Benzodiazepine

Triazolam

Approved 28 Dec 2022OralTablet

The FDA lists this product in 12 strengths and forms.

Indications

Triazolam tablets are indicated for the short-term treatment of insomnia (generally 7 to 10 days) in adults. Triazolam tablets are a benzodiazepine indicated for the short-term treatment of insomnia (generally 7 to 10 days) in adults.

Contraindications

Triazolam is contraindicated in: Patients with known hypersensitivity to triazolam, any of component of triazolam, 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 )

Warnings and precautions

Persistent or Worsening Insomnia : Since sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. 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 that should be evaluated. ( 5.4 ) "Sleep-driving" and Other Complex Behaviors : Complex behaviors such as "sleep-driving" have been reported.

The use of alcohol and other central nervous system (CNS) depressants with sedative-hypnotics appears to increase the risk, as well as doses exceeding the maximum recommended dose. ( 5.5 ) CNS Manifestations: An increase in daytime anxiety, abnormal thinking, and behavioral changes have been reported. Emergence of any new behavioral changes require careful and immediate evaluation. ( 5.6 ) Effects on Driving and Operating Heavy Machinery: Patients receiving triazolam should be cautioned against driving or operating heavy machinery, as well as avoiding concomitant use with alcohol and other CNS depressant drugs.

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 )

7.1Drugs 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 management 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 effectiveness 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 with any of these drugs. [see Warnings and Precautions ( 5.8 )].

Pregnancy and breastfeeding

8.1Pregnancy 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.

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 Syndrome [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 Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 1,003 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=1,003) % Patients Reporting Placebo (N=997) % Patients Reporting Central Nervous System Drowsiness 14

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 Table1, 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.

6.2Postmarketing 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 complications: 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

Triazolam

Indications

Contraindications

Warnings and precautions

Two medicines in one question?

5.1Risks From Concomitant Use With Opioids

5.2Abuse, Misuse and Addiction

5.3Dependence and Withdrawal Reactions

5.4Persistent or Worsening Insomnia

5.6Central Nervous System Manifestations

Interactions

7.1Drugs Having Clinically Important Interactions With Triazolam Table

Pregnancy and breastfeeding

8.1Pregnancy Pregnancy Exposure Registry

Adverse reactions

6.1Clinical Trials Experience

6.2Postmarketing Experience

Composition

Strengths and forms

Official product information

At a glance

Guidelines