Megestrol Acetate

MEGESTROL ACETATE- megestrol acetate suspension
Cardinal Health

I07761019 R10/19

Rx Only

DESCRIPTION

Megestrol Acetate Oral Suspension, USP contains megestrol acetate, a synthetic derivative of the steroid hormone, progesterone. Megestrol acetate is a white, crystalline solid chemically designated as 17α-(acetyloxy)-6-methylpregna-4,6-diene-3,20-dione .Solubility at 37°C in water is 2 µg per mL, solubility in plasma is 24 µg per mL. Its molecular weight is 384.51.

The empirical formula is C 24 H 32 O 4 and the structural formula is represented as follows:

Chemical Structure
(click image for full-size original)

Megestrol Acetate Oral Suspension, USP is supplied as an oral suspension, containing 40 mg of micronized megestrol acetate per mL.

Megestrol Acetate Oral Suspension, USP contains the following inactive ingredients: alcohol (max. 0.34% v/v from flavor), citric acid anhydrous, lemon-lime flavor, poloxamer124, propylene glycol, purified water, sodium benzoate, sodium citrate dihydrate, sucrose and xanthan gum. It may contain 10% citric acid solution or 10% sodium citrate solution for pH adjustment. The pH range is between 3.0 and 4.7.

CLINICAL PHARMACOLOGY

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 part 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 Megestrol Acetate Oral Suspension, USP 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 (C max ) of megestrol acetate was 753 (±539) ng/mL. Mean area under the concentration time-curve (AUC) was 10476 (±7788) ng × hr/mL. Median T max 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, USP. The treatment was administered for 14 days. Mean C max and AUC values were 490 (±238) ng/mL and 6779 (±3048) ng × hr/mL, respectively. The median T max value was three hours. The mean C min value was 202 (±101) ng/mL. The mean percent of fluctuation value was 107 (±40).

The effect of food on the bioavailability of Megestrol Acetate Oral Suspension, USP has not been evaluated.

DESCRIPTION OF CLINICAL STUDIES

The clinical efficacy of Megestrol Acetate Oral Suspension, USP 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 (seeclinical study 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 tabel). 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, no statistically significant differences were seen between the treatment groups with regard to laboratory abnormalities, new opportunistic infections, lymphocyte counts, T 4 counts, T 8 counts, or skin reactivity tests (see ADVERSE REACTIONS).

Presented below are the results of mean weight changes for patients evaluable for efficacy in Trials 1 and 2.

Figure
(click image for full-size original)

Megestrol Acetate Oral Suspension, USP Clinical Efficacy Trials

Figure
(click image for full-size original)

Megestrol Acetate Oral Suspension, USP Clinical Efficacy Trials

Megestrol Acetate Oral Suspension, USP Clinical Efficacy Trials
Trial 1 Study Accrual Dates 11/88 to 12/90 Trial 2 Study Accrual Dates 5/89 to 4/91
*
Based on bioelectrical impedance analysis determinations at last evaluation in 12 weeks.

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 Wt. 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

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