A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Restoril Pharmacology, Pharmacokinetics, Studies, Metabolism - Temazepam
Restoril Pharmacology, Pharmacokinetics, Studies, Metabolism - Temazepam
CLINICAL PHARMACOLOGY
Pharmacokinetics
In a single and multiple
dose absorption, distribution,
metabolism, and excretion
(ADME) study, using 3H labeled drug. Temazepam was well
absorbed and found to have minimal
(8%) first pass metabolism. There were no active metabolites formed
and the only significant
metabolite present in blood
was the O-conjugate. The unchanged drug
was 96% bound to plasma
proteins. The blood level
decline of the parent
drug was biphasic and the
short half-life ranging
from 0.4-0.6 hours and the terminal
half life ranging from 3.5-18.4 hours (mean 8.8 hours), depending
on the study population and the method
of determination. Metabolites were formed with a half-life
of 10 hours and excreted with a half-life
of approximately 2 hours. Thus, formation
of the major metabolite
is the rate limiting step
in the biodisposition of temazepam. There is no accumulation of
metabolites. A dose-proportional relationship has been established
for the area under the
plasma concentration/time
curve over the 15-30 mg
dose range.
Temazepam was completely metabolized through conjugation
prior to excretion: 80%-90% of the dose
appeared in the urine. The major metabolite
was th O-conjugate of temazepam (90%): the O-conjugate of N- desmethyl
temazepam was a minor
metabolite (7%).
Bioavailability, Induction, and Plasma Levels
Following ingestion
of a 30 mg temazepam capsule,
measurable plasma concentrations were achieved 10-20 minutes after
dosing with peak plasma levels ranging from 666-982 ng/ml (mean
865 ng/ml) occurring approximately 1.2-1.6 hours (mean 1.5 hours)
after dosing.
In a 7 day study, in which subjects were given a 30 mg
temazepam capsule 1 hour before retiring, steady-state (as measured
by the attainment of maximal trough
concentrations) was achieved by the third dose. Mean plasma levels
of temazepam (for days 2-7) were 260 ±
210 ng/ml at 9 hours and 75 ±
80 ng/ml at 24 hours after dosing. A slight trend
toward declining 24 hour plasma levels was seen after day 4 in the
study, however, the 24 hour plasma
levels were quite variable.
At a dose of 30 mg
once-a-day for 8 weeks, no evidence
of enzyme induction was
found in man.
Elimination Rate of Benzodiazepine Hypnotics and Profile of
Common Untoward Effects
The type and duration
of unwanted effects during administration
of benzodiazepine hypnotics may be influenced by the biologic
half-life of the administered
drug and for some hypnotics, the half-life
of any active metabolites formed. Benzodiazepine hypnotics have
a spectrum of half-
lives from short (<4 hours) or long (>20 hours). When half-lives
are long, drug (and for
some drugs their inactive metabolites) may accumulate during periods
of nightly administration
and may be associated with impairments of cognitive and/or motor
performance during
waking hours; the possibility of interaction with other psychoactive
drugs or alcohol will
be enhanced. In contrast,
if half-lives are shorter, drug
(and for some drug their
active metabolites may be accumulate during periods of nightly administration
and be associated with impairments of cognitive and/or motor
performance during
waking hours; the possibility of interaction with other psychotropic
drugs or alcohol will be enhanced. In
contrast, if half-lives are shorter, drug
(and, where appropriate, its active metabolites) will
be cleared before the next dose is ingested, and carry-over
effects related to excessive sedation
or CNS depression should be minimized 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 elimination half-life, it is possible that a relative
deficiency of the drug, or, if appropriate, its active metabolites
(i.e., 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 2 clinical
findings reported to occur after several weeks of nightly use of
rapidly eliminated benzodiazepines hypnotics, namely increased wakefulness
during the last third of the night, and the appearance
of daytime anxiety.
CLINICAL STUDIES
Temazepam improved sleep
parameters in clinical
studies. Residual medication effects ("hangover") were
essentially absent. Early morning awakening, a particular problem
in the geriatric patient, was significantly reduced.
Patients with chronic
insomnia were evaluated
in 2 week, placebo controlled
sleep laboratory studies with temazepam at doses of 7.5 mg, 15 mg,
and 30 mg, given 30 minutes prior to bedtime. There was a linear
dose-response improvement in total sleep
time and sleep
latency, with significant
drug-placebo differences at 2 weeks occurring only for total sleep
differences at the 2 higher doses, and for sleep
latency only at the highest dose.
In these sleep laboratory
studies, REM sleep
was essentially unchanged and
wave sleep
was decreased. No measurable effects on daytime alertness or performance
occurred following temazepam treatment
or during the withdrawal period, even through a transient
sleep disturbance
in some sleep laboratory
parameters was observed following withdrawal
of the highest dose. There was no evidence
of tolerance development
in sleep laboratory parameters
when patients were given temazepam nightly for at least 2 weeks.
In addition, normal
subjects with transient
insomnia associated
with first night adaptation
to the sleep laboratory
were evaluated in 24 hour, placebo controlled sleep
laboratory studies with temazepam at doses of 7.5 mg, 15 mg, and
30 mg, given 30 minutes prior to bedtime. There was a linear
dose-response improvement in total sleep
time, sleep latency and
number of awakenings, with significant
drug-placebo differences occurring for sleep
latency at all doses, for total sleep
time at the 2 higher doses
and for number of awakenings
only at the 30 mg dose.
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