Health and Prostate

Drug Approvals

(BANM, US Adopted Name, rINNM)

Pharmacopoeias. In China, Europe, and US.

European Pharmacopoeia, 6th ed. (Megestrol Acetate). A white or almost white crystalline powder. Practically insoluble in water sparingly soluble in alcohol soluble in acetone. Protect from light.

The United States Pharmacopeia 31, 2008 (Megestrol Acetate). A white to creamy-white, essentially odourless, crystalline powder. Insoluble in water sparingly soluble in alcohol soluble in acetone very soluble in chloroform slightly soluble in ether and in fixed oils. Protect from light.

Adverse Effects and Precautions

As for progestogens in general (see Progesterone). The weight gain that may occur with megestrol acetate appears to be associated with an increased appetite and food intake rather than with fluid retention. Megestrol acetate may have glucocorticoid effects when given long term.

Effects on carbohydrate metabolism. Megestrol therapy has been associated with hyperglycaemia or diabetes mellitus in AIDS patients being treated for cachexia. It has been suggested that megestrol produces peripheral insulin resistance due to a glucocorticoid action.

Effects on the musculoskeletal system. Severe pain of the hands similar to carpal tunnel syndrome occurred in 4 women while taking megestrol acetate and melphalan megestrol appeared to be responsible.

Osteoporosis and vertebral compression fractures occurred in 2 postmenopausal women taking megestrol for anorexia. In both cases there was evidence of adrenocortical insufficiency that recovered after megestrol therapy was stopped, suggesting that the glucocorticoid effect of megestrol may have contributed to the development of osteoporosis.

Effects on the respiratory system. Hyperpnoea occurred in 2 patients given megestrol acetate 80 mg three times daily.

Glucocorticoid effects. Megestrol has glucocorticoid-like properties that can cause adrenocortical suppression in a significant number of patients. There are also reports of adrenal insufficiency severe enough to require replacement therapy with hydrocortisone.

Porphyria. Megestrol is considered to be unsafe in patients with porphyria because it has been shown to be porphyrinogenic in animals.

Interactions

As for progestogens in general (see Progesterone).

Pharmacokinetics

Megestrol acetate is absorbed from the gastrointestinal tract and peak plasma concentrations occur 1 to 3 hours after an oral dose. Megestrol acetate is highly protein bound in plasma. It undergoes hepatic metabolism, with 57 to 78% of a dose being excreted in the urine and 8 to 30% in the faeces.

Uses and Administration

Megestrol acetate is a progestogen structurally related to progesterone.

It is used for the palliative treatment of some hormone-dependent malignant neoplasms (see below). Oral doses of 40 to 320 mg daily in divided doses may be given in endometrial carcinoma, and doses of 40 mg four times daily or 160 mg once daily may be used in breast cancer.

Megestrol acetate is also used in the treatment of anorexia and cachexia (see below) in patients with cancer or AIDS. The usual dose is 400 to 800 mg daily, as tablets or oral suspension. A suspension of megestrol acetate that has an increased bioavailability is also available (Megace ES Par Pharmaceutical, USA) and is given in a dose of 625 mg in 5 mL daily for anorexia, cachexia, or unexplained significant weight loss in patients with AIDS.

Cachexia. In some patients with severe chronic disorders or malignant neoplasms, anorexia (loss of appetite) forms part of a syndrome of metabolic abnormalities and progressive physical wasting known as cachexia. Improved nutrition and dietary counselling are usually insufficient to reverse cachexia, and drug therapy has been tried to stimulate appetite and promote weight gam.

In cancer-related cachexia, corticosteroids are frequently used for appetite stimulation in patients with advanced malignancies, although they do not appear to promote weight gain. However, because their effect is usually temporary, and adverse effects occur with prolonged use, they tend to be reserved for short-term treatment in patients with a limited life expectancy of weeks. Megestrol has produced weight gain in some randomised controlled studies, although some of this may result from increase in fat mass rather than increase in lean body-mass. It is generally used in patients with a longer life expectancy of months Similar properties have been reported with medroxyprogesterone. A systematic review concluded that only corticosteroids and the progestogens megestrol and medroxyprogesterone had sufficient evidence to support their use in cancer-related anorexia. Anabolic steroids have also been tried, but further evaluation is necessary: a comparison of megestrol or dexamethasone with fluoxymesterone found the latter to be less effective than the progestogen or the corticosteroid. Prokinetic drugs such as metoclopramide may be useful in patients whose symptoms are secondary to decreased gastrointestinal motility, although relief of nausea may not necessarily lead to improved caloric intake or appetite. It has been suggested that NS AIDs might inhibit the effects of pro-inflammatory cytokines associated with weight loss in cancer patients. The addition of ibuprofen improved the response to megestrol in one small study, but more work is needed. There has also been interest in the effects of eicosapentaenoic acid, which may inhibit muscle protein degradation, but study results have been mixed and a systematic review concluded that there was insufficient evidence to recommend the use of eicosapentaenoic acid. Further investigation is needed to confirm its clinical effects, possibly using higher doses or treating for longer periods than have been so far reported. Thalidomide was found to attenuate weight loss in a study of patients with advanced pancreatic cancer, but quality of life and duration of survival were not significantly improved. Other drugs studied but with little, if any, benefit include cannabinoids, cyproheptadine and hydrazine. Other compounds under investigation include the endogenous hormones ghrelin and melatonin.

High-dose megestrol or oxandrolone are effective in HIV-related cachexia, a topic discussed under HIV-associated Wasting.

Hot flushes. Megestrol has been used to treat hot flushes in women with breast cancer (to avoid the potentially tumour-stimulating effects of an oestrogen — see Malignant Neoplasms, under Precautions of HRT), as well as in men with hot flushes after orchidectomy or anti-androgen therapy for prostate cancer. Therapy, which involved low oral doses of 20 mg twice daily, was associated with a decrease in frequency of flushes of 50% or more in about three-quarters of all patients. About 3 years after the study had finished, these patients were asked about any ongoing use of megestrol and the occurrence of hot flushes. Although symptoms still occurred in many of the patients taking megestrol, they were less common and less severe than in those who had stopped therapy, which included some who had stopped because of no perceived benefit. In patients taking megestrol, most were on doses of 20 mg or less daily. Information collected about adverse effects of megestrol revealed unexpected reports of chills, but these were described as being not as disabling as the hot flushes had been.

Malignant neoplasms. Like some other progestogens megestrol acetate is used in endometrial cancer, and it has been reported to have similar efficacy to anastrozole and tamoxifen in postmenopausal women with advanced breast cancer. There was no advantage in terms of response or survival in escalating the standard dose of megestrol (160 mg daily) to 800 or 1600 mg daily in a randomised study in women with breast cancer

Preparations

British Pharmacopoeia 2008: Megestrol Tablets

The United States Pharmacopeia 31, 2008: Megestrol Acetate Oral Suspension Megestrol Acetate Tablets

Proprietary Preparations

Argentina: Megace Megacorp Meltonar Varigestrol

Australia:: Megace

Austria: Megace

Belgium: Megace

Brazil: Femigestrol Gynodal Megestat

Canada: Megace

Chile: Megace Mestrel

Czech Republic: Megace Megaplex

Denmark: Megace

Finland: Megace Megestin

France: Megace

Germany: Megestat

Greece: Megace

Hong Kong: Megace

Hungary: Megace Megesin

India: Endace

Ireland: Megace

Israel: Megace

Italy: Megace Megestil Meprogest

Malaysia: Megace

Mexico: Megace Mestrel

The Netherlands: Megace

Norway: Megace

New Zealand: Megace

Philippines: Megace

Poland: Cachexan Gestar Megace Megalia Megesin

Portugal: Acestrol Megace

Russia: Megaplex

Singapore: Megace

Spain: Borea Maygace Megefren Megostat

Sweden: Megace

Switzerland: Megestat

Thailand: Megace Megaplex Mestrel

Turkey: Megace

UK: Megace

USA: Megace

Venezuela: Megase