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MEGESTOL
Overview
What is MEGESTOL?
Megestrol Acetate Oral Suspension USP contains megestrol acetate,
a synthetic derivative of the naturally occurring steroid hormone, progesterone.
Megestrol acetate is a white, crystalline solid chemically designated as
pregna-4,6-diene-3,20-dione, 17-(acetyloxy)-6-methyl-. Solubility at 37°C in
water is 2 mcg per mL, solubility in plasma is 24 mcg per mL. Its molecular
weight is 384.51.
The molecular formula is CH0 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: citric acid, lemon-lime flavor, microcrystalline
cellulose/carboxymethylcellulose, purified water, sodium benzoate, sodium
citrate, and sucrose.
The suspension meets the requirements of USP Dissolution Test 3 in the USP
monograph for Megestrol Acetate Oral Suspension, USP
What does MEGESTOL look like?
What are the available doses of MEGESTOL?
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What should I talk to my health care provider before I take MEGESTOL?
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How should I use MEGESTOL?
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What interacts with MEGESTOL?
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What are the warnings of MEGESTOL?
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What are the precautions of MEGESTOL?
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What are the side effects of MEGESTOL?
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What should I look out for while using MEGESTOL?
What might happen if I take too much MEGESTOL?
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Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
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.
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 mg 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 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 x 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 Megestrol Acetate Oral Suspension. The treatment
was administered for 14 days. Mean C and AUC values
were 490 (±238) ng/mL and 6779 (±3048) hr x ng/mL, respectively. The median
T value was three hours. The mean C value was 202 (±101) ng/mL. The mean percentage of
fluctuation value was 107 (±40).
The effect of food on the bioavailability of Megestrol Acetate Oral
Suspension has not been evaluated.
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 ). 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 ). 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.
Non-Clinical Toxicology
See and for interaction with CNS drugs and alcohol.Methocarbamol may inhibit the effect of pyridostigmine bromide. Therefore, methocarbamol should be used with caution in patients with myasthenia gravis receiving anticholinesterase agents
Megestrol Acetate Oral Suspension USP is indicated for the treatment of anorexia, cachexia, or an unexplained, significant weight loss in patients with a diagnosis of acquired immunodeficiency syndrome (AIDS).
History of hypersensitivity to megestrol acetate or any component of the formulation. Known or suspected pregnancy.
Megestrol acetate may cause fetal harm when administered to a pregnant woman. For animal data on fetal effects, see : : . 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 : .)
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. In addition, clinical cases of adrenal insufficiency have been observed in patients receiving or being withdrawn from chronic megestrol 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 therapy. Therefore, the possibility of adrenal insufficiency should be considered in any patient receiving or being withdrawn from chronic megestrol 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 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).
Therapy with Megestrol Acetate Oral Suspension, USP 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.
Exacerbation of pre-existing diabetes with increased insulin requirements have been reported in association with the use of megestrol acetate.
Patients using megestrol acetate should receive the following instructions:
Pharmacokinetic studies show that there are no significant alterations in pharmacokinetic 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.
Long-term treatment with 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.
Data on carcinogenesis were obtained from studies conducted in dogs, monkeys and rats treated with megestrol acetate at doses 53.2, 26.6 and 1.3 times than the proposed dose (13.3 mg/kg/day) for humans. No males were used in the dog and monkey studies. In female beagles, megestrol acetate (0.01, 0.1 or 0.25 mg/kg/day) administered for up to 7 years induced both benign and malignant tumors of the breast. In female monkeys, no tumors were found following 10 years of treatment with 0.01, 0.1 or 0.5 mg/kg/day megestrol acetate. Pituitary tumors were observed in female rats treated with 3.9 or 10 mg/kg/day of megestrol acetate for 2 years. The relationship of these tumors in rats and dogs to humans is unknown but should be considered in assessing the risk-to-benefit ratio when prescribing Megestrol Acetate Oral Suspension and in surveillance of patients on therapy (see ).
No mutagenesis data are currently available.
Perinatal/postnatal (segment III) toxicity studies were performed in rats at doses (0.05 to 12.5 mg/ kg) than that indicated for humans (13.3 mg/kg); in these low dose studies, the reproductive capability of male offspring of megestrol acetate-treated females was impaired. Similar results were obtained in dogs. Pregnant rats treated with megestrol acetate showed a reduction in fetal weight and number of live births, and feminization of male fetuses. No toxicity data are currently available on male reproduction (spermatogenesis).
(See and : : .) No adequate animal teratology information is available at clinically relevant doses.
Because of the potential for adverse effects on the newborn, nursing should be discontinued if Megestrol Acetate Oral Suspension is required.
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.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of Megesterol 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 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.
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 Megestrol Acetate 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: alopecia, herpes, pruritus, vesiculobullous rash, sweating and skin disorder
Special Senses:
Urogenital System:
Postmarketing reports associated with Megestrol Acetate Oral Suspension include thromboembolic phenomena including thrombophlebitis and pulmonary embolism, and glucose intolerance (see and ).
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.
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.
A plastic dosage cup with 5, 10, 15 and 20 mL markings is provided for convenience.
Megestrol Acetate Oral Suspension USP, 40 mg/mL
Smooth, viscous, white, lemon-lime flavored suspension containing 40 mg of micronized megestrol acetate per mL
NDC 0054-3542-58: Bottles of 240 mL (8 fl. oz).
Storage
Store between 15° to 25°C (59° to 77°F) and dispense in a tight container. Protect from heat.
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 and -). Women at risk of pregnancy should avoid such exposure.
10000312/06
Revised November 2007
© RLI, 2007
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
While we update our database periodically, we cannot guarantee it is always updated to the latest version.
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