1.1 Limitations of Use

Other Treatable Causes

• Therapy with megestrol acetate 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, renal disease or psychiatric diseases.

Prophylactic Use

• Megestrol acetate is not intended for prophylactic use to avoid weight loss.

4.1 Hypersensitivity Reaction

• History of hypersensitivity to megestrol acetate or any component of the formulation.

4.2 Pregnancy

• Known or suspected pregnancy.

5.1 General

• Effects on HIV viral replication have not been determined.
• Use with caution in patients with a history of thromboembolic disease.

5.2 Fetal Effects

Megestrol acetate may cause fetal harm when administered to a pregnant woman. For animal data on fetal effects, see NonClinical Toxicology: Impairment of Fertility (13.1). 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.

5.3 Adrenal Insufficiency

• The glucocorticoid activity of megestrol acetate oral suspension has not been fully evaluated. Clinical cases of overt Cushing's Syndrome have been reported in association with the chronic use of megestrol acetate. In addition, clinical cases of adrenal insufficiency have been observed in patients receiving or being withdrawn from chronic megestrol acetate therapy in the stressed and non-stressed state.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 acetate therapy. Therefore, the possibility of adrenal insufficiency should be considered in any patient receiving or being withdrawn from chronic Megace® ES therapy who presents with symptoms and/or signs suggestive of hypoadrenalism (e.g., hypotension, nausea, vomiting, dizziness, or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 Megace® ES therapy, consideration should be given to the use of empiric therapy with stress doses of a rapidly acting glucocorticoid during stress or serious intercurrent illness (e.g., surgery, infection).

5.4 Diabetics

• Clinical cases of new onset diabetes mellitus and exacerbation of pre-existing diabetes mellitus have been reported in association with the chronic use of megestrol acetate.

6.1 Serious and Otherwise Important Adverse Reactions

• The following serious reactions and otherwise important adverse drug reactions are discussed in greater detail in other sections of the labeling:
• Hypersensitivity [see Contraindications (4.1)]
• Pregnancy [see Contraindications (4.2)]
• Fetal Effects [see Warnings and Precautions (5.2)]
• Thromboembolic Disease [see Warnings and Precautions (5.1)]
• Adrenal Insufficiency [see Warnings and Precautions (5.3)]

6.2 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of Megace® ES (megestrol acetate oral suspension, 125 mg/mL) was based on three studies of megestrol acetate oral suspension (40 mg/mL). The adverse reaction profile of these 3 studies are presented below.

Adverse events which occurred in at least 5% of patients in any arm of the two clinical efficacy trials and the open trial for megestrol acetate oral suspension are listed below by treatment group. All patients listed had at least one post baseline visit during the 12 study weeks.

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 - abdominal pain, chest pain, infection, moniliasis and sarcoma

Cardiovascular System - cardiomyopathy and palpitation

Digestive System - constipation, dry mouth, hepatomegaly, increased salivation and oral moniliasis

Hemic and Lymphatic System - leukopenia

Metabolic and Nutritional - LDH increased, edema and peripheral edema

Nervous System - paresthesia, confusion, convulsion, depression, neuropathy, hypesthesia and abnormal thinking

Respiratory System - dyspnea, cough, pharyngitis and lung disorder

Skin and Appendages - alopecia, herpes, pruritus, vesiculobullous rash, sweating and skin disorder

Special Senses - amblyopia

Urogenital System - albuminuria, urinary incontinence, urinary tract infection and gynecomastia.

6.3 Postmarketing Experience

• Postmarketing reports associated with megestrol acetate oral suspension include thromboembolic phenomena including thrombophlebitis, deep vein thrombosis, and pulmonary embolism; and glucose intolerance [see Warnings and Precautions (5.1,5.4)].

7.1 Indinavir

• Due to the significant decrease in the exposure of indinavir by megestrol acetate, administration of a higher dose of indinavir should be considered when coadministering with megestrol acetate [See Clinical Pharmacology (12.3)].

7.2 Zidovudine and Rifabutin

• No dosage adjustment for zidovudine and rifabutin is needed when megestrol acetate is coadministered with these drugs [See Clinical Pharmacology (12.3)].

8.1 Pregnancy

• Pregnancy Category X [see Warnings and Precautions (5.2)]. No adequate animal teratology information is available at clinically relevant doses. Pregnant rats treated with low doses of megestrol acetate (0.02-fold the recommended clinical dose) resulted in a reduction in fetal weight and number of live births, and feminization of male fetuses.

8.3 Nursing Mothers

• Because of the potential for adverse effects on the newborn, nursing should be discontinued if Megace® ES oral suspension is required.

8.4 Pediatric Use

• Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

• Clinical studies of megestrol 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.

8.6 Use in Women

Megestrol acetate has had limited use in HIV infected women.

All 10 women in the clinical trials reported breakthrough bleeding. Megace® ES is a progesterone derivative, which may induce vaginal bleeding in women.

12.1 Mechanism of Action

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.

12.3 Pharmacokinetics

13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility

• Data on carcinogenesis were obtained from studies conducted in dogs, monkeys and rats treated with megestrol acetate at doses up to 0.01 to 0.1-fold the recommended clinical dose (13.3 mg/kg/day) based on body mass. 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 Megace® ES oral suspension and in surveillance of patients on therapy.
• Megestrol acetate induced unscheduled DNA synthesis in primary cultures of human hepatocytes, but not in rat hepatocytes. Megestrol administered to mice increased the frequency of sister chromatid exchange and chromosomal aberrations in bone marrow cells after single intraperitonial doses of 16.25 and 32.50 mg/kg. Perinatal/postnatal (segment III) toxicity studies were performed in rats at doses up to 0.02 -fold the recommended clinical dose (13.3 mg/kg/day) based on body mass. In these low dose studies, the reproductive capability of male offspring of megestrol acetate-treated females was impaired. Similar results were obtained in dogs. No toxicity data are currently available on male reproduction (spermatogenesis) [see Warnings and Precautions (5.2)].

13.2 Animal Pharmacology and/or Toxicology

• Long-term treatment with Megace® ES 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.

Trial 1

• 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 2.3 kg or more 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 3.5 kg, the 400 mg MA group by 1.9 kg, the 100 mg MA group by 0.9 kg and decreased in the placebo group by 0.7 kg. Mean weight changes at 4, 8 and 12 weeks for patients evaluable for efficacy in the two clinical trials is 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. 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.

Trial 2

• 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 5.1 kg in the MA-treated group and decreased 1.0 kg 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 Clinical Studies table). 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, T4 counts, T8 counts, or skin reactivity tests [see Adverse Reactions (6)].

Figure 2: Mean Weight Change for Patients Evaluable for Efficacy in Trial 1

Figure 3: Mean Weight Change for Patients Evaluable for Efficacy in Trial 2

16.1 How Supplied

• Megace ES® oral suspension is a milky white, lemon-lime flavored oral suspension containing 125 mg of megestrol acetate per mL. Available in bottles of 150 mL (5 fl oz) NDC 49884-949-69.

16.2 Storage

• Store Megace® ES oral suspension between 15° to 25° C (59° to 77° F) and dispense in a tight container. Protect from heat.

16.3 Safe 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 Precautions (5) and Adverse Reactions (6)]. Women at risk of pregnancy should avoid such exposure.