triazolam tablets, USP CIV
DESCRIPTION
HALCION Tablets contain triazolam, a triazolobenzodiazepine hypnotic agent.
Triazolam 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 HALCION Tablet, for oral administration, contains 0.125 mg or 0.25 mg of triazolam. Inactive
ingredients: 0.125 mg—cellulose, corn starch, docusate sodium, lactose, magnesium stearate, silicon
dioxide, sodium benzoate; 0.25 mg—cellulose, corn starch, docusate sodium, FD&C Blue No. 2, lactose,
magnesium stearate, silicon dioxide, sodium benzoate.
CLINICAL PHARMACOLOGY
Triazolam is a hypnotic with a short mean plasma half-life reported to be in the range of
1.5 to 5.5 hours. 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. Peak plasma levels are
reached within 2 hours following oral administration. Following recommended doses of HALCION,
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.
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.
HALCION 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.
Extremely high concentrations of triazolam do not displace bilirubin bound to human serum albumin in vitro.
Triazolam 14C was administered orally to pregnant mice. Drug-related material appeared uniformly
distributed in the fetus with 14C concentrations approximately the same as in the brain of the mother.
In sleep laboratory studies, HALCION Tablets significantly decreased sleep latency, increased the duration
of sleep, and decreased the number of nocturnal awakenings. After 2 weeks of consecutive nightly
administration, the drug’s effect on total wake time is decreased, and the values recorded in the last third of
the night approach baseline levels. On the first and/or second night after drug discontinuance (first or second
post-drug night), total time asleep, percentage of time spent sleeping, and rapidity of falling asleep frequently
were significantly less than on baseline (predrug) nights. This effect is often called "rebound" insomnia.
The type and duration of hypnotic effects and the profile of unwanted effects during administration of
benzodiazepine drugs may be influenced by the biologic half-life of administered drug and any active
metabolites formed. When half-lives are long, the drug or metabolites may accumulate during periods of
nightly administration and be associated with impairments of cognitive and motor performance during
waking hours; the possibility of interaction with other psychoactive drugs or alcohol will be enhanced. In
contrast, if half-lives are short, the drug and metabolites will be cleared before the next dose is ingested, and
carry-over effects related to excessive sedation or CNS depression should be minimal or absent. However,
during nightly use for an extended period pharmacodynamic tolerance or adaptation to some effects of
benzodiazepine hypnotics may develop. If the drug has a short half-life of elimination, it is possible that a
relative deficiency of the drug or its active metabolites (ie, in relationship to the receptor site) may occur at
some point in the interval between each night’s use. This sequence of events may account for two clinical
findings reported to occur after several weeks of nightly use of rapidly eliminated benzodiazepine hypnotics:
1) increased wakefulness during the last third of the night and 2) the appearance of increased daytime anxiety
after 10 days of continuous treatment.
