triazolam (Rx)

>10%

Drowsiness (14%)

1-10%

Headache (5-10%)

Dizziness (5-10%)

Nervousness (5-10%)

Ataxia (4-5%)

Lightheadedness (4-5%)

N/V (4-5%)

<1%

Anterogade amnesia

Paradoxical reactions

Travelers amnesia-especially if combined with EtOH

Confusion

Cramps

Fatigue

Memory impairment

Depression

Visual disturbance

Xerostomia

Anterograde amnesia

Dreaming/nightmares

Confusion

Contraindications

Documented hypersensitivity

Acute alcohol intoxication

Myasthenia gravis (allowable in limited circumstances)

Narrow angle glaucoma (questionable)

Severe respiratory depression

Depressed neuroses, psychotic reactions

IV use in shock, coma, depressed respiration, patients who recently received other respiratory depressants

Medications that significantly impair oxidative metabolism mediated by cytochrome P450 3A (CYP 3A) including ketoconazole, itraconazole, nefazodone, and several HIV protease inhibitors

Caution

Use caution in COPD, sleep apnea, renal/hepatic disease, open-angle glaucoma (questionable), impaired gag reflex, depression, suicide ideation

Benzodiazepines may worsen depression; take appropriate precautions (e.g., limiting total prescription size and increased monitoring for suicidal ideation) in patients with depression

Anterograde amnesia may occur

Hypersensitivity reactions reported

Sleep related activities (sleep driving, sleep-cooking, sleep-eating etc) may occur

Hyperactive aggressive behavior may occur

May impair ability to perform hazardous tasks

Failure of insomnia to remit after 7 - 10 days of treatment may indicate presence of primary psychiatric and/or medical illness that should be evaluated

Increase in daytime anxiety may occur; consider therapy discontinuation if this occurs

Use caution and consider appropriate dose reduction when used concomitantly with weak or moderate CYP450 3A inhibitors

Therapy can cause drowsiness and a decreased level of consciousness; patients, particularly the elderly, are at higher risk of falls

Use of Halcion during later stages of pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in neonates; observe newborns for signs of sedation and neonatal withdrawal syndrome and manage accordingly

Benzodiazepines expose users to risks of abuse, misuse, and addiction, which can lead to overdose or death; abuse and misuse of benzodiazepines often (but not always) involve 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

Use of drug, particularly in patients at elevated risk of abuse, necessitates counseling about risks and proper use of drug along with monitoring for signs and symptoms of abuse, misuse, and addiction; do not exceed recommended dosing frequency

Avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (eg, opioid analgesics, stimulants); advise patients on proper disposal of unused drug; if a substance use disorder is suspected, evaluate patient and institute (or refer them for) early treatment, as appropriate

For patients treated more frequently than recommended, use a gradual taper to discontinue therapy (a patient-specific plan should be used to taper the dose), to reduce risk of withdrawal reactions

Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use

In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months

Withdrawal effects

• Withdrawal phenomena results in increased wakefulness during last third of the night, and appearance of increased signs of daytime anxiety or nervousness
• Withdrawal effects can occur after discontinuing these drugs following use for only a week or two, but may be more common and more severe after longer periods of continuous use
• A phenomena known as ‘rebound insomnia’ may occur after stopping therapy, on the first few nights after drug is stopped, insomnia is actually worse than before the sleeping pill was given
• Other withdrawal phenomena following abrupt stopping of benzodiazepine sleeping pills range from mild unpleasant feelings to a major withdrawal syndrome which may include abdominal and muscle cramps, vomiting, sweating, tremor, and convulsions

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to drug 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/

Infants born to mothers using benzodiazepines during later stages of pregnancy reported to experience symptoms of sedation and neonatal withdrawal

At this time, there is no clear evidence that triazolam exposure in early pregnancy can cause major birth defects

Benzodiazepines cross the placenta and may produce respiratory depression and sedation in neonates; monitor neonates exposed to therapy during pregnancy and labor for signs of sedation, respiratory depression, withdrawal, and feeding problems and manage accordingly

Animal data

• Oral administration 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/m² body surface area, but did cause an increase in number of stillbirths and postnatal pup mortalities at doses greater than or equal to approximately 40 times the MRHD based mg/m² body surface area

Lactation

There are no data on presence of drug in human milk or 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

The drug and its metabolites are present in the milk of lactating rats; 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 therapy and any potential adverse effects on the breastfed infant from drug or from underlying maternal condition

Infants exposed to drug through breast milk should be monitored for sedation, respiratory depression, withdrawal symptoms, and feeding problems; 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 therapy administration in order to minimize drug exposure to a breast fed infant

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing membrane permeability to chloride ions, which in turn increases the inhibitory activity of GABA on neuronal excitability.

Pharmacokinetics

Half-Life: 1.5-5.5 hr

Peak plasma time: 0.5-2 hr

Onset of action: 15-30 min

Vd: 0.8-1.8 L/kg

Protein binding: 89%

Duration: 6-7 hr

Peak plasma concentration: 1-6 ng/mL

Metabolism: CYP3A4, glucuronic acid conjugation

Metabolites: Inactive metabolites

Excretion: Urine