CLINICAL PHARMACOLOGYThere 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.
Mechanism of Action
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.
Pharmacokinetic Properties:
Plasma concentrations of
megestrol acetate after administration of 625 mg (125 mg/mL) of Megace® ES oral
suspension are equivalent under fed conditions to 800 mg (40 mg/mL) of megestrol
acetate oral suspension (see figure below).
Graph Image (Megacees Graph)
In order to characterize
the dose proportionality of Megace® ES, pharmacokinetic studies across a range
of doses were conducted when administered under fasting and fed conditions.
Pharmacokinetics of megestrol was linear in the dosing range between 150 mg and
675 mg after Megace® ES administration regardless of meal condition. The Cmax
and AUC under a high fat meal were increased by 48% and 36%, respectively,
compared to those under the fasting after 625 mg Megace® ES administration
(Table 1). However, a high fat meal significantly increased AUC and Cmax of
megestrol to 2-fold and 7-fold, respectively, compared to those under fasting
condition after administration of 800 mg in the original formulation. There was
no difference in safety following administration in the fed state, therefore
Megace® ES could be taken without regard to meals.
*megestrol acetate oral
suspension |
| Table 1 - Pharmacokinetic
Studies Conducted with Megace® ES |
| Amount Dosed | 150 mg | 250 mg | 375 mg | 450 mg | 575 mg | 625 mg | 675 mg | 800 mg* |
| Dose | 5 mL | 5 mL | 5 mL | 5 mL | 5 mL | 5 mL | 5 mL | 20 mL |
| | Fast | Fed | Fast | Fed | Fast | Fed | Fast | Fed | Fast | Fed | Fast | Fed | Fast | Fed | Fast | Fed |
| Cmax (ng/mL) | 412 | 379 | 647 | 588 | 810 | 958 | 955 | 1079 | - | 1421 | 1133 | 1618 | 1044 | 1616 | 187 | 1364 |
| AUC0-∞ (ng∙h/mL) | 3058 | 3889 | 5194 | 6328 | 7238 | 12193 | 9483 | 11800 | - | 14743 | 12095 | 16268 | 11879 | 17029 | 8942 | 18625 |
| Tmax (h) | 1.74 | 3.80 | 1.58 | 3.38 | 1.56 | 3.42 | 1.74 | 3.16 | - | 3.75 | 1.72 | 2.91 | 1.96 | 2.76 | 5.89 | 3.85 |
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 megestrol acetate 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
megestrol acetate oral suspension. The treatment was administered for 14 days.
Mean Cmax and AUC values were 490 (±238) ng/mL and 6779 (±3048) hr x ng/mL,
respectively. The median Tmax value was three hours. The mean Cmax value was 202
(±101) ng/mL. The mean % of fluctuation value was 107 (±40).
Metabolism
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 part of the radioactivity not found in urine and
feces.
Elimination
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%).
Special Populations
The pharmacokinetics of
megestrol acetate has not been studied in any special populations.
ANIMAL PHARMACOLOGY AND/OR TOXICOLOGYLong-term treatment with
Megace ® ES (megestrol acetate) may increase the risk of
respiratory infections. A trend toward increased frequency of respiratory
infections, decreased lymphocyte counts and increased neutrophil counts was
observed in a two-year chronic toxicity/carcinogenicity study of megestrol
acetate conducted in rats.
DESCRIPTION OF CLINICAL STUDIESMegestrol acetate oral
suspension at a dose of 800 mg/20 mL is equivalent to 625 mg/5 mL of Megace
® ES. The clinical efficacy of megestrol acetate 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). 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, placebo-controlled 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). 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 MA-treated 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 ADVERSEREACTIONS
section).
| Megestrol Acetate Oral
Suspension Clinical Efficacy Trials |
| | Trial 1 | Trial 2 |
| | Study Accrual Dates | Study Accrual Dates |
| | 11/88 to 12/90 | 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 Maximum Weight Change | 50 | 72 | 72 | 93 | | 48 | 69 |
| At Last Evaluation in 12 Weeks | 50 | 72 | 68 | 89 | | 38 | 67 |
| Mean Change in Daily Caloric Intake: | | | | | | | |
| Baseline to Time of Maximum Weight Change | -107 | 326 | 308 | 646 | | 30 | 464 |
| *Based on bioelectrical impedance analysis
determinations at last evaluation in 12 weeks |
Presented below are the
results of mean weight changes for patients evaluable for efficacy in trials 1
and 2.
Trial1 Image (Megacees Trial1)
Trial2 Image (Megacees Trial2)
