Megace Information
Megace (Megestrol) Description
Megace (Megestrol) (megestrol acetate, USP) Oral Suspension contains megestrol acetate, a synthetic derivative of the naturally occurring 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 CHO and the structural formula is represented as follows:
Megace (Megestrol) Oral Suspension is supplied as an oral suspension containing 40 mg of micronized megestrol acetate per mL.
Megace (Megestrol) Oral Suspension contains the following inactive ingredients: alcohol (max. 0.06% v/v from flavor), citric acid, lemon-lime flavor, polyethylene glycol, polysorbate 80, purified water, sodium benzoate, sodium citrate, sucrose, and xanthan gum.
Megace (Megestrol) 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.
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 Megace (Megestrol) 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 (C) of megestrol acetate was 753 (±539) ng/mL. Mean area under the concentration-time curve (AUC) was 10476 (±7788) ng × hr/mL. Median T 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 (Megestrol) Oral Suspension. The treatment was administered for 14 days. Mean C and AUC values were 490 (±238) ng/mL and 6779 (±3048) hr × ng/mL, respectively. The median T value was three hours. The mean C value was 202 (±101) ng/mL. The mean percent of fluctuation value was 107 (±40).
The effect of food on the bioavailability of Megace (Megestrol) Oral Suspension has not been evaluated.
Megace (Megestrol) Description Of Clinical Studies
The clinical efficacy of Megace (Megestrol) 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, T counts, T counts, or skin reactivity tests (see ).
Presented below are the results of mean weight changes for patients evaluable for efficacy in Trials 1 and 2.
Megace (Megestrol) Indications And Usage
Megace (Megestrol) Oral Suspension is indicated for the treatment of anorexia, cachexia, or an unexplained, significant weight loss in patients with a diagnosis of acquired immunodeficiency syndrome (AIDS).
Megace (Megestrol) Contraindications
History of hypersensitivity to megestrol acetate or any component of the formulation. Known or suspected pregnancy.
Megace (Megestrol) Precautions
Therapy with Megace (Megestrol) Oral Suspension for weight loss should only be instituted after treatable causes of weight loss are sought and addressed. These treatable causes include possible malignancies, systemic infections, gastrointestinal disorders affecting absorption, endocrine disease, and renal or psychiatric diseases.
Effects on HIV viral replication have not been determined.
Use with caution in patients with a history of thromboembolic disease.
Pregnancy Category X.
Although megestrol acetate has been used extensively in women for the treatment of endometrial and breast cancers, its use in HIV-infected women has been limited.
All 10 women in the clinical trials reported breakthrough bleeding.
Clinical studies of Megace (Megestrol) Oral Suspension in the treatment of anorexia, cachexia, or an unexplained, significant weight loss in patients with AIDS did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Megestrol acetate is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Megace (Megestrol) Adverse Reactions
Adverse events which occurred in at least 5% of patients in any arm of the two clinical efficacy trials and the open trial are listed below by treatment group. All patients listed had at least one post baseline visit during the 12 study weeks. These adverse events should be considered by the physician when prescribing Megace (Megestrol) Oral Suspension.
Adverse events which occurred in 1% to 3% of all patients enrolled in the two clinical efficacy trials with at least one follow-up visit during the first 12 weeks of the study are listed below by body system. Adverse events occurring less than 1% are not included. There were no significant differences between incidence of these events in patients treated with megestrol acetate and patients treated with placebo.
Body as a Whole:
Cardiovascular System:
Digestive System:
Hemic and Lymphatic System:
Metabolic and Nutritional:
Nervous System:
Respiratory System:
Skin and Appendages:
Special Senses:
Urogenital System:
Breakthrough bleeding was observed in all 10 female patients participating in the clinical trials (see).
Less frequent adverse reactions including heart failure, hot flashes, mood changes, cushingoid facies, tumor flare (with or without hypercalcemia), carpal tunnel syndrome, and lethargy have also been reported with the use of megestrol acetate.
Megace (Megestrol) Overdosage
No serious unexpected side effects have resulted from studies involving Megace (Megestrol) Oral Suspension administered in dosages as high as 1200 mg/day. Reports of overdose have been received in the postmarketing setting. Signs and symptoms reported in the context of overdose included diarrhea, nausea, abdominal pain, shortness of breath, cough, unsteady gait, listlessness, and chest pain. There is no specific antidote for overdose with Megace (Megestrol) Oral Suspension. In case of overdose, appropriate supportive measures should be taken. Megestrol acetate has not been tested for dialyzability; however, due to its low solubility, it is postulated that dialysis would not be an effective means of treating overdose.
Megace (Megestrol) Dosage And Administration
The recommended adult initial dosage of Megace (Megestrol) Oral Suspension is 800 mg/day (20 mL/day). Shake container well before using.
In clinical trials evaluating different dose schedules, daily doses of 400 and 800 mg/day were found to be clinically effective.
A plastic dosage cup with 10 mL and 20 mL markings is provided for convenience.
Megace (Megestrol) How Supplied
Megace (Megestrol) (megestrol acetate, USP) Oral Suspension is available as a lemon-lime flavored oral suspension containing 40 mg of micronized megestrol acetate per mL.
NDC 0015-0508-42 Bottles of 240 mL (8 fl. oz.)
Megace (Megestrol) Storage
Store Megace (Megestrol) Oral Suspension between 15°C-25°C (59°F-77°F) and dispense in a tight container. Protect from heat.
Megace (Megestrol)
Megace (Megestrol)
