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
Xanax XR Pharmacology, Pharmacokinetics, Studies, Metabolism - Alprazolam
Xanax XR Pharmacology, Pharmacokinetics, Studies, Metabolism - Alprazolam
CLINICAL PHARMACOLOGY
Pharmacodynamics
CNS agents of the 1,4 benzodiazepine class presumably exert
their effects by binding at stereospecific receptors at several sites within
the central nervous system. Their exact mechanism of action is unknown. Clinically,
all benzodiazepines cause a dose-related central nervous system depressant activity
varying from mild impairment of task performance to hypnosis.
Pharmacokinetics
Absorption
Following oral administration of XANAX (immediate-release)
Tablets, alprazolam is readily absorbed.
Peak concentrations in the plasma occur in one to two hours
following administration. Plasma levels are proportional to the dose given;
over the dose range of 0.5 to 3.0 mg,peak levels of 8.0 to 37 ng/mL were observed.
Using a specific assay methodology, the mean plasma elimination half-life of
alprazolam has been found to be about 11.2 hours (range:6.3–26.9 hours) in healthy
adults.
The mean absolute bioavailability of alprazolam from XANAX
XR Tablets is approximately 90%,and the relative bioavailability compared to
XANAX Tablets is 100%.The bioavailability and pharmacokinetics of alprazolam
following administration of XANAX XR Tablets are similar to that for XANAX Tablets,
with the exception of a slower rate of absorption. The slower absorption rate
results in a relatively constant concentration that is maintained between 5
and 11 hours after the dosing. The pharmacokinetics of alprazolam and two of
its major active metabolites (4-hydroxyal-prazolam and a-hydroxyalprazolam)
are linear, and concentrations are proportional up to the recommended maximum
daily dose of 10 mg given once daily. Multiple dose studies indicate that the
metabolism and elimination of alprazolam are similar for theimmediate-release
and the extended-release products.
Food has a significant influence on the bioavailabil-ity of
XANAX XR Tablets. A high-fat meal given up to 2 hours before dosing with XANAX
XR Tablets increased the mean Cmax by about 25%.The effect of this
meal on Tmax depended on the timing of the meal, with a reduction
in Tmax by about 1/3 for subjects eating immediately before dosing
and an increase in Tmax by about 1/3 for subjects eating 1hour or
more after dosing. The extent of exposure (AUC) and elimination half-life (t1/2)
were not affected by eating.
There were significant differences in absorption rate for the
XANAX XR Tablet, depending on the time of day administered, with the Cmax
increased by 30% and the Tmax decreased by an hour following dosing at night,
compared to morning dosing.
Distribution
The apparent volume of distribution of alprazolam is similar
for XANAX XR and XANAX Tablets. In vitro, alprazolam is bound (80%) to human
serum protein. Serum albumin accounts for the majority of the binding.
Metabolism
Alprazolam is extensively metabolized in humans, primarily
by cytochrome P450 3A4 (CYP3A4),to two major metabolites in the plasma:4-hydroxyalprazo-lam
and a-hydroxyalprazolam. A benzophenone derived from
alprazolam is also found in humans. Their half-lives appear to be similar to
that of alprazolam. The pharmacokinetic parameters at steady-state for the two
hydroxylated metabolites of alprazolam (4-hydroxyalprazolam and a-hydroxy-alprazolam)
were similar for XANAX and XANAX XR Tablets, indicating that the metabolism
of alprazolam is not affected by absorption rate. The plasma concentrations
of 4-hydroxyalprazolam and a-hydroxyalprazolam relative
to unchanged alprazolam concentration after both XANAX XR and XANAX Tablets
were always less than 10% and 4%,respectively.The reported relative potencies
in benzodiazepine receptor binding experiments and in animal models of induced
seizure inhibition are 0.20 and 0.66,respectively,for 4-hydroxy-alprazolam and
a-hydroxyalprazolam. Such low concentrations
and the lesser potencies of 4-hydroxy-alprazolam and a-hydroxyalprazolam
suggest that they are unlikely to contribute much to the pharmacological effects
of alprazolam. The benzophenone metabolite is essentially inactive.
Elimination
Alprazolam and its metabolites are excreted primarily in the
urine. The mean plasma elimination half-life of alprazolam following administration
of XANAX XR Tablet ranges from 10.7-15.8 hours in healthy adults. Special Populations
While pharmacokinetic studies have not been performed in special populations
with XANAX XR Tablets, the factors (such as age,gender, hepatic or renal impairment)
that would affect the pharmacokinetics of alprazolam after the administration
of XANAX
Tablets would not be expected to be different with the administration
of XANAX XR Tablets.
Changes in the absorption, distribution, metabolism, and excretion
of benzodiazepines have been reported in a variety of disease states including
alcoholism, impaired hepatic function, and impaired renal function. Changes
have also been demonstrated in geriatric patients. A mean half-life of alprazolam
of 16.3hours has been observed in healthy elderly subjects (range:9.0–26.9 hours,n=16)
compared to 11.0hours (range:6.3–15.8 hours,n=16) in healthy adult subjects.
In patients with alcoholic liver disease the half-life of alprazolam ranged
between 5.8 and 65.3 hours (mean:19.7 hours,n=17) as compared to between 6.3
and 26.9 hours (mean=11.4 hours,n=17) in healthy subjects. In an obese group
of subjects the half-life of alprazolam ranged between 9.9 and 40.4 hours (mean=21.8
hours,n=12) as compared to between 6.3 and 15.8 hours (mean=10.6 hours,n=12)
in healthy subjects.
Because of its similarity to other benzodiazepines, it is assumed
that alprazolam undergoes transplacental passage and that it is excreted in
human milk. Race—Maximal concentrations and half-life of alprazolam are approximately
15% and 25% higher in Asians compared to Caucasians.
Pediatrics—The pharmacokinetics of alprazolam after administration
of the XANAX XR Tablet in pediatric patients have not been studied.
Gender—Gender has no effect on the pharmacokinetics of alprazolam.
Cigarette Smoking—Alprazolam concentrations may be reduced
by up to 50% in smokers compared to non-smokers.
Drug-Drug Interactions
Alprazolam is primarily eliminated by metabolism via cytochrome
P450 3A (CYP3A).Most of the interactions that have been documented with alprazolam
are with drugs that inhibit or induce CYP3A4.
Compounds that are potent inhibitors of CYP3A would be
expected to increase plasma alprazolam concentrations. Drug products that
have been studied in vivo, along with their effect on increasing alprazolam
AUC, are as follows:ketoconazole,3.98 fold;itra-conazole,2.70 fold;nefazodone,1.98fold;fluvoxamine,
1.96 fold; and erythromycin,1.61 fold (see CONTRAINDICATIONS,
WARNINGS, and PRECAUTIONS–Drug
Interactions).
CYP3A inducers would be expected to decrease alprazolam concentrations
and this has been observed in vivo. The oral clearance of alprazolam (given
in a 0.8mg single dose) was increased from 0.90±0.21 mL/min/kg to 2.13±0.54
mL/min/kg and the elimination t1/2 was shortened
(from 17.1±4.9 to 7.7±1.7 h) following administration of 300mg/day carbamazepine
for 10 days (see PRECAUTIONS–Drug
Interactions).However, the carbamazepine dose used in this study
was fairly low compared to the recommended doses (1000-1200mg/day);the
effect at usual carbamazepine doses is unknown.
The ability of alprazolam to induce or inhibit human hepatic
enzyme systems has not been determined. However, this is not a property of benzodiazepines
in general. Further, alprazolam did not affect the pro-thrombin or plasma warfarin
levels in male volunteers administered sodium warfarin orally.
CLINICAL EFFICACY TRIALS
The efficacy of XANAX XR Tablets in the treatment of panic
disorder was established in two 6-week, placebo-controlled studies of XANAX
XR in patients with panic disorder.
In two 6-week,flexible-dose,placebo-controlled studies in patients
meeting DSM-III criteria for panic disorder, patients were treated with XANAX
XR in a dose range of 1 to 10 mg/day, on a once-a-day basis. The effectiveness
of XANAX XR was assessed on the basis of changes in various measures of panic
attack frequency, on various measures of the Clinical Global Impression, and
on the Overall Phobia Scale. In all, there were seven primary efficacy measures
in these studies, and XANAX XR was superior to placebo on all seven outcomes
in both studies. The mean dose of XANAX XR at the last treatment visit was 4.2mg/day
in the first study and 4.6 mg/day in the second.
In addition, there were two 8-week,fixed-dose, placebo-controlled
studies of XANAX XR in patients with panic disorder, involving fixed XANAX XR
doses of 4 and 6 mg/day, on a once-a-day basis, that did not show a benefit
for either dose of XANAX XR.
The longer-term efficacy of XANAX XR in panic disorder has
not been systematically evaluated.
Analyses of the relationship between treatment outcome and
gender did not suggest any differential responsiveness on the basis of gender.
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