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
Megace Pharmacology, Pharmacokinetics, Studies, Metabolism - Megestrol acetate
Megace Pharmacology, Pharmacokinetics, Studies, Metabolism - Megestrol acetate
CLINICAL PHARMACOLOGY
Several investigators have reported on the appetite
enhancing property of megestrol acetate
and its possible use in cachexia. The precise mechanism by which
megestrol acetate produces
effects in anorexia
and cachexia is unknown
at the present time.
There are several analytical methods used to estimate megestrol
acetate plasma concentrations, including gas
chromatography-mass fragmentography (GC-MF), high pressure
liquid chromatography
(HPLC) and radioimmunoassay (RIA). The GC-MF and HPLC
methods are specific
for megestrol acetate
and yield equivalent
concentrations. The RIA
method reacts to megestrol
acetate metabolites and is, therefore, non- specific
and indicates higher concentrations than the GC-MF and HPLC
methods. Plasma concentrations are dependent, not only on the method
used, but also on intestinal
and hepatic inactivation
of the drug, which may
be affected by factors such
as intestinal tract
motility, intestinal
bacteria, antibiotics
administered, body weight,
diet and liver function.
The major route of drug
elimination in humans
is urine. When radiolabeled megestrol acetate
was administered to humans in doses of 4 to 90 mg, the urinary excretion
within 10 days ranged from 56.5 to 78.4% (mean 66.4%) and fecal
excretion ranged from
7.7 to 30.3% (mean 19.8%). The total recovered radioactivity varied
between 83.1 and 94.7% (mean 86.2%). Megestrol acetate metabolites
which were identified in urine
constituted 5 to 8% of the dose administered. Respiratory excretion
as labeled carbon dioxide
and fat storage may have
accounted for at least proof
of the radioactivity
not found in urine and feces.
Plasma steady state pharmacokinetics
of megestrol acetate
were evaluated in 10 adult, cachectic male
patients with acquired
immunodeficiency
syndrome (AIDS) and an involuntary
weight loss
greater than 10% of baseline. Patients received single oral
doses of 800 mg/day of MEGACE Oral Suspension for 21 days. Plasma
concentration
data obtained on day 21 were evaluated for up to 48 hours past the
last dose.
Mean (± 1SD) peak plasma
concentration
(Cmax) of megestrol acetate was 753 (± 539) ng/mL.
Mean area under the concentration
time-curve (AUC) was 10476 (± 7788) ng
x hr/mL. Median Tmax value was five hours. Seven of 10
patients gained weight
in three weeks.
Additionally, 24 adult, asymptomatic
HIV seropositive
male subjects were dosed
once daily with 750 mg of
MEGACE Oral Suspension. The treatment was administered for 14 days.
Mean Cmax and AUC
values 490 (± 238) ng/ mL and 6779 (± 3048) hr
x ng/ mL, respectively. The median Tmax value
was three hours. The mean
Cmin value
was 202 (± 101) ng/ mL. The mean
% of fluctuation
value was 107 (±
40).
The relative bioavailability
of MEGACE 40 mg tablets and
MEGACE Oral Suspension has not been evaluated. The effect
of food on the bioavailability
of MEGACE Oral Suspension has not been evaluated.
DESCRIPTION
OF CLINICAL STUDIES
The clinical efficacy
of MEGACE Oral Suspension was assessed in two clinical trials. One
was a multicenter, randomized, double-blind, placebo-controlled
study comparing megestrol acetate
(MA) at doses of 100 mg, 400 mg, and 800 mg
per day versus placebo
in AIDS patients with anorexia/
cachexia and significant
weight loss. Of the 270
patients entered on study, 195 met all inclusion/exclusion criteria,
had at least two additional post baseline weight
measurements over a 12 week period
or had one post baseline
weight measurement but dropped out for therapeutic
failure. The percent of patients gaining five or more pounds at
maximum weight
gain in 12 study weeks
was statistically significantly greater for the 800 mg
(64%) and 400 mg (57%) MA-treated
groups than for the placebo
group (24%). Mean weight
increased from baseline
to last evaluation
in 12 study weeks in the 800 mg MA-treated group
by 7.8 pounds, the 400 mg
MA group
by 4.2 pounds, the 100 mg
MA group
by 1.9 pounds, and decreased in the placebo
group by 1.6 pounds. Mean
weight changes at 4,
8 and 12 weeks for patients evaluable for efficacy
in the two clinical
trials are shown graphically. Changes in body
composition during the 12 study weeks as measured by bioelectrical
impedance analysis
showed increases in non-water body
weight in the MA- treated
groups (see Clinical Studies Table below). In
addition, edema developed or worsened in only 3 patients.
Greater percentages of MA- treated patients in the 800 mg
group (89%), the 400 mg
group (68%) and the 100
mg group
(72%), than in the placebo group (50%), showed an improvement in
appetite at last evaluation
during the 12 study weeks. A statistically significant
difference was observed between the 800 mg
MA- treated group and
the placebo group
in the change in caloric
intake from baseline
to time of maximum
weight change. Patients
were asked to assess weight
change, appetite, appearance, and overall perception of well- being
in a 9 question survey. At
maximum weight
change only the 800 mg MA-
treated group gave responses
that were statistically significantly more favorable to all questions
when compared to the placebo- treated group. A dose
response was noted
in the survey with positive
responses correlating with higher dose
for all questions.
The second trial was a multicenter, randomized, double-blind, placebocontrolled
study comparing megestrol acetate
800 mg/ day versus placebo
in AIDS patients with anorexia/
cachexia and significant
weight loss. Of the 100
patients entered on study, 65 met all inclusion/ exclusion
criteria, had at least two additional post
baseline weight
measurements over a 12 week period or had one post
baseline weight
measurement but dropped out for therapeutic failure. Patients in
the 800 mg MA- treated group
had a statistically significantly larger increase in mean
maximum weight
change than patients in the placebo group. From baseline
to study week 12, mean
weight increased by 11.2
pounds in the MA- treated group
and decreased 2.1 pounds in the placebo
group. Changes in body
composition as measured by bioelectrical impedance
analysis showed increases in non- water
weight in the MA- treated
group (see Clinical
Studies Table below). No
edema was reported in
the MA- treated group. A greater percentage of MA- treated patients
(67%) than placebo- treated patients (38%) showed an improvement
in appetite at last
evaluation during
the 12 study weeks; this difference was statistically significant.
There were no statistically
significant differences
between treatment
groups in mean caloric
change or in daily caloric
intake at time
to maximum weight change.
In the same 9 question survey
referenced in the first trial, patients’ assessments of weight
change, appetite, appearance, and overall perception of well- being
showed increases in mean
scores in MAtreated patients as compared to the placebo
group.
In both trials, patients tolerated the drug
well and no statistically
significant differences were seen between the treatment
groups with regard to laboratory
abnormalities, new opportunistic infections, lymphocyte
counts, T4 counts, T8 counts, or skin
reactivity tests
(see ADVERSE REACTIONS).
|
MEGACE (megestrol acetate) Oral Suspension
Clinical Efficacy Trials
|
| |
Trial 2
Study Accrual Dates
11/ 88 to 12/ 90
|
Trial 1
Study Accrual Dates
5/ 89 to 4/ 91
|
| Megestrol Acetate,
mg/ day |
0
|
100
|
400
|
800
|
0
|
800
|
| Entered Patients
|
38
|
82
|
75
|
75
|
48
|
52
|
| Evaluable Patients
|
28
|
61
|
53
|
53
|
29
|
36
|
| Mean Change in Weight
(lb.) Baseline to 12 Weeks |
0.0
|
2.9
|
9.3
|
10.7
|
-2.1
|
11.2
|
| % Patients
>/=5 Pound Gain
at Last Evaluation in 12 Weeks
|
21
|
44
|
57
|
64
|
28
|
47
|
| Mean Changes in Body
Composition* |
|
| Fat Body Mass (lb.) |
0.0
|
2.2
|
2.9
|
5.5
|
1.5
|
5.7
|
| Lean Body Mass (lb.) |
-1.7
|
-0.3
|
1.5
|
2.5
|
-1.6
|
-0.6
|
| : Water (liters)
|
-1.3
|
-0.3
|
0.0
|
0.0
|
-0.1
|
-0.1
|
| % Patients With Improved
Appetite: |
|
| At Time of Max. Wt.
Change |
50
|
72
|
72
|
93
|
48
|
69
|
| At Last Evaluation
in 12 Wk. |
50
|
72
|
68
|
89
|
38
|
67
|
| Mean Change in Daily
Caloric Intake: Maximum Weight Change Baseline to Time of
|
-107
|
326
|
308
|
646
|
30
|
464
|
| *Based on bioelectrical
impedance analysis determinations at last evaluation
in 12 weeks |
top
