U.S. Food and Drug Administration Center for Drug Evaluation and Research
FDA Oncology Tools Product Label Details in Conventional Order for megestrol acetate

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Application
Supplement Number 016979
Complete Label
Formatted in PDF MEGACE
Description
Mechanism of Action MEGACE ® (megestrol acetate tablets, USP) is a synthetic, antineoplastic and progestational drug. Megestrol acetate is a white, crystalline solid chemically designated as 17 ??-acetyloxy-6- methylpregna-4,6-diene-3,20-dione. 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 empirical formula is C24H 32O4 and the structural formula is represented as follows: megestrol acetate, USP MEGACE is supplied as tablets for oral administration containing 20 mg and 40 mg megestrol acetate. MEGACE tablets contain the following inactive ingredients: acacia, calcium phosphate, FD&C Blue No. 1 Aluminum Lake, lactose, magnesium stearate, silicon dioxide olloidal, and starch.
Generic Drug Name megestrol acetate tablets
Manufacturer
Manufacturer Bristol-Myers Squibb Company Princeton, NJ 08543 USA
Distributor
Distributor Bristol-Myers Squibb Company Princeton, NJ 08543 USA
Clinical Pharmacology
Summary While the precise mechanism by which MEGACE produces its antineoplastic effects against endometrial carcinoma is unknown at the present time, inhibition of pituitary gonadotrophin production and resultant decrease in estrogen secretion may be factors. There is evidence to suggest a local effect as a result of the marked changes brought about by the direct instillation of progestational agents into the endometrial cavity. The antineoplastic action of megestrol acetate on carcinoma of the breast is effected by modifying the action of other steroid hormones and by exerting a direct cytotoxic effect on tumor cells. In metastatic cancer, hormone receptors may be present in some tissues but not others. The receptor mechanism is a cyclic process whereby estrogen produced by the ovaries enters the target cell, forms a complex with cytoplasmic receptor and is transported into the cell nucleus. There it induces gene transcription and leads to the alteration of normal cell functions. Pharmacologic doses of megestrol acetate not only decrease the number of hormone-dependent human breast cancer cells but also is capable of modifying and abolishing the stimulatory effects of estrogen on these cells. It has been suggested that progestins may inhibit in one of two ways: by interfering with either the stability, availability, or turnover of the estrogen receptor complex in its interaction with genes or in conjunction with the progestin receptor complex, by interacting directly with the genome to turn off specific estrogen-responsive genes. There are several analytical methods used to estimate MEGACE plasma levels, including mass fragmentography, gas chromatography (GC), high pressure liquid chromatography (HPLC) and radioimmunoassay. The plasma levels by HPLC assay or radioimmunoassay methods are about one-sixth those obtained by the GC method. The plasma levels 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. Metabolites account for only 5% to 8% of the administered dose and are considered negligible. The major route of drug elimination in humans is the 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%). Respiratory excretion as labeled carbon dioxide and fat storage may have accounted for at least part of the radioactivity not found in the urine and feces. In normal male volunteers (n=23) who received 160 mg of megestrol acetate given as a 40 mg qid regimen, the oral absorption of MEGACE appeared to be variable. Plasma levels were assayed by a high pressure liquid chromatographic (HPLC) procedure. Peak drug levels for the first 40 mg dose ranged from 10 to 56 ng/mL (mean 27.6 ng/mL) and the times to peak concentrations ranged from 1.0 to 3.0 hours (mean 2.2 hours). Plasma elimination half-life ranged from 13.0 to 104.9 hours (mean 34.2 hours). The steady state plasma concentrations for a 40 mg qid regimen have not been established.
Indications and Usage
Summary MEGACE is indicated for the palliative treatment of advanced carcinoma of the breast or endometrium (i.e., recurrent, inoperable, or metastatic disease). It should not be used in lieu of currently accepted procedures such as surgery, radiation, or chemotherapy.
Contraindications
Summary History of hypersensitivity to megestrol acetate or any component of the formulation.
Warnings
Summary Megestrol acetate may cause fetal harm when administered to a pregnant woman. Fertility and reproduction studies with high doses of megestrol acetate have shown a reversible feminizing effect on some male rat fetuses. 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. The use of MEGACE in other types of neoplastic disease is not recommended. (See also PRECAUTIONS: Carcinogenesis, Mutagenesis, and Impairment of Fertility section). The glucocorticoid activity of MEGACE Tablets 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 MEGACE. In addition, clinical cases of adrenal insufficiency have been observed in patients receiving or being withdrawn from chronic MEGACE 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 MEGACE therapy. Therefore, the possibility of adrenal insufficiency should be considered in any patient receiving or being withdrawn from chronic MEGACE 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-pituitaryadrenal axis may result in death. Finally, in patients who are receiving or being withdrawn from chronic MEGACE 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).
Precautions
Summary General Close surveillance is indicated for any patient treated for recurrent or metastatic cancer. Use with caution in patients with a history of thromboembolic disease. Use in Diabetics Exacerbation of pre-existing diabetes with increased insulin requirements has been reported in association with the use of MEGACE. Information for the Patients Patients using megestrol acetate should receive the following instructions. 1. This medication is to be used as directed by the physician. 2. Report any adverse reaction experiences while taking this medication. Laboratory Tests Breast malignancies in which estrogen and/or progesterone receptors are positive are more likely to respond to MEGACE. Carcinogenesis, Mutagenesis and Impairment of Fertility Administration of megestrol acetate to female dogs for up to 7 years is associated with an increased incidence of both benign and malignant tumors of the breast. Comparable studies in rats and studies in monkeys are not associated with an increased incidence of tumors. The relationship of the dog tumors to humans is unknown but should be considered in assessing the benefit-to-risk ratio when prescribing MEGACE and in surveillance of patients on therapy. (See WARNINGS section.) Pregnancy Pregnancy Category D. (See WARNINGS section.) Nursing Mothers Because of the potential for adverse effects on the newborn, nursing should be discontinued if MEGACE is required for treatment of cancer. Pediatric Use Safety and effectiveness in pediatric patients have not been established.
Adverse Reactions
Summary Weight Gain Weight gain is a frequent side effect of MEGACE. This gain has been associated with increased appetite and is not necessarily associated with fluid retention. Thromboembolic Phenomena Thromboembolic phenomena including thrombophlebitis and pulmonary embolism (in some cases fatal) have been reported. Glucocorticoid Effects (See WARNINGS section.) Other Adverse Reactions Heart failure, nausea and vomiting, edema, breakthrough menstrual bleeding, dyspnea, tumor flare (with or without hypercalcemia), hyperglycemia, glucose intolerance, alopecia, hypertension, carpal tunnel syndrome, mood changes, hot flashes, malaise, asthenia, lethargy, sweating and rash.
Overdosage
Summary No serious unexpected side effects have resulted from studies involving MEGACE administered in dosages as high as 1600 mg/day. Oral administration of large, single doses of megestrol acetate (5 g/kg) did not produce toxic effects in mice. Megestrol acetate has not been tested for dialyzability; however, due to its low solubility it is postulated that this would not be an effective means of treating overdose.
Dosage and Administration
Summary Breast cancer: 160 mg/day (40 mg q.i.d.) Endometrial carcinoma: 40-320 mg/day in divided doses. At least 2 months of continuous treatment is considered an adequate period for determining the efficacy of MEGACE.
How Supplied
Summary MEGACE ® (megestrol acetate tablets, USP) is available as light blue, scored tablets containing 20 mg or 40 mg megestrol acetate,USP. Bottles contain a desiccant canister. NDC 0015-0595-01 Bottles of 100 20 mg tablet NDC 0015-0596-41 Bottles of 100 40 mg tablet STORAGE Store at 25° C (77° F); excursions permitted to 15° - 30° C (59° - 86° F) [see USP Controlled Room Temperature]. Protect from temperatures above 40° C (104° F). 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.
NDC
NDC 0015-0508-42
Date
Date July 2002
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