Megace (Megestrol Acetate)

MEGACE® MEGACE® OS

Bristol

Megestrol Acetate

Antineoplastic – Progestogen – Antianorexic – Anticachectic

Antianorexic – Anticachectic

Action And Clinical Pharmacology: The precise mechanism of action by which megestrol produces its antineoplastic effects is unknown at present. Pharmacologic doses of megestrol exerted a direct cytotoxic effect on human breast cancer cells in vitro and proved capable of modifying and abolishing the stimulatory effects of estrogen on breast cancer cell lines.

Megestrol interacts with progesterone receptors to stimulate cell maturation through a progestin-inducing mechanism. It has also been shown to have certain androgenic properties and may also modify glucocorticoid action by binding to the glucocorticoid receptor.

In previously untreated breast cancer patients with ERRreceptor status, endocrine therapy has been shown to produce responses in up to 81% of patients.

Inhibition of persistent endometrial hyperplasia and of persistent endometrial adenocarcinoma was observed upon administration of megestrol in doses of 160 mg/day. Megestrol partially inhibited expression of estrogen dependent secretory proteins and certain constituent proteins in the rat uterine epithelium.

Metastatic carcinoma of the prostate responds to a variety of hormone manipulations that decrease the level of androgens in androgen-sensitive tissue. The primary mechanism of action of megestrol and DES is the suppression of luteinizing hormone from the pituitary gland, which leads to suppression of serum androgens arising from the testicle.

Megestrol may have other mechanisms of action as well, including an antiandrogen activity, suppression of adrenal androgens, and possibly the inhibition of enzymes, e.g., 5 a-reductase, critical to androgen metabolism within the prostate. The precise mechanism of action by which megestrol produces its antianorexic and anticachectic effects is also unknown at present. The gain in weight associated with megestrol is associated with increased appetite, an increase in fat and body cell mass.

Pharmacokinetics: In 24* healthy male volunteers (age 19 to 44 years) who received 160 mg of megestrol given as a 40 mg q.i.d. regimen, the oral absorption of Megace appeared to be variable. 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 9.9 to 104.9 hours (mean 34.2 hours). The steady state plasma concentrations for a 40 mg q.i.d. regimen have not been established.

*Pharmacokinetic data from 1 patient excluded due to unusually high drug levels.

Plasma steady-state pharmacokinetics of Megace OS were evaluated in 10 adult cachectic male patients (age 26 to 49 years) with acquired immunodeficiency syndrome (AIDS) and an involuntary weight loss greater than 10% of baseline. Patients received a single oral dose of 800 mg/day of megestrol for 21 days. Plasma concentration data obtained on day 21 were evaluated for up to 48 hours past the last dose. A high degree of interpatient variability in rate and extent of absorption was observed. Median peak plasma concentration (Cmax) of megestrol was 602 ng/mL (range 77 to 1 670 ng/mL).

Steady-state plasma pharmacokinetics of Megace OS were evaluated in 24 asymptomatic HIV seropositive male patients (age 21 to 40 years). Patients received single oral dose of 750 mg of megestrol for 14 days. The mean plasma concentration (Cmax) of megestrol was 490 ng/mL (range 156 to 1 169 ng/mL).

Estimates of plasma levels of megestrol are dependent on the measurement method used. Plasma levels depend on intestinal and hepatic inactivation of the drug, which may be affected by intestinal tract motility, intestinal bacteria, concomitant antibiotic administration, body weight, diet and hepatic function.

Pharmacodynamics: A single oral dose of radioactive megestrol given to 1 male produced a maximum blood level in 1 to 3 hours and gradually fell over a 24-hour period. Megestrol when given orally to women exhibited an average excretion of 86.2% (range 83.1 to 94.7%), fecal excretion accounted for 19.8% (range 7.7 to 30.3%) and urinary excretion for 66.4% (range 56.5 to 78.4%). The biological half-life for doses of 60 to 90 mg was 3.5 days. The half-life of a 160 mg dose was 37.6 hours. The excretion occurred as 3 glucuronide conjugates with hydroxylation occurring at either the 2-a, or the 6-methyl position or at both positions. Other metabolites occur but only account for 5 to 8% of the dose.

Respiratory excretion and fat storage may account for the fraction of an administered dose not found in urine or feces.

Indications And Clinical Uses: Tablets: For adjunctive or palliative treatment of recurrent, inoperable or metastatic carcinoma of the breast and endometrium and for palliative treatment of hormone responsive advanced (Stage D2) carcinoma of the prostate. Megestrol should not be used in lieu of currently accepted procedures such as surgery and radiation. Objective or subjective responses or arrest of tumor growth may occur for one to several months while on therapy.

Megestrol is also indicated in male or female patients for the treatment of anorexia, cachexia or weight loss secondary to metastatic cancer.

Oral Suspension: For the treatment of anorexia, cachexia, or an unexplained significant weight loss in patients with a diagnosis of acquired immunodeficiency syndrome (AIDS).

Contra-Indications: In those people who are sensitive to megestrol or any ingredients in the dosage forms. Megestrol preparations should not be used as a diagnostic test for pregnancy.

Manufacturers’ Warnings In Clinical States: Pregnancy: The use of progestational agents during the first 4 months of pregnancy is not recommended.

Progestational agents have been used beginning within the first trimester of pregnancy in an attempt to prevent habitual abortion or treat threatened abortion. There is no adequate evidence that such use is effective and there is evidence of potential harm to the fetus when such drugs are given during the first 4 months of pregnancy. Furthermore, in the vast majority of women, the cause of abortion is a defective ovum, which progestational agents could not be expected to influence. In addition, the use of progestational agents, with their uterine-relaxant properties, in patients with fertilized defective ova may cause a delay in spontaneous abortion.

Several reports suggest an association between intrauterine exposure to progestational drugs in the first trimester of pregnancy and genital abnormalities in male and female fetuses. The risk of hypospadias, 5 to 8 per 1 000 male births in the general population, may be approximately doubled with exposure to these drugs. There are insufficient data to quantify the risk to exposed female fetuses, but insofar as some of these drugs induce mild virilization of the external genitalia of the female fetus, and because of the increased association of hypospadias in the male fetus, it is prudent to avoid the use of these drugs during the first trimester of pregnancy.

If the patient is exposed to megestrol during the first 4 months of pregnancy or if she becomes pregnant while taking this drug, she should be apprised of the potential risks to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

Megestrol oral suspension is not intended for prophylactic use to avoid weight loss.

Precautions: General: Therapy with megestrol oral suspension for weight loss should only be instituted after treatable causes of weight loss are sought and addressed. These treatable causes include malignancies, systemic infections, gastrointestinal disorders affecting absorption, endocrine disease and renal or psychiatric disease.

Although the glucocorticoid effects of megestrol oral suspension in HIV-infected individuals have not been evaluated, laboratory evidence of adrenal suppression has been observed rarely in patients shortly after discontinuation of megestrol oral suspension therapy. The significance of these findings has not been fully established.

Effects of megestrol oral suspension on HIV viral replication have not been determined.

Use megestrol tablets and oral suspension with caution in patients with a history of thrombophlebitis. Close, customary surveillance is indicated as in any patient being treated for recurrent or metastatic cancer. Patients receiving large doses of progestational agents such as megestrol continuously for prolonged periods should be observed closely for possible adrenal cortical suppression.

Children: Safety and effectiveness in children have not been established.

Lactation: Because many drugs are excreted in human breast milk and because of the potential for adverse reactions in nursing infants, nursing should be discontinued when receiving megestrol therapy.

HIV Infected Women: Although megestrol 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 clinical trials reported breakthrough bleeding.

Drug Interactions: Possible interactions of megestrol with concomitant medications have not been investigated.

Information for the Patient: Patients should be advised to use megestrol as directed and report any adverse reaction experiences to their physician. Women of childbearing potential should be advised to avoid becoming pregnant and should exercise adequate contraceptive control. If patients become pregnant while taking megestrol, they should promptly notify their physician.

Adverse Reactions: Weight gain is a frequent side effect of megestrol when it is used in patients with cancer of the breast or endometrium. This gain has been associated with increased appetite. It is this effect which forms the basis for use of megestrol in patients with anorexia, cachexia or weight loss. Weight gain is associated with an increase in fat and body cell mass.

Untoward reactions that have been reported to occur in patients receiving megestrol include nausea, vomiting, edema, and breakthrough uterine bleeding and occur in approximately 1 to 2% of patients. Gynecomastia and loss of hearing have also been reported. Dyspnea, heart failure, hypertension, hot flashes, mood changes, cushingoid facies, tumor flare (with or without hypercalcemia), hyperglycemia, alopecia, carpal tunnel syndrome and rash have also occurred.

Thromboembolic phenomenon including thrombophlebitis and pulmonary embolism (in some cases fatal) have also been reported.

Laboratory evidence of pituitary-adrenal axis abnormalities has been observed in patients treated with megestrol. Although the significance of these laboratory findings has not been fully established, clinically apparent adrenal insufficiency has been reported to occur rarely in patients shortly after megestrol was discontinued. Patients should be observed for clinical evidence of adrenocortical insufficiency when megestrol is abruptly withdrawn.

In patients with advanced, non-endocrine-sensitive cancer who received doses of megestrol up to 480 mg/day in a clinical trial for anorexia and weight loss, dyspnea, nausea, edema, pain, lethargy and diarrhea were observed commonly. Constipation and urinary frequency also have been reported in patients who received high doses of megestrol in other clinical trials.

In clinical trials involving patients with acquired immune deficiency syndrome receiving megestrol oral suspension, only impotence was reported in at least 5% of patients treated with megestrol.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Usual safety measures as with the overdose of any medication should be instituted. However, no serious unexpected side effects have resulted from studies involving megestrol administered in dosages as high as 1 600 mg/day for 6 months or more. Megestrol 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.

Dosage And Administration: For the following indications, at least 2 months of continuous treatment is considered an adequate period for determining the efficacy of megestrol tablets and oral suspension.

Tablets: Palliative or Adjunctive Treatment of Breast Carcinoma: 160 mg or 125 mg/mdaily (40 mg 4 times a day or 160 mg daily).

Endometrial Carcinoma: 80 to 320 mg or 62.5 to 250 mg/mdaily in divided doses (40 to 80 mg 1 to 4 times daily or one to two 160 mg tablets daily).

Palliative Treatment of Hormone Responsive Advanced (Stage D2) Carcinoma of the Prostate: 120 mg (93.8 mg/m as a single daily dose in combination with diethylstilbestrol tablet, 0.1 mg.

Anorexia, Cachexia, or Significant Weight Loss in Patients with Cancer: Usual adult dose: 400 to 800 mg as a single daily dose.

Oral Suspension: Anorexia, Cachexia, or Significant Weight Loss in Patients with a Diagnosis of Acquired Immunodeficiency Syndrome (AIDS): Usual adult dose: 400 to 800 mg as a single daily dose (10 to 20 mL/day). Ten mL of oral suspension contain 400 mg of megestrol.

Shake container well before use.

Availability And Storage: Tablets: 40 mg: Each light blue, scored tablet contains: megestrol acetate 40 mg. Nonmedicinal ingredients: acacia, cornstarch, dibasic calcium phosphate, FD&C blue No. 1, lactose, magnesium stearate and colloidal silicon dioxide. Tartrazine-free. Bottles of 100.

160 mg: Each white oval, scored, tablet contains: megestrol acetate 160 mg. Nonmedicinal ingredients: lactose, magnesium stearate, microcrystalline cellulose, povidone, colloidal silicon dioxide and sodium starch glycolate. Tartrazine-free. Bottles of 30.

Oral Suspension: Each mL of lemon-lime flavored oral suspension contains: megestrol acetate 40 mg. Nonmedicinal ingredients: anhydrous citric acid, natural and artificial lemon-lime flavor, polyethylene glycol 1 450, polysorbate 80, purified water, sodium benzoate, sodium citrate dihydrate, sucrose and xanthan gum. Bottles of 120, 240 and 480 mL.

Store at room temperature (15 to 30°C). Protect from temperatures above 30°C.

MEGACE® MEGACE® OS Bristol Megestrol Acetate Antineoplastic – Progestogen – Antianorexic – Anticachectic

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