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Megace ES

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Megace ES

CLINICAL PHARMACOLOGY

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.

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).

Mean plasma concentrations of megestrol acetate after oral administration of 625 mg of Megace® ES (megestrol acetate) oral suspension and 800 mg of megestrol acetate oral suspension to healthy volunteers under fed conditions

Megace-es (Megestrol acetate)Mean plasma concentrations of megestrol acetate after oral administration of 625 mg of Megace® ES (megestrol acetate) oral suspension and 800 mg of megestrol acetate oral suspension to healthy volunteers under fed conditions

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 150mg and 675mg 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 625mg 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 800mg 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.

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
*megestrol acetate oral suspension

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.

Clinical Studies

Description of clinical Studies

Megestrol 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 ADVERSE REACTIONS section).

Megestrol Acetate Oral Suspension Clinical Efficacy Trials
  Trial
Study Accrual Dates
11/88 to12/90
Trial2
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 Charge in Weight (Ib.)
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.

Megace-es (Megestrol acetate) Presented below are the results of mean weight changes for patients evaluable for efficacy in trial 1 Megace-es (Megestrol acetate) Presented below are the results of mean weight changes for patients evaluable for efficacy in trial 2

Animal Toxicology

Long-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.

Last reviewed on RxList: 8/28/2008
This monograph has been modified to include the generic and brand name in many instances.

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