Megestrol Acetate 400 mg/10mL Suspension — NDC 0904-7577-18 (Billing 00904-7577-18)

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, and Impairment of Fertility .) The glucocorticoid activity of megestrol acetate 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 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 In addition, clinical cases of adrenal insufficiency have been observed in patients receiving or being withdrawn from chronic megestrol acetate therapy in the stressed and non-stressed state.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 revealedthe 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 Therefore, the possibility of adrenal insufficiency should be considered in any patient receiving or being withdrawn from chronic megestrol acetate therapy who presents with symptoms and/or signs suggestive of hypoadrenalism (e.g., hypotension, nausea, vomiting, dizziness, or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 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 Finally, in patients who are receiving or being withdrawn from chronic megestrol acetate therapy, consideration should be given to the use of empiric therapy with stress doses of a rapidly acting glucocorticoid in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 (e.g., surgery, infection).

ADVERSE REACTIONS 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 Reporting Trial 1 (N = 236) Trail 2 (N=87) Open Label Trial Megestrol Acetate mg/day No. of Patients 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 megestrol acetate oral suspension include thromboembolic phenomena including thrombophlebitis and pulmonary embolism and glucose intolerance (see WARNINGS and PRECAUTIONS ).

To report SUSPECTED ADVERSE REACTIONS, contact PAI Pharma at 1-800-845-8210 or FDA at 1-800-FDA-1088 or www.fds.gov/medwatch .

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.

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 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 megestrol acetate. Information for Patients 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.

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. 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.

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 megestrol acetate 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 to 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 No adequate animal teratology information is available at clinically relevant doses.

(See WARNINGS and PRECAUTIONS: Carcinogenesis, Mutagenesis, and Impairment of Fertility: Impairment of Fertility .) 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 oral suspension is a progesterone deriv… [Excerpted — this section continues on DailyMed.]