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PAR PHARM.
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49884028901

megestrol 20 mg tablet

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Uses

Neoplastic Diseases

Megestrol acetate is used in the palliative management of recurrent, inoperable, or metastatic endometrial carcinoma or breast cancer. The drug is also used as an adjunct to surgery or radiation. Megestrol acetate does not replace appropriate methods of treatment of advanced endometrial carcinoma or breast cancer such as surgery or radiation. The drug currently is not recommended for use in other neoplastic diseases, but studies are under way. Beneficial response to therapy has been reported in approximately one-half of patients with recurrent or metastatic adenocarcinoma of the endometrium receiving an adequate course of treatment with megestrol acetate. Objective response as evidenced by a decrease in the size of a soft tissue mass, radiographic evidence of improvement in metastatic lesions, cessation of vaginal bleeding, or decrease in size of fungating vaginal lesions were maintained for a minimum of six months in 27% of he patients studied. Precise evaluation of megestrol acetate effectiveness is difficult, however, because of potential variables and the impracticality of including ''control patients'' in such studies.

Cachexia

Megestrol acetate is used in the management of anorexia, cachexia, or an unexplained, substantial weight loss (i.e., loss of 10% or more of baseline body weight) in patients with acquired immunodeficiency syndrome (AIDS) and has been designated an orphan drug by the US Food and Drug Administration (FDA) for this use. In a multicenter, randomized, double-blind, placebo-controlled study in patients with AIDS, cachexia and/or anorexia, and substantial weight loss, therapy with megestrol acetate 100, 400, or 800 mg daily for 12 weeks resulted in a weight gain of about 0.8, 1.9, or 3.5 kg, respectively, compared with an average weight loss of about 0.7 kg in those receiving placebo. In addition, a weight gain of 2.3 kg or more occurred in about 64 or 57% of patients receiving 800 or 400 mg of megestrol acetate daily, respectively, compared with 24% of those receiving placebo. Weight gain was associated with increases in nonwater body weight; edema developed or worsened in only 3 patients. Increased appetite occurred in about 89, 68, or 72% of patients receiving 800, 400, or 100 mg of megestrol acetate daily, respectively, compared with 50% of those receiving placebo at the last evaluation of the 12-week study; however, a subjective improvement in weight, appetite, appearance, and an overall sense of well-being and increased caloric intake during megestrol therapy was favorably reported only in those receiving 800 mg of megestrol acetate daily compared with those receiving placebo. In another multicenter, randomized, double-blind, placebo-controlled study in patients with AIDS, anorexia and/or cachexia, and substantial weight loss, therapy with 800 mg daily of megestrol acetate resulted in an average weight gain of about 5 kg compared with an average weight loss of about 1 kg in those receiving placebo. Weight gain was associated with increases in nonwater body weight; edema was not reported in any of the patients receiving megestrol therapy. Increased appetite occurred in about 67% of patients receiving megestrol compared with 38% of those receiving placebo; however, daily caloric intake was similar in patients receiving megestrol and those receiving placebo.

Results of other controlled and uncontrolled studies also indicate that megestrol therapy (100-800 mg daily for 2-72 weeks) is associated with weight gain (about 3-7 kg), increased appetite, and an overall sense of well-being in patients with HIV infection and severe anorexia and/or cachexia; no improvement in immunologic function has been observed to date, although some increases (mean increases of 69/ mm) in helper/inducer (CD4) T-cell counts have been reported occasionally. Several treatment failures, however, have been reported in patients receiving up to 640 mg/day of megestrol for the management of anorexia and cachexia associated with HIV infection.

Megestrol acetate also has been used to stimulate appetite and promote weight gain in a limited number of patients with cachexia associated with neoplastic disease. In a large controlled study in patients with anorexia (i.e., an estimated daily caloric intake of less than 20 calories/kg) and/or cachexia (i.e., a weight loss of at least 2.3 kg in the period up to 2 months preceding the study) associated with advanced cancer (excluding endometrial carcinoma and breast cancer), therapy with megestrol acetate (800 mg daily) for a median time of 1.6 months resulted in a weight gain of at least 6.8 kg in 16% of patients compared with 2% of those receiving placebo; in megestrol-treated patients, this weight gain was 10% or more of baseline body weight. Patients receiving megestrol acetate reportedly had a higher incidence of improved appetite and food intake and a lower incidence of nausea and vomiting than those receiving placebo. Some evidence suggests that weight gain occurs in approximately one third of patients with metastatic carcinoma receiving usual dosages of megestrol acetate (160 mg daily) for the treatment of anorexia. However, increased appetite and weight gain (median weight gain of 5.1 kg; range: 0.9-20.1 kg) occurred in nearly all patients who received 6 weeks or more of high-dose (480-1600 mg daily) megestrol therapy for the palliative management of advanced breast cancer. Current evidence suggests that the rate of weight gain in patients with neoplastic disease is not related to antineoplastic response, pretreatment body weight, or extent of disease; however, some, but not all, evidence indicates that megestrol-induced weight gain may be dose-related.

Megestrol therapy generally has been well tolerated by most patients receiving the drug for the management of cachexia, and many patients with HIV infection or neoplastic disease have reported a subjective improvement in their sense of well-being during megestrol therapy. However, hyperpnea reportedly has occurred in at least 2 HIV-infected patients receiving 240 mg of the drug daily.(See Cautions.)Additional studies are necessary to fully establish the safety and efficacy of megestrol for the management of cachexia associated with HIV infection or neoplastic disease, and to determine the optimum dosage of megestrol for these conditions. In addition, some clinicians have mentioned theoretically the possible effects of megestrol's potential glucocorticoid action on HIV and the expression of HIV infection.

Other Uses

Megestrol acetate has been used alone or in combination or sequential regimens with estrogens for ovulation control in the prevention of conception. The drug has also been used in the treatment of prostatic hypertrophy, endometriosis, and endometrial hyperplasia.

Dosage and Administration

Administration

Megestrol acetate is administered orally.

Megestrol acetate oral suspensions containing 200 mg/5 mL are not bioequivalent with the more concentrated oral suspension containing 625 mg/5 mL (Megace ES). Threfore, the formulations are not interchangeable on a mg-per-mg basis. Patients receiving Megace ES should be informed about the formulation differences to avoid overdosing or underdosing of the drug.

Dosage

Breast Cancer

The usual dosage of megestrol acetate in the palliative treatment of advanced breast cancer has been 160 mg daily in 4 equally divided doses, although some clinicians suggest that single daily doses may be justified based on the drug's pharmacokinetics. However, higher dosages (480-1600 mg daily in divided doses) are being evaluated, and the optimum dosage remains to be established.

Dosages substantially higher than usual currently are being investigated for this and other cancers.

Endometrial Carcinoma

The usual dosage of megestrol acetate in the palliative treatment of advanced endometrial carcinoma is 40-320 mg daily administered in divided doses. An adequate trial period for determining the antineoplastic effectiveness of megestrol acetate is 2 months.

Dosages substantially higher than usual currently are being investigated for this and other cancers.

Cachexia

The initial dosage of megestrol acetate in the management of anorexia, cachexia, or an unexplained, substantial weight loss in adults with acquired immunodeficiency syndrome (AIDS) is 800 mg daily. Lower dosages (e.g., 100-400 mg daily) of megestrol acetate also have been used effectively in the management of AIDS-related cachexia.

Alternatively, when the more concentrated (625 mg/5 mL) formulation of megestrol acetate oral suspension is used (Megace ES) in the management of anorexia, cachexia, or an unexplained, substantial weight loss in adults with AIDS, the usual initial dosage is 625 mg daily. Based on clinical experience with the original less concentrated formulation (200 mg/5 mL), clinically effective dosages of the more concentrated formulation (625 mg/5 mL) are expected to range from 312.5-625 mg daily.

For the management of anorexia or cachexia in adults with neoplastic disease, megestrol acetate dosages of 480-600 mg daily generally have been used. However, some patients may exhibit weight gain with dosages as low as 160 mg daily.

Cautions

Megestrol acetate usually is well tolerated. The manufacturer states that no statistically significant differences regarding laboratory abnormalities; new opportunistic infections; lymphocyte, helper/inducer (CD4, T4) T-cell, and suppressor/cytotoxic (CD8, T8) T-cell counts; or skin reactivity have been observed in patients with AIDS-related cachexia who were receiving 100, 400, or 800 mg of megestrol acetate daily for 12 weeks. The manufacturer states that no serious adverse effects have occurred in studies in which megestrol acetate was administered in dosages as high as 800 mg daily.

GI Effects

Adverse GI effects of megestrol occurring in at least 5% of patients include diarrhea, flatulence, nausea, and vomiting. Constipation, dyspepsia, dry mouth, increased salivation, and oral candidiasis have been reported in about 1-4% of patients.

Genitourinary Effects

Impotence and decreased libido have been reported in at least 5% of patients with AIDS-related cachexia receiving megestrol. Urinary frequency, urinary incontinence, and urinary tract infection also have been reported. Vaginal bleeding and discharge (including breakthrough bleeding) have occurred in patients receiving usual dosages of the drug for the palliative management of breast cancer.

Cardiovascular Effects

Hypertension or mild elevation in blood pressure (approximately 10 mm Hg) has been reported in patients receiving high-dose (480-1600 mg daily) megestrol acetate therapy. Cardiomyopathy, palpitation, chest pain, chest pressure, edema, peripheral edema, and congestive heart failure also have been reported. These adverse effects generally were mild in severity, and manifestations such as elevated blood pressure and congestive heart failure reportedly resolved following initiation of diuretic therapy or adjustment of the patient's preexisting antihypertensive regimen.

Respiratory Effects

Pneumonia has been reported in about 2% of patients receiving megestrol acetate for AIDS-related cachexia. Dyspnea, cough, pharyngitis, and lung disorder occurred in about 1-3% of patients receiving megestrol.

Hyperpnea has been reported in at least 2 HIV-infected patients receiving 240 mg of megestrol acetate daily for the management of cachexia. Although the mechanism for this adverse effect has not been clearly established, it was suggested that megestrol, like other progestins, may stimulate respiration, particularly in patients receiving relatively high dosages of the drug.

Nervous System Effects

Insomnia, headache, asthenia, paresthesia, confusion, seizures, depression, neuropathy, hypesthesia, and abnormal thinking have been reported in patients with AIDS-related cachexia receiving megestrol acetate.

Other Adverse Effects

Fever, anemia, leukopenia, hepatomegaly, pain (including abdominal pain), infections, candidiasis, herpes, pruritus, vesiculobullous rash, sweating, skin disorders, amblyopia, increases in LDH, and sarcoma have been reported in patients with AIDS-related cachexia receiving megestrol acetate therapy. Carpal tunnel syndrome, thromboembolic phenomena (e.g., deep-vein thrombophlebitis, pulmonary embolism), gynecomastia, tumor flare (with or without hypercalcemia), hyperglycemia, rash, feeling of coldness, and alopecia also have been reported in patients receiving megestrol therapy. In at least one patient receiving megestrol therapy for AIDS-related cachexia, diabetes mellitus (requiring insulin therapy) was reported.

Weight gain and increased appetite have been reported in some patients receiving usual or higher dosages of megestrol acetate, and some evidence suggests that such effects may be dose-related; these effects generally are considered therapeutic rather than adverse effects in patients with anorexia and cachexia associated with neoplastic disease or HIV infection. (See Pharmacology and also see Uses: Cachexia.)

Precautions and Contraindications

Megestrol acetate therapy for weight loss should be initiated only after treatable causes (e.g., possible malignancies; systemic infections; GI disorders [which may affect absorption]; endocrine, renal, or psychiatric diseases) of the condition have been evaluated. Although the potential glucocorticoid effects of megestrol acetate have not been evaluated in patients with HIV infection, laboratory evidence of megestrol-induced adrenal suppression has been observed; however, it appears to be clinically insignificant. Effects of megestrol acetate on viral replication have not been determined.

Patients should be advised that megestrol acetate should only be used as directed by a clinician, and patients should be advised to report any adverse effects that occur during megestrol acetate therapy to their clinician. Although megestrol acetate has been used extensively in the management of endometrial carcinoma and breast cancer, experience with the drug in women with HIV infection is limited. In one clinical study using megestrol acetate in women with HIV infection, breakthrough bleeding occurred in all patients receiving the drug.

Megestrol acetate is not intended for prophylactic use to avoid weight loss. Megestrol acetate should not be used as a diagnostic test for pregnancy.

Pediatric Precautions

Safety and efficacy of megestrol acetate in children have not been established.

Mutagenicity and Carcinogenicity

Mutagenicity studies of megestrol acetate have not been performed to date.

In female beagles receiving megestrol acetate dosages of 0.01, 0.1, or 0.25 mg/kg daily for 7 years, both benign and malignant breast tumors occurred. No tumors were reported in female monkeys receiving megestrol acetate dosages of 0.01, 0.1, or 0.5 mg/kg daily for 10 years. Pituitary tumors were observed in female rats receiving megestrol acetate dosages of 3.9 or 10 mg/kg daily for 2 years. The relevance of these animal findings to humans has not been established; however, the drug should be used only when the potential benefits justify the possible risks to the patient. It also should be considered that megestrol acetate dosages in these animal studies were 1.3-53.2 times lower than the usual recommended (13.3 mg/kg daily) dosage in humans.

Pregnancy, Fertility, and Lactation

Pregnancy

Although there are no adequate and controlled studies to date using megestrol acetate in pregnant women, the drug has been shown to produce fetal harm in rats. Administration of the drug to rats produced decreases in fetal weight and live births and feminization of male fetuses. No teratogenicity studies in animals have been performed using megestrol acetate dosages that are clinically relevant to humans. Although progestins have been used beginning in the first trimester of pregnancy to prevent habitual abortion, there is no adequate evidence from well-controlled studies to substantiate the efficacy of progestins for these uses during any phase of pregnancy; however, there is evidence of potential adverse effects on the fetus when these drugs are administered during pregnancy. In addition, in most women, the cause of abortion is a defective ovum, which progestins could not be expected to influence. Because of their uterine-relaxant effects, progestins may delay spontaneous abortion of fertilized defective ova. There is evidence of increased risk of hypospadias in male neonates associated with progestin use during pregnancy; however, there are insufficient data about the risk in female fetuses. Because of increased genital abnormalities caused by progestins in both male and female fetuses, the manufacturer states that megestrol acetate is not recommended during pregnancy. If a woman becomes pregnant while receiving megestrol acetate or is inadvertently exposed to the drug during pregnancy, she should notify her physician and should be advised of the potential risks to the fetus. Women of childbearing potential should be advised not to become pregnant while receiving megestrol acetate therapy, and they should be advised to use an effective form of contraception while receiving the drug.

Fertility

Reproduction studies in female rats using megestrol acetate dosages of 0.05-12.5 mg/kg daily (lower than the recommended [13.3 mg/kg daily] dosage in humans) have revealed evidence of impaired fertility in male offspring of mothers receiving megestrol acetate; similar results were obtained in dogs. No information on fertility (spermatogenesis) in male animals receiving megestrol acetate is currently available.

Lactation

The manufacturer states that because of the potential for serious adverse reactions to megestrol acetate in nursing infants, women receiving the drug should discontinue nursing.

Pharmacokinetics

Megestrol acetate appears to be well absorbed from the GI tract. The relative oral bioavailability of megestrol acetate suspensions and tablets has not been evaluated. Plasma megestrol acetate concentrations achieved with a 625-mg dose of the more concentrated oral suspension (Megace ES 625 mg/5 mL) are equivalent to those achieved with an 800-mg dose of the original formulation (200 mg/5 mL) under fed conditions. Peak concentrations and AUC were 54.8 and 43.3% higher, respectively, under fed conditions compared with fasting for the concentrated suspension and were 12.9 and 24.4% higher, respectively, under fed conditions compared with fasting for the original formulation.

Following oral administration of radiolabeled megestrol acetate, peak plasma concentrations of the drug and its metabolites were attained within 1-5 hours. Following daily oral administration of single 800-mg doses of megestrol acetate (as the suspension) for 21 days in cachectic patients with acquired immunodeficiency syndrome (AIDS) who had substantial weight loss (i.e., loss of more than 10% of baseline body weight), steady-state peak plasma megestrol concentrations on day 21 occurred about 5 hours after administration of the drug and averaged 753 ng/mL. Following daily oral administration of single 750-mg doses of megestrol acetate (as the suspension) in patients with asymptomatic human immunodeficiency virus (HIV; formerly HTLV-III/LAV) infection for 14 days, peak plasma megestrol concentrations occurred within 3 hours after administration of the drug and averaged about 490 ng/mL. Megestrol acetate appears to be completely metabolized in the liver to free steroids and glucuronide conjugates of 17α-acetoxy-2α-hydroxy-6-methylpregna-4,6-diene-3,20-dione, 17α-acetoxy-6-hydroxymethylpregna-4,6-diene-3,20-dione, and 17α-acetoxy-2α-hydroxy-6-hydroxymethylpregna-4,6-diene-3,20-dione. The major route of elimination of megestrol appears to be urinary excretion. Following oral administration of 4-90 mg of radiolabeled megestrol acetate, about 66% (range: 57-78%) of the dose was excreted in urine and about 20% (range: 8-30%) of the dose was excreted in feces within 10 days. About 5-8% of a dose is excreted in urine as identified metabolites.

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