Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality. Protracted Withdrawal Syndrome Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used. Tolerance Tolerance to triazolam may develop from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of triazolam may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

10 OVERDOSAGE Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal [see Warnings and Precautions ( 5.2 )] . Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage. In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information. Consider contacting the Poison Help line at (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

7 DRUG INTERACTIONS Use with Opioids: Increase the risk of respiratory depression ( 7.1 ) Use with Other CNS Depressants: Produces additive CNS depressant effects ( 7.1 ) Use with CYP 3A4 Inhibitors: Increased risk of adverse reactions ( 4 , 5.8 , 7.1 ) 7.1 Drugs Having Clinically Important Interactions With Triazolam Table 2 includes clinically significant drug interactions with triazolam [see Clinical Pharmacology ( 12.3 )] . Table 2: Clinically Important Drug Interactions with Triazolam Opioids Clinical implication 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. Prevention or managemen t Limit dosage and duration of concomitant use of triazolam and opioids, and monitor patients closely for respiratory depression and sedation [see Warnings and Precautions ( 5.1 )] . CNS Depressants Clinical implication Triazolam produces additive CNS depressant effects when co-administered with other CNS depressants. Prevention or management Limit dosage and duration of triazolam during concomitant use with CNS depressants. Strong Inhibitors of CYP 3A Clinical implication Concomitant use of triazolam with strong CYP3A inhibitors has a profound effect on the clearance of triazolam, resulting in increased concentrations of triazolam and increased risk of adverse reactions [see Clinical Pharmacology ( 12.3 )]. Prevention or management Do not administer triazolam with a strong CYP3A4 inhibitor [see Contraindications ( 4 ), Warnings and Precautions ( 5.8 )] . Moderate and Weak Inhibitors of CYP 3A Clinical implication Concomitant use of triazolam with moderate or weak inhibitors of CYP3A inhibitors may increase the concentrations of triazolam, resulting in increased risk of adverse reactions [see Clinical Pharmacology ( 12.3 )] . Prevention or management Use with caution and consider appropriate dose reduction of triazolam when coadministered with moderate and weak CYP3A inhibitors [see Warnings and Precautions ( 5.8 )] . Strong Inducers of CYP 3A Clinical implication Coadministration of triazolam with strong inducers of CYP3A4 can significantly decrease the plasma concentration of triazolam and may decrease effiectiveness of triazolam. Prevention or management Caution is recommended during coadministration of triazolam with strong inducers of CYP3A4. Interactions Based on Experience with Other Benzodiazepines or in vitro Studies with Triazolam Clinical implication Available data from clinical studies of benzodiazepines other than triazolam, from in vitro studies with triazolam, or from in vitro studies with benzodiazepines other than triazolam suggest a possible drug interaction with triazolam [see Clinical Pharmacology ( 12.3 )]. Prevention or management Caution is recommended during coadministration of triazolam tablets with any of these drugs. [see Warnings and Precautions ( 5.8 )] .

12 CLINICAL PHARMACOLOGY 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. 12.3 Pharmacokinetics Absorption Peak plasma levels of triazolam are reached within 2 hours following oral administration. Following recommended doses of triazolam tablets, triazolam peak plasma levels in the range of 1 to 6 ng/mL are seen. The plasma levels achieved are proportional to the dose given. In normal subjects treated for 7 days with four times the recommended dosage, there was no evidence of altered systemic bioavailability, rate of elimination, or accumulation. Distribution Extremely high concentrations of triazolam do not displace bilirubin bound to human serum albumin in vitro. Elimination Triazolam has a mean plasma elimination half-life in the range of 1.5 to 5.5 hours. Metabolism The initial step in triazolam metabolism is cytochrome P450 3A (CYP 3A)-mediated hydroxylation to form 1-hydroxytriazolam and 4-hydroxytriazolam, which are subsequently conjugated to form glucuronides. Excretion Triazolam and its metabolites, principally as conjugated glucuronides which are presumably inactive, are excreted primarily in the urine. Only small amounts of unmetabolized triazolam appear in the urine. The two primary metabolites accounted for 79.9% of urinary excretion. Urinary excretion appeared to be biphasic in its time course. Specific Populations Geriatric Patients In a study of elderly (62 to 83 years old) versus younger subjects (21 to 41 years old) who received triazolam at the same dose levels (0.125 mg and 0.25 mg), the elderly experienced both greater sedation and impairment of psychomotor performance. These effects resulted largely from higher plasma concentrations of triazolam in the elderly. Drug Interaction Studies The effect of other drugs on 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%. Cimetidine Coadministration of cimetidine increased the maximum plasma concentration of triazolam by 51%, decreased clearance by 55%, and increased half-life by 68%. 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%. 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. 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. The effect of triazolam on other drugs: Warfarin Triazolam tablets 0.5 mg, in two separate studies, did not affect the prothrombin times or plasma warfarin levels in male volunteers administered sodium warfarin orally.

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.

12.3 Pharmacokinetics Absorption Peak plasma levels of triazolam are reached within 2 hours following oral administration. Following recommended doses of triazolam tablets, triazolam peak plasma levels in the range of 1 to 6 ng/mL are seen. The plasma levels achieved are proportional to the dose given. In normal subjects treated for 7 days with four times the recommended dosage, there was no evidence of altered systemic bioavailability, rate of elimination, or accumulation. Distribution Extremely high concentrations of triazolam do not displace bilirubin bound to human serum albumin in vitro. Elimination Triazolam has a mean plasma elimination half-life in the range of 1.5 to 5.5 hours. Metabolism The initial step in triazolam metabolism is cytochrome P450 3A (CYP 3A)-mediated hydroxylation to form 1-hydroxytriazolam and 4-hydroxytriazolam, which are subsequently conjugated to form glucuronides. Excretion Triazolam and its metabolites, principally as conjugated glucuronides which are presumably inactive, are excreted primarily in the urine. Only small amounts of unmetabolized triazolam appear in the urine. The two primary metabolites accounted for 79.9% of urinary excretion. Urinary excretion appeared to be biphasic in its time course. Specific Populations Geriatric Patients In a study of elderly (62 to 83 years old) versus younger subjects (21 to 41 years old) who received triazolam at the same dose levels (0.125 mg and 0.25 mg), the elderly experienced both greater sedation and impairment of psychomotor performance. These effects resulted largely from higher plasma concentrations of triazolam in the elderly. Drug Interaction Studies The effect of other drugs on 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%. Cimetidine Coadministration of cimetidine increased the maximum plasma concentration of triazolam by 51%, decreased clearance by 55%, and increased half-life by 68%. 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%. 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. 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. The effect of triazolam on other drugs: Warfarin Triazolam tablets 0.5 mg, in two separate studies, did not affect the prothrombin times or plasma warfarin levels in male volunteers administered sodium warfarin orally.

20230817

8

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 )

Triazolam Triazolam LACTOSE MONOHYDRATE MICROCRYSTALLINE CELLULOSE STARCH, CORN SODIUM STARCH GLYCOLATE TYPE A POTATO DOCUSATE SODIUM/SODIUM BENZOATE SILICON DIOXIDE MAGNESIUM STEARATE FD&C BLUE NO. 1 TRIAZOLAM TRIAZOLAM elliptical ING646

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No evidence of carcinogenic potential was observed in rats or mice administered triazolam in the diet for 24-months at doses greater than or equal to 900 times the MRHD of 0.5 mg, based on mg/m 2 body surface area. Mutagenesis Triazolam was not mutagenic in the in vitro Ames bacterial reverse mutation assay, and no DNA damage was observed in an in vitro alkaline elution assay in Chinese hamster lung fibroblast cells. Impairment of Fertility Female rats were administered triazolam in the diet for 14 days before cohabitation, during gestation, and until 21 days post parturition, and male rats for 60 days before cohabitation. No effects on mating or fertility were observed in rats up to 5 mg/kg/day which is approximately 100 times the MRHD of 0.5 mg/day, based on mg/m 2 body surface area.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No evidence of carcinogenic potential was observed in rats or mice administered triazolam in the diet for 24-months at doses greater than or equal to 900 times the MRHD of 0.5 mg, based on mg/m 2 body surface area. Mutagenesis Triazolam was not mutagenic in the in vitro Ames bacterial reverse mutation assay, and no DNA damage was observed in an in vitro alkaline elution assay in Chinese hamster lung fibroblast cells. Impairment of Fertility Female rats were administered triazolam in the diet for 14 days before cohabitation, during gestation, and until 21 days post parturition, and male rats for 60 days before cohabitation. No effects on mating or fertility were observed in rats up to 5 mg/kg/day which is approximately 100 times the MRHD of 0.5 mg/day, based on mg/m 2 body surface area.

ANDA214219

Triazolam

Triazolam

72789-349

HUMAN PRESCRIPTION DRUG

ORAL

0.25 mg 100 Tablets CIV Triazolam Tablets, USP 0.25 mg PHARMACIST: Dispense the Medication Guide to each patient. Rx only 72789349 Label

Warnings and Precautions ( 5.10 ) 1/2023

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Risks from Concomitant Use with Opioids Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when triazolam is used with opioids and not to use such drugs concomitantly unless supervised by a healthcare provider. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined [ see Warnings and Precautions ( 5.1 ), Drug Interactions ( 7.1 ) ] . Abuse, Misuse, and Addiction Inform patients that the use of triazolam, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances. Inform patients about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug [see Warnings and Precautions ( 5.2 ), Drug Abuse and Dependence ( 9.2 )] . Withdrawal Reactions Inform patients that the continued use of triazolam may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of triazolam may precipitate acute withdrawal reactions, which can be life-threatening. Inform patients that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months. Instruct patients that discontinuation or dosage reduction of triazolam may require a slow taper [see Warnings and Precautions ( 5.3 ), Drug Abuse and Dependence ( 9.3 )] . “Sleep-driving” and Other Complex Behaviors There have been reports of people getting out of bed after taking a sedative-hypnotic and driving their cars while not fully awake, often with no memory of the event. Advise patients to report similar experiences to their healthcare provider immediately, since “sleep-driving” can be dangerous. This behavior is more likely to occur when sedative-hypnotics are taken with alcohol or other CNS depressants [ see Warnings and Precautions ( 5.5 ) ] . Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative hypnotic. As with sleep-driving, patients usually do not remember these events. Advise patients that increased drowsiness and decreased consciousness may increase the risk of falls in some patients. Effects on Driving and Operating Heavy Machinery Caution patients against driving a motor vehicle or operating heavy machinery until the effects of taking triazolam are determined due to its CNS depressant effects. Also advise patients to avoid the use of alcohol or other CNS depressants while taking triazolam [ see Warnings and Precautions ( 5.7 ) ] . Patients with Depression Advise patients, their families and caregivers to look out for any signs of suicidality or worsening depression, and to inform the patient’s prescriber or healthcare provider immediately [ see Warnings and Precautions ( 5.9 ) ] . Concomitant Medications Advise patients to inform their healthcare provider of all medicines they take, including prescription and nonprescription medicines, vitamins and herbal supplements [ see Drug Interactions ( 7.1 ) ] . Grapefruit Juice Advise patients to avoid eating grapefruit or drinking grapefruit juice while taking triazolam [ see Drug Interactions ( 7.1 ) ] . Pregnancy Advise pregnant females that use of triazolam late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns [see Warnings and Precautions ( 5.10 ), Use in Specific Populations ( 8.1 )] . Instruct patients to inform their healthcare provider if they are pregnant. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to triazolam during pregnancy [see Use in Specific Populations ( 8.1 )] . Lactation Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients using triazolam to monitor infants for excessive sedation, poor feeding and poor weight gain, and to seek medical attention if they notice these signs. A lactating woman may consider pumping and discarding breastmilk during treatment and for 28 hours after triazolam administration to minimize drug exposure to a breastfed infant [ see Use in Specific Populations ( 8.2 ) ] . Manufactured for: Ingenus Pharmaceuticals, LLC Orlando, FL 32811 554405 Rev. 01/2023 Dispense with Medication Guide available at: www.ingenus.com/medguide/triazolam-tablets.pdf ingenus

Dispense with Medication Guide available at: www.ingenus.com/medguide/triazolam-tablets.pdf MEDICATION GUIDE Triazolam Tablets USP CIV (trye az’ oh lam) This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised 01/2023 What is the most important information I should know about Triazolam Tablets? Triazolam tablets are a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death. Get emergency help right away if any of the following happens: shallow or slowed breathing breathing stops (which may lead to the heart stopping) excessive sleepiness (sedation) Do not drive or operate heavy machinery until you know how taking triazolam tablets with opioids affects you. Risk of abuse, misuse, and addiction. There is a risk of abuse, misuse, and addiction with benzodiazepines, including triazolam which can lead to overdose and serious side effects including coma and death. Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including triazolam. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. You can develop an addiction even if you take triazolam tablets as prescribed by your healthcare provider. Take triazolam tablets exactly as your healthcare provider prescribed. Do not share your triazolam tablets with other people. Keep triazolam tablets in a safe place and away from children. Physical dependence and withdrawal reactions. Triazolam can cause physical dependence and withdrawal reactions. Do not suddenly stop taking triazolam tablets. Stopping triazolam tablets suddenly can cause serious and life-threatening side effects, including unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms. Some people who suddenly stop benzodiazepines, have symptoms that can last for several weeks to more than 12 months , including, anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears. Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction. Do not take more triazolam tablets than prescribed or take triazolam tablets for longer than prescribed. After taking triazolam tablets, you may get up out of bed while not being fully awake and do an activity that you do not know you are doing. The next morning, you may not remember that you did anything during the night. You have a higher chance for doing these activities if you drink alcohol or take other medicines that make you sleepy with triazolam tablets. Reported activities include: driving a car ("sleep-driving") making and eating food talking on the phone having sex sleep-walking Call your healthcare provider right away if you find out that you have done any of the above activities after taking triazolam tablets. What are Triazolam tablets? Triazolam is a prescription medicine used in adults for the short-term treatment of a sleep problem called insomnia. Triazolam tablets is usually taken for 7 to 10 days. Triazolam tablets are a federal controlled substance (CIV) because it contains trizolam that can be abused or lead to dependence. Keep triazolam tablets in a safe place to prevent misuse and abuse. Selling or giving away triazolam tablets may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs. It is not known if triazolam is safe and effective in children. It is not known if triazolam is safe and effective for use longer than 2 to 3 weeks. Do not take triazolam tablets if you : are allergic to triazolam, other benzodiazepines, or any of the ingredients in triazolam tablets. Severe allergic reactions including swelling of the tongue or throat, trouble breathing and throat closing have happened and may lead to death. Get medical help right away if you have an allergic reaction to triazolam tablets. See the end of this Medication Guide for a complete list of ingredients in triazolam tablets. take antifungal medicines including ketoconazole and itraconazole take a medicine to treat depression called nefazodone take medicines to treat human immunodeficiency virus (HIV)-1 infection called protease inhibitors. Before you take triazolam tablets, tell your healthcare provider about all of your medical conditions, including if you: have a history of depression, mood problems, mental illness, suicidal thoughts or behavior have a history of drug or alcohol abuse or addiction have lung problems, breathing problems, or sleep apnea are pregnant or plan to become pregnant. Taking triazolam late in pregnancy may cause your baby to have symptoms of sedation (breathing problems, sluggishness, low muscle tone), and/or withdrawal symptoms (jitteriness, irritability, restlessness, shaking, excessive crying, feeding problems). Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with triazolam. There is a pregnancy registry for women who take triazolam during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. If you become pregnant during treatment with triazolam, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychiatric Medications. You can register by calling 1-866-961-2388 or visiting https://womensmentalhealth.org/pregnancyregistry/. are breastfeeding or plan to breastfeed. It is not known if triazolam can pass through your breast milk. Breastfeeding during treatment with triazolam may cause your baby to have sleepiness, feeding problems, and decreased weight gain. Talk to your healthcare provider about the best way to feed your baby if you take triazolam tablets. Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking triazolam tablets with certain other medicines can cause side effects or affect how well triazolam or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider. How should I take triazolam tablets? Take triazolam tablets exactly as your healthcare provider tells you to take it. Take triazolam tablets right before you get into bed. Do not eat grapefruit or drink grapefruit juice during treatment with triazolam tablets. Call your healthcare provider if your insomnia worsens or is not better within 7 to 10 days of treatment with triazolam tablets. This may mean that there is another condition causing your sleep problem. If you take too much triazolam tablets, call your healthcare provider or have somebody drive you to the nearest hospital emergency room right away. What are the possible side effects of Triazolam tablets? Triazolam tablets may cause serious side effects, including: See " What is the most important information I should know about triazolam tablets? " Increased daytime anxiety. Abnormal thoughts and behavior. Symptoms include more outgoing or aggressive behavior than normal, confusion, agitation, hallucinations, worsening of depression, and suicidal thoughts or actions. Memory loss Triazolam tablets can make you sleepy or dizzy and can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how triazolam tablets affect you. Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking triazolam tablets without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, triazolam tablets may make your sleepiness or dizziness much worse. Worsening depression . Call your healthcare provider right away if you have any thoughts of suicide or dying or worsening depression. The most common side effects of Triazolam tablets include: drowsiness dizziness light-headedness difficulty with coordination Elderly people have an increased risk of dose related side effects during treatment with triazolam tablets. These are not all the possible side effects of triazolam tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store Triazolam Tablets, USP? Store triazolam tablets at room temperature between 68°F to 77°F (20°C to 25°C). Keep triazolam tablets and all medicines out of the reach of children General information about the safe and effective use of triazolam tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use triazolam tablets for a condition for which it was not prescribed. Do not give triazolam tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about triazolam tablets that is written for healthcare professionals. What are the ingredients in Triazolam Tablets, USP? Active Ingredient: 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. Manufactured for: Ingenus Pharmaceuticals, LLC Orlando, FL 32811 Rev. 01/2023 ingenus If you would like more information, call 1-877-748-1970.

8.5 Geriatric Use Elderly patients exhibit higher plasma triazolam concentrations due to reduced clearance as compared with younger subjects at the same dose. Because elderly patients are especially susceptible to dose related adverse reactions and to minimize oversedation, the smallest effective dose should be used [ see Dosage and Administration ( 2.2 ), Clinical Pharmacology ( 12.3 ) ] .

8.4 Pediatric Use Safety and effectiveness of triazolam has not been established in pediatric patients.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including triazolam, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/pregnancyregistry/. Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [ see Warnings and Precautions ( 5.10 ) and Clinical Considerations ] . Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data) . The 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, hypotonia, and sedation in neonates. Monitor neonates exposed to triazolam during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to triazolam during pregnancy for signs of withdrawal. Manage these neonates accordingly [ see Warnings and Precautions ( 5.10 ) ] . 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. 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 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 psychiatric medications, including triazolam, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/pregnancyregistry/. Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [ see Warnings and Precautions ( 5.10 ) and Clinical Considerations ] . Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data) . The 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, hypotonia, and sedation in neonates. Monitor neonates exposed to triazolam during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to triazolam during pregnancy for signs of withdrawal. Manage these neonates accordingly [ see Warnings and Precautions ( 5.10 ) ] . 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. 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 reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. There are no data on the presence of triazolam in human milk or the effects on milk production. Triazolam and its metabolites are present in the milk of lactating rats (see Data) . When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for triazolam and any potential adverse effects on the breastfed infant from triazolam or from the underlying maternal condition. Clinical Considerations Infants exposed to triazolam through breast milk should be monitored for sedation, poor feeding and poor weight gain. A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment and for 28 hours (approximately 5 elimination half-lives) after triazolam administration in order to minimize drug exposure to a breast fed infant. Data Both triazolam and triazolam metabolites were detected in milk of rats. Lactating rats were orally administered 0.3 mg/kg 14 C-triazolam; drug and metabolite levels were determined in milk collected at 6 and 24 hours after administration. 8.4 Pediatric Use Safety and effectiveness of triazolam has not been established in pediatric patients. 8.5 Geriatric Use Elderly patients exhibit higher plasma triazolam concentrations due to reduced clearance as compared with younger subjects at the same dose. Because elderly patients are especially susceptible to dose related adverse reactions and to minimize oversedation, the smallest effective dose should be used [ see Dosage and Administration ( 2.2 ), Clinical Pharmacology ( 12.3 ) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING Triazolam Tablets, USP are available in the following strength and package size: 0.25 mg tablets are supplied as a blue colored, elliptical shaped tablets with “ING646” debossed on one side and scored on other side: NDC 72789-349-30: Bottles of 30 Store at controlled room temperature 20° to 25°C (68° to 77°F) [ see USP Controlled Room Temperature ] .

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation [see Warnings and Precautions ( 5.1 ), Drug Interactions ( 7.1 )] . The use of benzodiazepines, including triazolam, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing triazolam and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction [see Warnings and Precautions ( 5.2 )] . The continued use of benzodiazepines, including triazolam, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of triazolam after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue triazolam or reduce the dosage [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.3 )] . WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS See full prescribing information for complete boxed warning. Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation ( 5.1 , 7.1 ). The use of benzodiazepines, including triazolam, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Before prescribing triazolam and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction ( 5.2 ). Abrupt discontinuation or rapid dosage reduction of triazolam after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue triazolam or reduce the dosage ( 2.3 , 5.3 ).