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CLINICAL PHARMACOLOGY 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. Pharmacokinetics Absorption And Distribution Mean plasma concentrations of megestrol acetate after administration of 625 mg (125 mg/mL) of Megace® ES oral suspension are equivalent under fed conditions to 800 mg (40 mg/mL) of megestrol acetate oral suspension in healthy volunteers. In order to characterize the dose proportionality of Megace® ES, pharmacokinetic studies across a range of doses were conducted when administered under fasting and fed conditions. Pharmacokinetics of megestrol acetate was linear in the dosing range between 150 mg and 675 mg after Megace® ES administration regardless of meal condition. The mean peak plasma concentration (Cmax) and the mean area under the concentration time-curve (AUC) after a high fat meal were increased by 48% and 36%, respectively, compared to those under the fasting condition after 625 mg Megace® ES administration. This food effect is less than that seen for the original formulation, megestrol acetate 800 mg/20 mL, where a high fat meal significantly increased AUC and Cmax of megestrol acetate to 2-fold and 7-fold, respectively, compared to those under the fasting condition. There was no difference in safety following administration in the fed state, therefore Megace® ES could be taken without regard to meals. Plasma steady state pharmacokinetics of megestrol acetate was evaluated in 10 adult, cachectic male adult patients with acquired immunodeficiency syndrome (AIDS) and an involuntary weight loss greater than 10% of baseline who received single oral doses of 800 mg/day of megestrol acetate oral suspension for 21 days. The Mean (±1SD) Cmax of megestrol acetate was 753 (±539) ng/mL. The mean AUC was 10476 (±7788) ng x hr/mL. Median Tmax value was five hours. In another study, 24 asymptomatic HIV seropositive male adult subjects were dosed once daily with 750 mg of megestrol acetate oral suspension for 14 days. Mean Cmax and AUC values were 490 (±238) ng/mL and 6779 (±3048) hr x ng/mL, respectively. The median Tmax value was three hours. The mean Cmjn value was 202 (±101) ng/mL. The mean % of fluctuation value was 107 (±40). Metabolism And Excretion The major route of drug elimination in humans is urine. When radio-labeled 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%). Megestrol acetate metabolites which were identified in urine constituted 5% to 8% of the dose administered. Respiratory excretion as labeled carbon dioxide and fat storage may have accounted for at least part of the radioactivity not found in urine and feces. The mean elimination half-life of megestrol ranged from 20 to 50 hours in healthy subjects. Specific Populations The pharmacokinetics of megestrol acetate has not been studied in specific population, for example, pediatric, renal impairment, and hepatic impairment. Drug Interactions The effects of indinavir, zidovudine or rifabutin on the pharmacokinetics of megestrol acetate were not studied. Zidovudine Pharmacokinetic studies show that there are no significant alterations in exposure of zidovudine when megestrol acetate is administered with this drug. Rifabutin Pharmacokinetic studies show that there are no significant alterations in exposure of rifabutin when megestrol acetate is administered with this drug. Indinavir A pharmacokinetic study in healthy male subjects demonstrated that coadministration of megestrol acetate (675 mg for 14 days) and indinavir (single dose 800 mg) results in a significant decrease in the pharmacokinetic parameters (~32% for Cmax and ~21% for AUC) of indinavir. 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. Clinical Studies The efficacy of Megace® ES (megestrol acetate oral suspension, 125 mg/mL) was based on two trials of megestrol acetate oral suspension (40 mg/mL). These two trials are described below. 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%) MAtreated 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 w ere 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 nonwater 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]. Table 2: Megestrol Acetate Oral Suspension Clinical Efficacy Trials Megestrol Acetate Oral Suspension Clinical Efficacy Trials Trial 1 - Study Accrual Dates 11/88 to 12/90 Trial 2 - Study Accrual Dates 5/89 to 4/91 Megestrol Acetate, mg/day 0 100 400 800 0 800 Entered Patients 38 82 75 75 48 52 Evaluable Patients 28 61 53 53 29 36 Mean Change in Weight (kg) Baseline to 12 Weeks 0.0 1.3 4.2 4.9 -1.0 5.1 % Patients ≥ 2.3 kg Gain at Last Evaluation in 12 Weeks 21 44 57 64 28 47 Mean Changes in Body Composition*: Fat Body Mass (kg) 0.0 1.0 1.3 2.5 0.7 2.6 Lean Body Mass (kg) -0.8 -0.1 0.7 1.1 -0.7 -0.3 Water (liters) -1.3 -0.3 0.0 0.0 -0.1 -0.1 % Patients With Improved Appetite: At Time of Maximum Weight Change 50 72 72 93 48 69 At Last Evaluation in 12 Weeks 50 72 68 89 38 67 Mean Change in Daily Caloric Intake: Baseline to Time of Maximum Weight Change -107 326 308 646 30 464 *Based on bioelectrical impedance analysis determinations at last evaluation in 12 weeks. 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

CLINICAL PHARMACOLOGY 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. There are several analytical methods used to estimate megestrol acetate plasma concentrations, including gas chromatography-mass fragmentography (GC-MF), high pressure liquid chromatography (HPLC), and radioimmunoassay (RIA). The GC-MF and HPLC methods are specific for megestrol acetate and yield equivalent concentrations. The RIA method reacts to megestrol acetate metabolites and is, therefore, non-specific and indicates higher concentrations than the GC-MF and HPLC methods. Plasma concentrations 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. The major route of drug elimination in humans is 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%). Megestrol acetate metabolites which were identified in urine constituted 5% to 8% of the dose administered. Respiratory excretion as labeled carbon dioxide and fat storage may have accounted for at least part of the radioactivity not found in urine and feces. Plasma steady-state pharmacokinetics of megestrol acetate were evaluated in 10 adult, cachectic male patients with acquired immunodeficiency syndrome (AIDS) and an involuntary weight loss greater than 10% of baseline. Patients received single oral doses of 800 mg/day of MEGACE Oral Suspension for 21 days. Plasma concentration data obtained on day 21 were evaluated for up to 48 hours past the last dose. Mean (±1SD) peak plasma concentration (Cmax) of megestrol acetate was 753 (±539) ng/mL. Mean area under the concentration-time-curve (AUC) was 10476 (±7788) ng × hr/mL. Median Tmax value was five hours. Seven of 10 patients gained weight in three weeks. Additionally, 24 adult, asymptomatic HIV seropositive male subjects were dosed once daily with 750 mg of MEGACE Oral Suspension. The treatment was administered for 14 days. Mean Cmax and AUC values were 490 (±238) ng/mL and 6779 (±3048) ng × hr/mL respectively. The median Tmax value was three hours. The mean Cmin value was 202 (±101) ng/mL. The mean percent of fluctuation value was 107 (±40). The effect of food on the bioavailability of MEGACE Oral Suspension has not been evaluated. Description Of Clinical Studies The clinical efficacy of MEGACE Oral Suspension was assessed in two clinical trials. 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 five or more pounds 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 7.8 pounds, the 400 mg MA group by 4.2 pounds, the 100 mg MA group by 1.9 pounds, and decreased in the placebo group by 1.6 pounds. Mean weight changes at 4, 8, and 12 weeks for patients evaluable for efficacy in the two clinical trials are shown graphically. Changes in body composition during the 12 study weeks as measured by bioelectrical impedance analysis showed increases in nonwater body weight in the MA-treated groups (see Clinical Studies table). 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 MAtreated 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. 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 11.2 pounds in the MA-treated group and decreased 2.1 pounds 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). MEGACE (megestrol acetate, USP) Oral Suspension Clinical Efficacy Trials Trial 1 Study Accrual Dates 11/88 to 12/90 Trial 2 Study Accrual Dates 5/89 to 4/91 Megestrol Acetate, mg/day 0 100 400 800 0 800 Entered Patients 38 82 75 75 48 52 Evaluable Patients 28 61 53 53 29 36 Mean Change in Weight (lb.) Baseline to 12 Weeks 0.0 2.9 9.3 10.7 -2.1 11.2 % Patients > 5-Pound Gain at Last Evaluation in 12 Weeks 21 44 57 64 28 47 Mean Changes in Body Composition* Fat Body Mass (lb.) 0.0 2.2 2.9 5.5 1.5 5.7 Lean Body Mass (lb.) -1.7 -0.3 1.5 2.5 -1.6 -0.6 Water (liters) -1.3 -0.3 0.0 0.0 -0.1 -0.1 % Patients With Improved Appetite At Time of Maximum Wt. Change At Last Evaluation in 12 50 72 72 93 48 69 Weeks 50 72 68 89 38 67 Mean Change in Daily Caloric Intake: Baseline to Time of Maximum Weight Change -107 326 308 646 30 464 * Based on bioelectrical impedance analysis determinations at last evaluation in 12 weeks Presented below are the results of mean weight changes for patients evaluable for efficacy in Trials 1 and 2. Animal Toxicology Long-term treatment with MEGACE 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 2-year chronic toxicity/carcinogenicity study of megestrol acetate conducted in rats.

Find Lowest Prices on Megace® ES (megestrol acetate) Oral Suspension DESCRIPTION Megace® ES oral suspension contains megestrol acetate, a synthetic derivative of the naturally occurring steroid hormone, progesterone. Megestrol acetate is a white, crystalline solid chemically designated as 17-Hydroxy-6-methyl pregna-4,6-diene-3,20-dione acetate. Solubility at 37° C in water is 2 mcg per mL, solubility in plasma is 24 mcg per mL. Its molecular weight is 384.52. The chemical formula is C24 H32 O4 and the structural formula is represented as follows: Figure 1: Megestrol Acetate Chemical Structure Megace® ES is an oral suspension containing 125  mg of megestrol acetate per mL. Megace® ES oral suspension contains the following inactive ingredients: alcohol (max 0.06% v/v from flavor), artificial lime flavor, citric acid monohydrate, docusate sodium, hydroxypropyl methylcellulose (hypromellose), natural and artificial lemon flavor, purified water, sodium benzoate, sodium citrate dihydrate, and sucrose.

Find Lowest Prices on Megace® (megestrol acetate, USP) Oral Suspension DESCRIPTION MEGACE® (megestrol acetate, USP) Oral Suspension contains megestrol acetate, a synthetic derivative of the naturally occurring steroid hormone, progesterone. 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 μg per mL, solubility in plasma is 24 μg per mL. Its molecular weight is 384.51. The empirical formula is C24H32O4 and the structural formula is represented as follows: megestrol acetate, USP MEGACE Oral Suspension is supplied as an oral suspension containing 40 mg of micronized megestrol acetate per mL. MEGACE Oral Suspension contains the following inactive ingredients: alcohol (max. 0.06% v/v from flavor), citric acid, lemon-lime flavor, polyethylene glycol, polysorbate 80, purified water, sodium benzoate, sodium citrate, sucrose, and xanthan gum.

INDICATIONS Megace® ES oral suspension is indicated for the treatment of anorexia, cachexia, or an unexplained significant weight loss in patients with a diagnosis of acquired immunodeficiency syndrome (AIDS). 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. DOSAGE AND ADMINISTRATION The recommended adult initial dosage of Megace® ES oral suspension is 625 mg/day (5 mL/day or one teaspoon daily). Shake the container well before using. This strength (125 mg/mL) is not substitutable with other strengths (e.g., 40 mg/mL). Refer to the prescribing information of the 40 mg/mL product for dosage recommendations for the 40 mg/mL strength. HOW SUPPLIED Dosage Forms And Strengths Megace® ES is a milky white, lemon-lime flavored oral suspension containing 125 mg of megestrol acetate per mL. Megace® ES does not contain the same amount of megestrol acetate as Megace® oral suspension or any of the other megestrol acetate oral suspensions. Storage And Handling 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 -94969. Storage Store Megace® ES oral suspension between 15° to 25° C (59° to 77° F) and dispense in a tight container. Protect from heat. 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 and ADVERSE REACTIONS]. Women at risk of pregnancy should avoid such exposure. Manufactured by: PAR PHARMACEUTICAL COMPANIES, INC., Spring Valley, New York 10977. Revised: Mar 2014.

INDICATIONS MEGACE Oral Suspension is indicated for the treatment of anorexia, cachexia, or an unexplained, significant weight loss in patients with a diagnosis of acquired immunodeficiency syndrome (AIDS). DOSAGE AND ADMINISTRATION The recommended adult initial dosage of MEGACE Oral Suspension is 800 mg/day (20 mL/day). Shake container well before using. In clinical trials evaluating different dose schedules, daily doses of 400 and 800 mg/day were found to be clinically effective. A plastic dosage cup with 10 mL and 20 mL markings is provided for convenience. HOW SUPPLIED MEGACE® (megestrol acetate, USP) Oral Suspension is available as a lemon-lime flavored oral suspension containing 40 mg of micronized megestrol acetate per mL. NDC 0015-0508-42 Bottles of 240 mL (8 fl. oz.) Storage Store MEGACE Oral Suspension between 15°C-25°C (59°F-77°F) and dispense in a tight container. Protect from heat. 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). Women at risk of pregnancy should avoid such exposure. Distributed by: Bristol-Myers Squibb Company, Princeton, New Jersey 08543 USA. Revised: May 2016

OVERDOSE No serious unexpected side effects have resulted from studies involving megestrol acetate oral suspension administered in dosages as high as 1200 mg/day. In post-marketing experience, limited reports of overdose have been received. Signs and symptoms reported in the context of overdose included diarrhea, nausea, abdominal pain, shortness of breath, cough, unsteady gait, listlessness, and chest pain. There is no specific antidote for overdose with Megace® ES oral suspension. In case of overdose, appropriate supportive measures should be taken. Megestrol acetate 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. CONTRAINDICATIONS Hypersensitivity Reaction History of hypersensitivity to megestrol acetate or any component of the formulation. Pregnancy Known or suspected pregnancy.

OVERDOSE No serious unexpected side effects have resulted from studies involving MEGACE Oral Suspension administered in dosages as high as 1200 mg/day. In post-marketing experience, limited reports of overdose have been received. Signs and symptoms reported in the context of overdose included diarrhea, nausea, abdominal pain, shortness of breath, cough, unsteady gait, listlessness, and chest pain. There is no specific antidote for overdose with MEGACE Oral Suspension. In case of overdose, appropriate supportive measures should be taken. Megestrol acetate 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. CONTRAINDICATIONS History of hypersensitivity to megestrol acetate or any component of the formulation. Known or suspected pregnancy.

SIDE EFFECTS 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] Pregnancy [see CONTRAINDICATIONS] Fetal Effects [see WARNINGS AND PRECAUTIONS] Thromboembolic Disease [see WARNINGS AND PRECAUTIONS] Adrenal Insufficiency [see WARNINGS AND PRECAUTIONS] 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 1 2 study weeks. Table 1: Adverse Events Percentage of Patients Reporting Adverse Events Trial 1 (N=236) Trial 2 (N=87) Open Label Trial Placebo Placebo Megestrol Acetate mg/day 0 100 400 800 0 800 1200 No. of Patients N—34 N—68 N—69 N—65 N—38 N—49 N—176 Diarrhea 15 13 8 15 8 6 10 Impotence 3 4 6 14 0 4 7 Rash 9 9 4 12 3 2 6 Flatulence 9 0 1 9 3 10 6 Hypertension 0 0 0 8 0 0 4 Asthenia 3 2 3 6 8 4 5 Insomnia 0 3 4 6 0 0 1 Nausea 9 4 0 5 3 4 5 Anemia 6 3 3 5 0 0 0 Fever 3 6 4 5 3 2 1 Libido Decreased 3 4 0 5 0 2 1 Dyspepsia 0 0 3 3 5 4 2 Hyperglycemia 3 0 6 3 0 0 3 Headache 6 10 1 3 3 0 3 Pain 6 0 0 2 5 6 4 Vomiting 9 3 0 2 3 6 4 Pneumonia 6 2 0 2 3 0 1 Urinary Frequency 0 0 1 2 5 2 1 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 1 2 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. 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]. DRUG INTERACTIONS 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]. Zidovudine And Rifabutin No dosage adjustment for zidovudine and rifabutin is needed when megestrol acetate is coadministered with these drugs [See CLINICAL PHARMACOLOGY].

SIDE EFFECTS Clinical Adverse Events Adverse events which occurred in at least 5% of patients in any arm of the two clinical efficacy trials and the open trial are listed below by treatment group. All patients listed had at least one post baseline visit during the 12 study weeks. These adverse events should be considered by the physician when prescribing MEGACE Oral Suspension. ADVERSE EVENTS Megestrol Acetate, mg/day No. of Patients T rial 1 (N=236) Trial 2 (N=87) Open Label Trial Placebo 0 N=34 100 N=68 400 N=69 800 N=65 Placebo 0 N=38 800 N=49 1200 N=176 Diarrhea 15 13 8 15 8 6 10 Impotence 3 4 6 14 0 4 7 Rash 9 9 4 12 3 2 6 Flatulence 9 0 1 9 3 10 6 Hypertension 0 0 0 8 0 0 4 Asthenia 3 2 3 6 8 4 5 Insomnia 0 3 4 6 0 0 1 Nausea 9 4 0 5 3 4 5 Anemia 6 3 3 5 0 0 0 Fever 3 6 4 5 3 2 1 Libido Decreased 3 4 0 5 0 2 1 Dyspepsia 0 0 3 3 5 4 2 Hyperglycemia 3 0 6 3 0 0 3 Headache 6 10 1 3 3 0 3 Pain 6 0 0 2 5 6 4 Vomiting 9 3 0 2 3 6 4 Pneumonia 6 2 0 2 3 0 1 Urinary Frequency 0 0 1 2 5 2 1 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 Postmarketing Postmarketing reports associated with MEGACE Oral Suspension include thromboembolic phenomena including thrombophlebitis and pulmonary embolism, and glucose intolerance (see WARNINGS AND PRECAUTIONS). DRUG INTERACTIONS Pharmacokinetic studies show that there are no significant alterations in pharmacokinetic parameters of zidovudine or rifabutin to warrant dosage adjustment when megestrol acetate is administered with these drugs. The effects of zidovudine or rifabutin on the pharmacokinetics of megestrol acetate were not studied.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS General Effects on HIV viral replication have not been determined. Use with caution in patients with a history of thromboembolic disease. 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. There are no adequate and wellcontrolled 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. 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). 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. Nonclinical Toxicology 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]. Use In Specific Populations Pregnancy Pregnancy Category X [see WARNINGS AND PRECAUTIONS]. No adequate animal teratology information is available at clinically relevant doses. Pregnant rats treated with low doses of megestrol acetate (0 .0 2 -fold the recommended clinical dose) resulted in a reduction in fetal weight and number of live births, and feminization of male fetuses. Nursing Mothers Because of the potential for adverse effects on the newborn, nursing should be discontinued if Megace® ES oral suspension is required. Pediatric Use Safety and effectiveness in pediatric patients have not been established. 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. 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.

WARNINGS Megestrol acetate may cause fetal harm when administered to a pregnant woman. For animal data on fetal effects, see PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility: Impairment of Fertility. 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. Megestrol acetate is not intended for prophylactic use to avoid weight loss. (See also PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility.) The glucocorticoid activity of MEGACE (megestrol acetate, USP) Oral Suspension has not been fully evaluated. Clinical cases of new onset diabetes mellitus, exacerbation of preexisting 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 (eg, 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 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 (eg, surgery, infection). PRECAUTIONS General Therapy with MEGACE Oral Suspension 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, and renal or psychiatric diseases. Effects on HIV viral replication have not been determined. Use with caution in patients with a history of thromboembolic disease. Use In Diabetics Exacerbation of preexisting diabetes with increased insulin requirements has been reported in association with the use of MEGACE. Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenesis Data on carcinogenesis were obtained from studies conducted in dogs, monkeys, and rats treated with megestrol acetate at doses 53.2, 26.6, and 1.3 times lower than the proposed dose (13.3 mg/kg/day) for humans. 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 Oral Suspension and in surveillance of patients on therapy. (See WARNINGS.) Mutagenesis No mutagenesis data are currently available. Impairment Of Fertility Perinatal/postnatal (segment III) toxicity studies were performed in rats at doses (0.05–12.5 mg/kg) less than that indicated for humans (13.3 mg/kg); in these low dose studies, the reproductive capability of male offspring of megestrol acetate-treated females was impaired. Similar results were obtained in dogs. Pregnant rats treated with megestrol acetate showed a reduction in fetal weight and number of live births, and feminization of male fetuses. No toxicity data are currently available on male reproduction (spermatogenesis). Pregnancy Pregnancy Category X. (See WARNINGS and PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility: Impairment of Fertility.) No adequate animal teratology information is available at clinically relevant doses. Nursing Mothers Because of the potential for adverse effects on the newborn, nursing should be discontinued if MEGACE Oral Suspension is required. Use In Women Breakthrough bleeding was observed in all 10 female patients participating in the clinical trials. Megace is a progesterone derivative, which may induce vaginal bleeding in women. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of MEGACE 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.