Megestrol Acetate 40 MG/ML Oral Suspension
WARNINGS
Megestrol acetate may cause fetal harm when administered to a pregnant woman.
For animal data on fetal effects, (see PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility: Impairment of Fertility ).
There are no adequate and well-controlled studies in pregnant women.
If this drug is used during pregnancy, or if the patient becomes pregnant while taking (receiving) this drug, the patient should be apprised of the potential hazard to the fetus.
Women of childbearing potential should be advised to avoid becoming pregnant.
Megestrol acetate is not intended for prophylactic use to avoid weight loss.
(See also PRECAUTIONS: Carcinogenesis, Mutagenesis, and Impairment of Fertility section.) The glucocorticoid activity of megestrol acetate oral suspension has not been fully evaluated.
Clinical cases of new onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and overt Cushing’s Syndrome have been reported in association with the chronic use of megestrol acetate.
In addition, clinical cases of adrenal insufficiency have been observed in patients receiving or being withdrawn from chronic megestrol acetate therapy in the stressed and non-stressed state.
Furthermore, adrenocorticotropin (ACTH) stimulation testing has revealed the frequent occurrence of asymptomatic pituitary-adrenal suppression in patients treated with chronic megestrol acetate therapy.
Therefore, the possibility of adrenal insufficiency should be considered in any patient receiving or being withdrawn from chronic megestrol acetate therapy who presents with symptoms and/or signs suggestive of hypoadrenalism (e.g., hypotension, nausea, vomiting, dizziness, or weakness) in either the stressed or non-stressed state.
Laboratory evaluation for adrenal insufficiency and consideration of replacement or stress doses of a rapidly acting glucocorticoid are strongly recommended in such patients.
Failure to recognize inhibition of the hypothalamic-pituitary-adrenal axis may result in death.
Finally, in patients who are receiving or being withdrawn from chronic megestrol acetate therapy, consideration should be given to the use of empiric therapy with stress doses of a rapidly acting glucocorticoid in conditions of stress or serious intercurrent illness (e.g., surgery, infection).
DRUG INTERACTIONS
Drug Interactions Pharmacokinetic studies show that there are no significant alterations in pharma-cokinetic parameters of zidovudine or rifabutin to warrant dosage adjustment when megestrol acetate is administered with these drugs.
The effects of zidovudine or rifabutin on the pharmacokinetics of megestrol acetate were not studied.
OVERDOSAGE
No serious unexpected side effects have resulted from studies involving megestrol acetate oral suspension administered in dosages as high as 1200 mg/day.
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.
DESCRIPTION
Megestrol acetate 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 17-Hydroxy-6-methylpregna-4,6-diene-3,20-dione acetate.
Solubility at 37°C in water is 2 mcg per mL, solubility in plasma is 24 mcg per mL.
Its molecular weight is 384.52.
The chemical formula is C 24 H 32 O 4 and the structural formula is represented as follows: Megestrol acetate oral suspension is supplied as an oral suspension containing 40 mg of micronized megestrol acetate per mL.
Megestrol acetate oral suspension contains the following inactive ingredients: alcohol (max 0.06% v/v from flavor), artificial lime flavor, citric acid monohydrate, docusate sodium, glycerin, natural and artificial lemon flavor, purified water, sodium benzoate, sodium citrate dihydrate, sucrose and xanthan gum.
Megestrol acetate oral suspension, 40 mg/mL complies with USP Dissolution Test 2.
Chemical Structure
CLINICAL STUDIES
DESCRIPTION OF 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 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 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 4 counts, T 8 counts, or skin reactivity tests (see ADVERSE REACTIONS section).
Megestrol Acetate Oral Suspension Clinical Efficacy Trials Trial 1 Study Accrual Dates 11/88 to 12/90 Trial 2 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 Based on bioelectrical impedance analysis determinations at last evaluation in 12 weeks.
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 The following figures are the results of mean weight changes for patients evaluable for efficacy in trials 1 and 2.
Trial 1 Image Trial 2 Image
HOW SUPPLIED
Megestrol acetate oral suspension is available as a milky white, lemon-lime flavored oral suspension containing 40 mg of micronized megestrol acetate per mL.
Bottles of 240 mL (8 fl.
oz.) NDC 54868-5389-0 Bottles of 480 mL (16 fl.
oz.) NDC 54868-5389-1 STORAGE Store the oral suspension between 20°-25°C (68°-77°F).
[See USP].
Dispense in a tight container.
Protect from heat.
SPECIAL HANDLING Health Hazard Data: There is no threshold limit value established by OSHA, NIOSH, or ACGIH.
Exposure or “overdose” at levels approaching recommended dosing levels could result in side effects described above (see WARNINGS and ADVERSE REACTIONS sections).
Women at risk of pregnancy should avoid such exposure.
GERIATRIC USE
Geriatric Use Clinical studies of Megestrol acetate 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 of 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.
INDICATIONS AND USAGE
Megestrol acetate 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).
PEDIATRIC USE
Pediatric Use Safety and effectiveness in pediatric patients have not been established.
PREGNANCY
Pregnancy Pregnancy Category X (See WARNINGS and PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility: Impairment of Fertility .
)
NUSRING MOTHERS
Nursing Mothers Because of the potential for adverse effects on the newborn, nursing should be discontinued if megestrol acetate oral suspension is required.
INFORMATION FOR PATIENTS
Information for Patients Patients using megestrol acetate should receive the following instructions: This medication is to be used as directed by the physician.
Report any adverse reaction experiences while taking this medication.
Use contraception while taking this medication if you are a woman capable of becoming pregnant.
Notify your physician if you become pregnant while taking this medication.
DOSAGE AND ADMINISTRATION
The recommended adult initial dosage of megestrol acetate 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.