MEGACE ® (megestrol acetate) 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 17a( 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:

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.

MEGACE (megestrol acetate) 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).

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.

MEGACE ® Oral Suspension is available as a lemon- lime flavored oral suspension containing 40 mg of micronized megestrol acetate per mL.

Storage

Store at 25° C (77° F); excursions permitted to 15° - 30° C (59° - 86° F) [see USP Controlled Room Temperature]. Protect from temperatures above 40° C (104° F).

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.

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 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 included thromboembolic phenomena including thrombophlebitis, pulmonary embolism and glucose intolerance (see WARNINGS and PRECAUTIONS).

Pharmacokinetic studies show that there are no significant alterations in pharmacokinetic parameters of zidovudine or with rifabutin to warrant dosage adjustment when megesterol acetate is administered with these drugs. The effects of zidovudine or rifabutin on the pharmacokinetics of megestrol acetate were not studied.

Megestrol acetate may cause fetal harm when administered to a pregnant woman. For animal data on fetal effects (see

PRECAUTIONS

: 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, and Impairment of Fertility sections)

The glucocorticoid activity of MEGACE Oral Suspension has not been fully evaluated. Clinical cases of new onset diabetes mellitus, exacerbation of pre- existing 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 (e.g., hypotension, nausea, vomiting, dizziness, or weakness) in either the stressed or non-stressed state. Laboratory evaluation for adrenal insufficiency and replacement or stress doses of a rapidly acting glucocorticoid are strongly recommended for 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 or a rapidly acting glucocorticoid in conditions of stress or serious intercurrent illness (e.g., surgery, infection).

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 pre- existing diabetes with increased insulin requirements have been reported in association with the use of MEGACE.

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 two- year chronic toxicity/ carcinogenicity study of megestrol acetate conducted in rats.

Information for the Patients

Patients using megestrol acetate should receive the following instructions:

1. This medication is to be used as directed by the physician.
2. Report any adverse reaction experiences while taking this medication.
3. Use contraception while taking this medication if you are a woman capable of becoming pregnant.
4. Notify your physician if you become pregnant while taking this medication.

Carcinogenesis, Mutagenesis, and 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) lessthan 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

Nursing Mothers

Because of the potential for adverse effects on the newborn, nursing should be discontinued if MEGACE (megestrol acetate) Oral Suspension is required.

Use in HIV- Infected Women: Although megestrol acetate 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 the clinical trials reported breakthrough bleeding.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

No serious unexpected side effects have resulted from studies involving MEGACE Oral Suspension administered in dosages as high as 1200 mg/ day. 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.

History of hypersensitivity to megestrol acetate or any component of the formulation. As a diagnostic test for pregnancy. Known or suspected pregnancy.

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 proof 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 (C_max) of megestrol acetate was 753 (± 539) ng/mL. Mean area under the concentration time-curve (AUC) was 10476 (± 7788) ng x hr/mL. Median T_max 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 C_max and AUC values 490 (± 238) ng/ mL and 6779 (± 3048) hr x ng/ mL, respectively. The median T_max value was three hours. The mean C_min value was 202 (± 101) ng/ mL. The mean % of fluctuation value was 107 (± 40).

The relative bioavailability of MEGACE 40 mg tablets and MEGACE Oral Suspension has not been evaluated. The effect of food on the bioavailability of MEGACE Oral Suspension has not been evaluated.

DESCRIPTION

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 non-water body weight in the MA- treated groups (see Clinical Studies Table below). 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.

The second trial was a multicenter, randomized, double-blind, placebocontrolled 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 below). 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 MAtreated 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).

Patients using megestrol acetate should receive the following instructions:

• This medication is to be used as directed by the physician.
• Report any adverse reaction experiences while taking this medication.
• Use contraception while taking this medication if you are a woman capable of becoming pregnant.
• Notify your physician if you become pregnant while taking this medication.

See also WARNINGS, CONTRAINDICATIONS, PRECAUTIONS.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

MEGESTROL - ORAL

(meh-JESS-troll)

COMMON BRAND NAME(S): Megace

USES: This medication is used to treat cancer of the breast or uterus. It may be used alone or with other treatments, including surgery and radiation, to stop the growth of your tumor.

It may also be used to increase your appetite and to prevent or reverse significant weight loss (e.g., muscle wasting in cancer or AIDS). This can result in an increase in your sense of well-being and your physical ability.

Megestrol is similar to a natural substance made by the body called progesterone. It is not known how megestrol helps appetite or stops tumor growth.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This medication may also be used to treat prostate cancer or certain conditions of the female reproductive system (e.g., endometriosis).

HOW TO USE: Take this medication by mouth, exactly as prescribed by your doctor. Your dosage is based on your medical condition and response to therapy.

Use this medication regularly in order to get the most benefit from it. To help you remember, take it at the same times each day. It may take several weeks of continued use to see a benefit. Inform your doctor if your condition does not improve or if it worsens.

SIDE EFFECTS: This medication can cause weight gain, changes in appetite, stomach upset, diarrhea, gas, trouble sleeping, decreased sexual ability/desire, or fever. Women may experience changes in their menstrual periods, including unpredictable bleeding. If any of these effects persist or worsen, inform your doctor promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these rare but serious side effects occur: fast/pounding heartbeat, headache, swelling of hands/feet, fatigue.

Seek immediate medical attention if any of these rare but very serious side effects occur: chest pain, confusion, mental/mood changes, weakness/numbness on one side of the body, pain/redness/swelling of arms or legs, slurred speech, trouble breathing, severe or sudden vision changes.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking megestrol, tell your doctor or pharmacist if you are allergic to it or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: adrenal gland problems (e.g., Cushing's syndrome), blood clots, congestive heart failure, diabetes, high blood pressure, kidney problems, unusual vaginal bleeding.

High blood sugar (hyperglycemia) and worsening of diabetes may occur. Symptoms of high blood sugar include thirst, increased urination, confusion, drowsiness, flushing, rapid breathing, or fruity breath odor. If these symptoms occur, tell your doctor immediately. People with diabetes should monitor their blood sugar levels more frequently when they start taking this medication and whenever the dose changes since they may need to change their doses of diabetic medications.

This drug may decrease adrenal gland activity. Make sure you tell your doctors and dentists of your megestrol use and when you stopped using it. After stopping this drug, additional corticosteroids (e.g., prednisone or hydrocortisone) may be necessary in stressful situations such as trauma, major surgery or serious infection. Consult your doctor or pharmacist for details. Symptoms of adrenal problems include unusual weakness, dizziness, nausea and rapid weight loss.

Kidney function declines as you grow older. This medication is removed by the kidneys. Therefore, elderly people may be more sensitive to this drug and to its side effects.

This medication must not be used during pregnancy. Megestrol may cause harm to your unborn baby. If you become pregnant or think you may be pregnant, inform your doctor immediately. Women of childbearing age should use an effective form of birth control while using this medication. Consult your doctor for more details.

Megestrol may pass into breast milk and could have undesirable effects on a nursing infant. Therefore, breast-feeding is not recommended while using this drug. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medication because a very serious interaction may occur: dofetilide.

If you are currently using the medication listed above, tell your doctor or pharmacist before starting megestrol.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal medicines you may use, especially of: indinavir, diabetes medication (e.g., glipizide, glyburide, insulin).

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Do not share this medication with others. Make sure you see your doctor regularly to see how well the medication is working and to check for any side effects, including high blood pressure or high blood sugar levels.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store the US product at room temperature at 77 degrees F (25 degrees C). Brief storage between 59 and 86 degrees F (15-30 degrees C) is permitted. Do not expose to temperatures above 104 degrees F (40 degrees C). .

Store the Canadian product at room temperature between 59-86 degrees F (15-30 degrees C).

Store the medication away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA), or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.