Megace 160 mg Tablets

1. Name Of The Medicinal Product

Megace 160 mg Tablets

2. Qualitative And Quantitative Composition

Each tablet contains Megestrol Acetate 160 mg.

Also contains 224.5 mg Lactose Monohydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablets

Off-white, oval, biconvex tablets with a break line, engraved '160' on one face.

The break line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4. Clinical Particulars

4.1 Therapeutic Indications

Megace is a progestational agent, indicated for the treatment of certain hormone dependent neoplasms, such as breast cancer.

4.2 Posology And Method Of Administration

Breast cancer:

160 mg/day taken once daily.

At least two months of continuous treatment is considered an adequate period for determining the efficacy of Megace.

Children:

Megace is not recommended for use in children.

Elderly:

No dosage adjustment is necessary.

4.3 Contraindications

Megace is contra-indicated in patients who have demonstrated hypersensitivity to the drug.

Megace Tablets have not been shown to be bioequivalent to Megace Oral Suspension and therefore should not be substituted for Megace Oral Suspension in the treatment of anorexia or weight loss secondary to AIDS.

4.4 Special Warnings And Precautions For Use

Precautions:

Megace should be used with caution in patients with a history of thrombophlebitis and in patients with severe impaired liver function.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None stated.

4.6 Pregnancy And Lactation

Megace should not normally be administered to women who are pregnant or to mothers who are breast feeding.

Fertility and reproduction studies with high doses of megestrol acetate have shown a reversible feminising effect on some male rat foetuses.

Several reports suggest an association between intrauterine exposure to progestational drugs in the first trimester of pregnancy and genital abnormalities in male and female foetuses. The risk of hypospadias in male foetuses may be approximately doubled with the exposure to progestational drugs. There are insufficient data to quantify the risk to exposed female foetuses, however some of these drugs induce mild virilisation of the external genitalia of the female foetuses.

If a patient is exposed to Megace during the first four months of pregnancy or if she becomes pregnant whilst taking Megace, she should be apprised of the potential risks to the foetus.

Women of child bearing potential should be advised to avoid becoming pregnant.

Because of the potential for adverse effects, nursing should be discontinued during treatment with Megace.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

The major side-effect experienced by patients while taking megestrol acetate, particularly at high doses, is weight gain, which is usually not associated with water retention, but which is secondary to an increased appetite and food intake. Other occasionally noted side effects are nausea, vomiting oedema and breakthrough uterine bleeding. Reports have been received of patients developing dyspnoea, heart failure, hypertension, hot flushes, mood changes, Cushingoid facies, tumour flare (with or without hypercalcaemia), hyperglycaemia, alopecia and carpal tunnel syndrome while taking megestrol acetate. Thromboembolic phenomena including thrombophlebitis and pulmonary embolism (in some cases fatal) have been reported. A rarely encountered side effect of prolonged administration of megestrol acetate is urticaria, presumably an idiosyncratic reaction to the drug. The drug is devoid of the myelosuppressive activity characteristic of many cytotoxic drugs and it causes no significant changes in haematology, blood chemistry or urinalysis.

Pituitary adrenal axis abnormalities including glucose intolerance, and Cushing's syndrome have been reported with the use of megestrol acetate. Clinically apparent adrenal insufficiency has been rarely reported in patients shortly after discontinuing megestrol acetate. The possibility of adrenal suppression should be considered in all patients taking or withdrawing from chronic megestrol acetate therapy. Replacement stress doses of glucocorticoids may be indicated.

4.9 Overdose

No serious side effects have resulted from studies involving Megace (megestrol acetate) administered in dosages as high as 1600 mg/day.

Reports of overdose have also been received in the postmarketing setting. Signs and symptoms reported in the context of overdose included diarrhoea, nausea, abdominal pain, shortness of breath, cough, unsteady gait, listlessness, and chest pain. There is no specific antidote for overdose with Megace. In case of overdose, appropriate supportive measures should be taken.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Megace (megestrol acetate) possesses pharmacologic properties similar to those of natural progesterone. Its progestational activity is slightly greater than that of medroxyprogesterone acetate, norethindrone, norethindrone acetate and norethynodrel; slightly less than that of chlormadinone acetate; and substantially less than that of norgestrel.

Megestrol acetate is a potent progestogen that exerts significant anti-oestrogenic effects. It has no androgenic or oestrogenic properties. It has anti-gonadotropic, anti-uterotropic and anti-androgenic/anti-myotropic actions. It has a slight but significant glucocorticoid effect and a very slight mineralocorticoid effect.

The progestational activity of megestrol acetate has been assessed in a number of standard tests, including Clauberg - McPhail, McGinty, uterotropic and carbonic anhydrase tests in rabbits; pregnancy maintenance and delay-of-implantation tests in rats; endometrial response in rhesus monkeys; conversion of an oestrogen-primed endometrium to a secretory one in normal women and in those with secondary amenorrhea with resultant withdrawal bleeding; induction of pseudopregnancy for treatment of endometriosis; and the delay-of-menses and thermogenic tests. In all these tests, progestational activity was high.

It has been demonstrated that megestrol acetate blocks oestrogen effects in the uteri of rats and mice in human cervical mucus and vaginal mucosa. Anti-gondotropic activity has been demonstrated in rats of both sexes.

5.2 Pharmacokinetic Properties

Animal

Peak plasma levels occur four to six hours after oral administration of radioactively labelled megestrol acetate to female rats. High concentrations are found in the liver, fat, adrenal glands, ovaries and kidneys. Radioactivity is almost wholly cleared within a week, chiefly by biliary excretion to the faeces.

In dogs, megestrol acetate metabolites are excreted primarily in the faeces. In rabbits, the principal route of metabolic excretion is urinary and the major metabolites are the 2-alpha-hydroxy-6-hydroxymethyl and 6-hydroxymethyl derivatives.

Human

Peak plasma levels of tritiated megestrol acetate and metabolites occur one to three hours after oral administration. When 4 to 91mg of c-labelled megestrol acetate were administered orally to women, the major route of drug elimination was in the urine. The urinary and fecal recovery of total radioactivity within 10 days ranged from 56.6% to 78.4% (mean 66.4%) and 7.7% to 30.3% (mean 19.8%), respectively. The total recovered radioactivity varied between 83.1% and 94.7% (mean 86.2%). Megestrol acetate metabolites, which were identified in the urine as glucuronide conjugates, were 17-alpha-acetoxy-2-alpha hydroxy-6-methylpregna-4, 6-diene-3, 20-dione; 17-alpha-acetoxy-6-hydroxymethylpregna-4, 6-diene-3, 20-dione; and 17-alpha-acetoxy-2 alpha-hydroxy-6-hydromethylpregna-4, 6-diene-3, 20-dione; these identified metabolites accounted for only 5-8% of the administered dose.

Serum concentrations were measured after the administration of single and multiple oral doses of megestrol acetate. Adult male and post-menopausal female volunteers, no more than 65 years of age participated in the study.

Megestrol acetate is readily absorbed following oral administration of 20, 40, 80 and 200 mg doses. Megestrol serum concentrations increase with increasing doses, the relationship between increasing dosage and increasing serum levels not being arithmetically proportional. Average peak serum concentrations for the four doses tested were 89, 190, 209 and 465 ng/ml.

Mean peak serum concentrations are found three hours after single-dose administration for all dosage levels studied. The serum concentration curve appears biphasic, and the beta-phase half-life is 15 to 20 hours long.

After multiple doses over a three-day period, serum levels increase each day and are estimated to reach 80% to 90% predicted steady-state levels on the third day.

5.3 Preclinical Safety Data

No further relevant data.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Colloidal anhydrous silica,

Lactose monohydrate,

Magnesium stearate,

Microcrystalline cellulose,

Povidone,

Sodium starch glycollate

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

36 months - Blister packs

6.4 Special Precautions For Storage

Do not store Megace Tablets above 25°C. Store in the original package in order to protect from moisture.

6.5 Nature And Contents Of Container

Blister packs of 30 tablets.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Bristol-Myers Squibb Holdings Limited

t/a Bristol-Myers Pharmaceuticals

Uxbridge Business Park

Sanderson Road

Uxbridge

Middlesex

UB8 1DH

8. Marketing Authorisation Number(S)

PL 0125/0173

9. Date Of First Authorisation/Renewal Of The Authorisation

20 November 1985 / 25 April 2002

10. Date Of Revision Of The Text

21 October 2011

LEGAL CATEGORY

POM