Anti-androgens.

Cyproterone

Each tablet contains 50 mg cyproterone acetate. Excipient: lactose 111mg.

Tablet. White, round tablet, scored on one side and embossed with the letters “BV” in a regular hexagon on the other side.

Control of libido in severe hypersexuality and/or sexual deviation in the adult male.

Adults including the elderly:

One tablet twice daily, after the morning and evening meals.

Androcur should not be given to youths under 18.

For oral administration.

Liver diseases, malignant tumours (except for carcinoma of the prostate) and wasting diseases (because of transient catabolic action). A history of or existing thrombosis or embolism. Severe diabetes with vascular changes. Sickle cell anaemia. Severe chronic depression.

Androcur should not be given to youths under 18 or to those whose bone maturation and testicular development are incomplete.

Hypersensitivity to any of the components of Androcur.

Liver: Direct hepatic toxicity, including jaundice, hepatitis and hepatic failure, which has been fatal in some cases, has been reported in patients treated with 200-300 mg cyproterone acetate. Most reported cases are in men with prostatic cancer. Toxicity is dose-related and develops, usually, several months after treatment has begun. Liver function tests should be performed pre-treatment, regularly during treatment and whenever any symptoms or signs suggestive of hepatotoxicity occur. If hepatotoxicity is confirmed, cyproterone acetate should normally be withdrawn, unless the hepatotoxicity can be explained by another cause, e.g. metastatic disease, in which case cyproterone acetate should be continued only if the perceived benefit outweighs the risk.

In rare cases benign and in even rarer cases malignant liver tumours leading in isolated cases to life-threatening intra-abdominal haemorrhage have been observed after the use of sex-steroids. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, a liver tumour should be considered in the differential diagnosis.

Thromboembolism: The occurrence of thromboembolic events has been reported patients using cyproterone acetate, although a causal relationship has not been established. Patients with previous arterial or venous thrombotic / thromboembolic events (e.g. deep vein thrombosis, pulmonary embolism, myocardial infarction), with a history of cerebrovascular accidents or with advanced malignancies are at increased risk of further thromboembolic events, and may be at risk of recurrence of the disease during Androcur therapy. 

Breathlessness: Shortness of breath may occur. This may be due to the stimulatory effect of progesterone and synthetic progestogens on breathing, which is accompanied by hypocapnia and compensatory alkalosis, and which is not considered to require treatment.

Adrenocortical function: During treatment adrenocortical function should be checked regularly, since suppression has been observed.

Diabetes: Androcur can influence carbohydrate metabolism. Parameters of carbohydrate metabolism should be examined carefully in all diabetics before and regularly during treatment.

Haemoglobin: Hypochromic anaemia has been found rarely during long-term treatment, and blood-counts before and at regular intervals during treatment are advisable.

Lactose: Androcur contains 111mg lactose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Patients who are on a lactose-free diet should take this amount into consideration.

Spermatogenesis: A spermatogram should be recorded before starting treatment in patients of procreative age, as a guard against attribution of pre-existing infertility to Androcur at a later stage. It should be noted that the decline in spermatogenesis is slow, and Androcur should, therefore, not be regarded as a male contraceptive.

Medico-legal considerations: Doctors are advised to ensure that the fully informed consent of the patient to Androcur treatment is witnessed and can be verified.

Diabetes: The requirement for oral antidiabetics or insulin can change. At high therapeutic cyproterone acetate doses of three times 100mg per day, cyproterone acetate may inhibit CYP2C8 (see below). Thiazolidinediones (i.e. the anti-diabetics pioglitazone and rosiglitazone) are substrates or CYP2C8 (increased blood levels of these anti-diabetics may require dose adjustment).

Chronic alcoholism: Alcohol appears to reduce the effect of Androcur which is of no value in chronic alcoholics.

Other interactions: Clinical interaction studies have not been performed. However, since cyproterone acetate is metabolised by CYP3A4, it is expected that ketoconazole, itraconazole, clotrimazole, ritonavir and other strong inhibitors of CYP3A4 inhibit the metabolism of cyproterone acetate. On the other hand, inducers of CYP3A4 such as rifampicin, phenytoin and products containing St. John's Wort may reduce the levels of cyproterone acetate.

Based on in vitro inhibition studies, an inhibition of the cytochrome P450 enzymes CYP2C8, 2C9, 2C19, 3A4 and 2D6 is possible at high cyproterone acetate doses of 100mg three times per day. (This is three times the maximum total daily dose).

The risk of statin-associated myopathy or rhabdomyolysis may be increased when those HMG-CoA inhibitors (statins) which are primarily metabolised by CYP3A4 are co-administered with high cyproterone acetate doses, since they share the same metabolic pathway.

The following approximate incidences were estimated from published reports of a number of small clinical trials and spontaneous ADR reports:

- very common: incidence 1:10

- common: incidence < 1:10 but 1:100

- uncommon: incidence < 1:100 but 1:1000

- rare: incidence < 1:1000 but 1:10,000

- very rare: incidence < 1:10,000

Blood and the lymphatic system disorders

Hypochromic anaemia has been found rarely during long-term treatment.

Immune system disorders

In rare cases, hypersensitivity reactions may occur and uncommonly, rashes may occur.

Endocrine disorders

Suppression of adrenocorticol function has been observed.

Metabolism and nutrition disorders

During long-term treatment, changes in bodyweight (chiefly weight gains in association with fluid retention) have been commonly reported.

Psychiatric disorders

Depressive moods and restlessness (temporary) can commonly occur.

Vascular disorders

The occurrence of thromboembolic events has been reported in patients using cyproterone acetate, although a causal relationship has not been established.

Respiratory, thoracic and mediastinal disorders

Dyspnoea may occur

Hepato-biliary disorders

Direct hepatic toxicity, including jaundice, hepatitis and hepatic failure, which has been fatal in some cases, has been reported in patients treated with 200-300 mg cyproterone acetate.

In rare cases benign and in even rarer cases malignant liver tumours leading in isolated cases to life-threatening intra-abdominal haemorrhage have been observed after the use of sex steroids.

Skin and subcutaneous tissue disorders

Reduction of sebum production leading to dryness of the skin and improvement of existing acne vulgaris has been reported as well as; transient patchy loss and reduced growth of body hair, increased growth of scalp hair, lightening of hair colour and female type of pubic hair growth.

Musculoskeletal and connective tissue disorders

As with other antiandrogenic treatments, long-term androgen deprivation may, very rarely, lead to osteoporosis.

Reproductive system disorders

Inhibition of spermatogenesis: The sperm count and the volume of ejaculate are very commonly reduced, infertility is usual, and there may be azoospermia after 8 weeks. There is usually slight atrophy of the seminiferous tubules. Follow-up examinations have shown these changes to be reversible, spermatogenesis usually reverting to its previous state about 3-5 months after stopping Androcur, or in some users, up to 20 months. That spermatogenesis can recover even after very long treatment is not yet known. There is evidence that abnormal sperms which might give rise to malformed embryos are produced during treatment with Androcur.

Gynaecomastia: Commonly, Androcur may lead to gynaecomastia (sometimes combined with tenderness to touch of the mamillae) which usually regresses after withdrawal of the preparation. In rare cases galactorrhoea and tender benign nodules have been reported. Symptoms mostly subside after discontinuation of treatment or reduction of dosage.

General disorders and administration site conditions

Hot flushes and sweating may occur and fatigue and lassitude are common.

Bayer plc

(POM)

20 August 2010