Indications and Usage
Megestrol acetate tablets are 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.
Dosage and Administration
Breast Cancer: 160 mg/day (40 mg qid).
Endometrial Carcinoma: 40 to 320 mg/day in divided doses.
At least 2 months of continuous treatment is considered an adequate period for determining the efficacy of megestrol acetate tablets.
Contraindications
History of hypersensitivity to megestrol acetate or any component of the formulation.
Adverse Reactions
Weight Gain
Weight gain is a frequent side effect of megestrol acetate. 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.
To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.
Overdosage
No serious unexpected side effects have resulted from studies involving megestrol acetate 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.
Description
Megestrol acetate tablets, USP are a synthetic, antineoplastic and progestational drug. 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 mcg per mL, solubility in plasma is 24 mcg per mL. The structural formula is represented as follows:
C24H32O4 M.W. 384.51
Megestrol acetate tablets, USP are supplied as tablets for oral administration containing 20 mg or 40 mg megestrol acetate.
Inactive Ingredients: Anhydrous lactose, dibasic calcium phosphate dihydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.
Megestrol Acetate Structural FormulaClinical Pharmacology
While the precise mechanism by which megestrol acetate 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 are 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 megestrol acetate 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 megestrol acetate 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 to 3 hours (mean 2.2 hours). Plasma elimination half-life ranged from 13 to 104.9 hours (mean 34.2 hours). The steady state plasma concentrations for a 40 mg qid regimen have not been established.
How Supplied / Storage and Handling
Megestrol acetate tablets, USP are available as:
20 mg: White, round, flat-faced, beveled-edge, scored tablet. Debossed with 555/606 on one side and stylized b on the other side. Available in bottles of 100 (NDC 0555-0606-02) Tablets.
40 mg: White, round, flat-faced, beveled-edge, scored tablet. Debossed with 555/607 on one side and stylized barr on the other side. Available in bottles of
100 (NDC 0555-0607-02) Tablets.
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Keep this and all medications out of the reach of children.
Patient Counseling Information
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.