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 In addition, clinical cases of adrenal insufficiency have been observed in patients receiving or being withdrawn from chronic MEGACE therapy in the stressed and non-stressed state.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 Therefore, the possibility of adrenal insufficiency should be considered in any patient receiving or being withdrawn from chronic MEGACE therapy who presents with symptoms and/or signs suggestive of hypoadrenalism (e.g., hypotension, nausea, vomiting, dizziness, or weakness)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 Finally, in patients who are receiving or being withdrawn from chronic MEGACE therapy, consideration should be given to the use of empiric therapy with stress doses or a rapidly acting glucocorticoid in conditions of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

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