GENERAL PRECAUTIONS SECTION.

General Therapy with megestrol acetate 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 history of thromboembolic disease.

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS To report SUSPECTED ADVERSE REACTIONS, contact Hi-Tech Pharmacal Co., Inc. at 1-800-262-9010 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 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 megestrol acetate oral suspension.ADVERSE EVENTS% of Patients ReportingMegestrol Acetate, mg/dayNo. of PatientsTrial 1(N=236)Placebo 100 400 800 N=34 N=68 N=69 N=65Trial 2(N=87)Placebo 800 N=38 N=49Open Label Trial1200N=176DiarrheaImpotenceRashFlatulenceHypertensionAstheniaInsomniaNauseaAnemiaFeverLibido DecreasedDyspepsiaHyperglycemiaHeadachePainVomitingPneumoniaUrinary Frequency 15 13 15 4 14 9 12 0 9 0 8 2 6 3 6 4 5 3 5 6 5 4 5 0 3 0 3 10 3 0 2 3 2 2 2 0 2 6NaN4 2 10NaN0 4NaN0 4NaN0 2NaN2 4NaN0 0 6 6 0 21076645150112334411Adverse 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 Whole: abdominal pain, chest pain, infection, moniliasis and sarcomaCardiovascular System: cardiomyopathy and palpitationDigestive System: constipation, dry mouth, hepatomegaly, increased salivation and oral moniliasisHemic and Lymphatic System: leukopeniaMetabolic and Nutritional: LDH increased, edema and peripheral edemaNervous System: paresthesia, confusion, convulsion, depression, neuropathy, hypesthesia and abnormal thinkingRespiratory System: dyspnea, cough, pharyngitis and lung disorderSkin and Appendages: alopecia, herpes, pruritus, vesiculobullous rash, sweating and skin disorderSpecial Senses: amblyopiaUrogenital System: albuminuria, urinary incontinence, urinary tract infection and gynecomastia. NaN4. 2. 10. NaN0. 4. NaN0. 4. NaN0. 2. NaN2. 4. NaN0. 0. 6. 6. 0. 2. Postmarketing Postmarketing reports associated with megestrol acetate oral suspension include thromboembolic phenomena including thrombophlebitis and pulmonary embolism, and glucose intolerance (see WARNINGS and PRECAUTIONS).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility CarcinogenesisData 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 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 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 megestrol acetate oral suspension and in surveillance of patients on therapy. (See WARNINGS.)MutagenesisNo mutagenesis data are currently available.Impairment of FertilityPerinatal/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 reduction in fetal weight and number of live births, and feminization of male fetuses. No toxicity data are currently available on male reproduction (spermatogenesis).

CLINICAL PHARMACOLOGY SECTION.

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 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 megestrol acetate 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 megestrol acetate oral suspension. The treatment was administered for 14 days. Mean Cmax and AUC values were 490 (+-238) ng/mL and 6779 (+-3048) hr ng/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 megestrol acetate oral suspension has not been evaluated.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS History of hypersensitivity to megestrol acetate or any component of the formulation. Known or suspected pregnancy.

DESCRIPTION SECTION.

DESCRIPTION Megestrol Acetate Oral Suspension, USP contains megestrol acetate, synthetic derivative of the naturally occurring steroid hormone, progesterone. Megestrol acetate is white, crystalline solid chemically designated as 17-(acetyloxy)-6-methylpregna-4,6-diene-3,20-dione. Solubility at 37C in water is ug per mL, solubility in plasma is 24 ug per mL. Its molecular weight is 384.51.The empirical formula is C24H32O4 and the structural formula is represented as follows:megestrol acetate, USPMegestrol acetate oral suspension is supplied as an oral suspension containing 40 mg of micronized megestrol acetate per mL.Megestrol acetate oral suspension contains the following inactive ingredients: citric acid, natural and artificial lemon-lime flavor, polyethylene glycol, polysorbate 80, purified water, sodium benzoate, sodium citrate, sucrose, and xanthan gum.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION The recommended adult initial dosage of megestrol acetate 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 in the 240 mL carton.

DRUG INTERACTIONS SECTION.

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.Megestrol acetate may interact with warfarin and increase International Normalized Ratio (INR). Closely monitor INR in patients taking megestrol acetate and warfarin.

GERIATRIC USE SECTION.

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.

HOW SUPPLIED SECTION.

HOW SUPPLIED Megestrol Acetate Oral Suspension, USP is available as milky white, lemon-lime flavored oral suspension containing 40 mg of micronized megestrol acetate per mL. It is available as follows:Bottles of 240 mL (8 fl. oz.) ..................NDC 50383-859-2410 mL unit dose in trays of ten cups .........NDC 50383-859-10Case of 40 ........................................NDC 50383-859-11Case of 100 .......................................NDC 50383-859-1220 mL unit dose in trays of ten cups ...........NDC 50383-859-20Case of 40 .........................................NDC 50383-859-21Case of 100 .......................................NDC 50383-859-22.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE Megestrol acetate oral suspension is indicated for the treatment of anorexia, cachexia, or an unexplained, significant weight loss in patients with diagnosis of acquired immunodeficiency syndrome (AIDS).

INFORMATION FOR PATIENTS SECTION.

Information for 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 woman capable of becoming pregnant. 4) Notify your physician if you become pregnant while taking this medication.

NURSING MOTHERS SECTION.

Nursing Mothers Because of the potential for adverse effects on the newborn, nursing should be discontinued if megestrol acetate oral suspension is required.. Use in Women Breakthrough bleeding was observed in all 10 female patients participating in the clinical trials. Megestrol acetate is progesterone derivative, which may induce vaginal bleeding in women.

OVERDOSAGE SECTION.

OVERDOSAGE 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 megestrol acetate 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Package/Label Display Panel AKORNNDC 50383-859-24Megestrol Acetate Oral Suspension, USP 40 mg/mLShake well immediately before dosing.Dosage cup included.Rx only240 mL (8 fl. oz.). Carton.

PEDIATRIC USE SECTION.

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

PRECAUTIONS SECTION.

PRECAUTIONS General Therapy with megestrol acetate 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 history of thromboembolic disease.. Use in Diabetics Exacerbation of preexisting diabetes with increased insulin requirements has been reported in association with the use of megestrol acetate.. Information for 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 woman capable of becoming pregnant. 4) Notify your physician if you become pregnant while taking this medication.. 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.Megestrol acetate may interact with warfarin and increase International Normalized Ratio (INR). Closely monitor INR in patients taking megestrol acetate and warfarin.. Animal Toxicology Long-term treatment with megestrol acetate may increase the risk of respiratory infections. trend toward increased frequency of respiratory infections, decreased lymphocyte counts, and increased neutrophil counts was observed in 2-year chronic toxicity/carcinogenicity study of megestrol acetate conducted in rats.. Carcinogenesis, Mutagenesis, Impairment of Fertility CarcinogenesisData 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 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 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 megestrol acetate oral suspension and in surveillance of patients on therapy. (See WARNINGS.)MutagenesisNo mutagenesis data are currently available.Impairment of FertilityPerinatal/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 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 megestrol acetate oral suspension is required.. Use in Women Breakthrough bleeding was observed in all 10 female patients participating in the clinical trials. Megestrol acetate is 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 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.

PREGNANCY SECTION.

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.

WARNINGS SECTION.

WARNINGS Megestrol acetate may cause fetal harm when administered to 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 megestrol acetate oral suspension, USP has not been fully evaluated. Clinical cases of new onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and overt Cushings 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 megestrol acetate 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 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 megestrol acetate therapy, consideration should be given to the use of empiric therapy with stress doses of rapidly acting glucocorticoid in conditions of stress or serious intercurrent illness (e.g., surgery, infection).