Megestrol

Megestrol acetate is a synthetic derivative of progesterone. Unlike the natural hormone it is active by mouth, and it acts as a progestogen with anti-oestrogenic activity. It also has antigonadotrophic and antiandrogenic effects, and only slight glucocorticoid and mineralocorticoid activity.

Mechanism of Action

• Hormonal blockade: like other progestogen derivatives, megestrol acetate interferes with circulating hormones by blocking both their production and their metabolic effect.
• Hormone-dependent cancer: its good tolerability, even in prolonged treatment, has allowed good results in the palliative treatment of hormone-dependent tumours such as advanced breast and endometrial carcinoma.
• Cachexia: clinical trials show it is useful in cancer-related (paraneoplastic) cachexia. The exact mechanism of this anti-cachectic effect is not known; it is thought to involve an increase in appetite and an increase in lipogenesis.

Pharmacokinetics

• Absorption: rapid after oral dosing, helped by the high micronisation of the active substance in the formulation. Peak plasma concentration is reached between 2 and 5 hours. The granules show a slight tendency to higher bioavailability than the tablets, which does not increase the risk of treatment-related reactions.
• Elimination: the kinetic profile is biphasic, with a half-life of about 20 hours.
• Metabolism and excretion: eliminated in urine as metabolites hydroxylated at C2 and C6. The amount excreted unchanged is negligible (0.01% of the dose).

Megestrol acetate (Borea) is indicated in adults for:

• Cachexia-anorexia syndrome associated with advanced cancer.
• Palliative treatment of advanced breast cancer or advanced endometrial cancer.

Safety and efficacy in children have not been established.

• Hypersensitivity to megestrol acetate or to any of the excipients.

No other contraindication is listed. See Special Instructions for the advice against use during the first 4 months of pregnancy and during breastfeeding.

Nausea, vomiting and heartburn are the only reactions listed as very common.

Very common (≥1/10): nausea, vomiting, heartburn.

Uncommon (≥1/1,000 to <1/100): tumour flare with or without hypercalcaemia, Cushingoid facies, dyspnoea, heart failure, hot flushes, hypertension.

Rare (≥1/10,000 to <1/1,000): rash, pruritus, alopecia, vaginal bleeding (spotting).

Not known: hyperglycaemia and thromboembolic events (thrombophlebitis, pulmonary embolism), both reported after marketing.

Abnormal laboratory results showing changes in the pituitary–adrenal axis have been seen. Their significance is not fully established, but clinically significant adrenal insufficiency has rarely been reported in patients whose megestrol acetate had recently been stopped. After abrupt withdrawal, patients should be observed for signs of adrenocortical insufficiency.

• Aminoglutethimide: lower plasma levels of the progestogen, with possible loss of therapeutic activity through induction of its metabolism, were recorded in a study.
• Hormones in general: as with all progestogen derivatives, megestrol acetate interferes with circulating hormones by blocking their production and their metabolic effect.
• The SmPC names no other interacting medicines.

Megestrol acetate is taken by mouth. Tablets are swallowed whole with a liquid, without chewing or crushing. For the granules, the contents of one sachet are dispersed in half a glass of water and stirred until completely dissolved before drinking.

Recommended Dose (Adults)

• Breast cancer: 1 tablet or sachet (160 mg megestrol acetate) per day.
• Endometrial cancer: 1–2 tablets or sachets (160–320 mg) per day.
• Cachexia-anorexia associated with advanced cancer: start with one 160 mg tablet or sachet per day and increase according to clinical response, up to a maximum of 800 mg per day (5 tablets or sachets). The usual dose is 320–800 mg per day.
• Duration: the longest clinical studies in cancer-related cachexia-anorexia lasted three months. To judge efficacy, at least two months of uninterrupted treatment is generally considered appropriate.

Special Populations

• Children: safety and efficacy have not been established.
• Other groups: the SmPC gives no separate dosing for elderly patients or for renal or hepatic impairment.

Starting Treatment for Cachexia-Anorexia

Treatment of cachexia-anorexia should be started only when the patient is able to chew and/or swallow.

Thromboembolism

Use with caution in patients with a history of thromboembolism. Treatment must be stopped if any thromboembolic episode occurs.

Diabetes and Cushing’s Syndrome

New-onset diabetes, exacerbation of existing diabetes and Cushing’s syndrome have been described with megestrol acetate. In exacerbations of diabetes, insulin requirements may increase.

Adrenal Function and Pregnancy Tests

Patients withdrawn abruptly from megestrol acetate should be observed for signs of adrenocortical insufficiency. The medicine can also alter the result of a diagnostic pregnancy test.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: progestogens can affect foetal development, especially when given during the first 4 months of pregnancy, so megestrol acetate must not be used in that period. In rats, feminisation of male foetuses has been seen. There are not enough data to quantify the risk to female foetuses, but some of these medicines cause moderate virilisation of the external genitalia in female foetuses and raise the risk of hypospadias in male foetuses, so they should be avoided in the first trimester.
• Breastfeeding: use during breastfeeding is not recommended.
• Fertility: the SmPC gives no data on fertility.

Excipients

The tablets contain lactose. Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them. They contain less than 23 mg (1 mmol) of sodium per tablet, so are essentially sodium-free. Each sachet of granules contains 2,310 mg of sorbitol: patients with hereditary fructose intolerance should not take the granules, and sorbitol may cause gastrointestinal discomfort and a mild laxative effect.

Effect on Driving

Megestrol acetate has no influence on the ability to drive and use machines.

Borea tablets and granules need no special storage precautions. The tablets are packed in white PVC/aluminium blisters and the granules in three-layer polyethylene/aluminium/paper sachets, in packs of 30 or 500. Keep out of the sight and reach of children.

3 years for both the tablets and the granules. Do not use after the expiry date on the pack.

Prescription only (Rx). Megestrol acetate is taken at home, so it is supplied to the patient or to the treating clinic on prescription. No cold chain is needed.