Androcur^® 50mg tablets

Each tablet contains 50 mg cyproterone acetate.

Excipient: lactose 111mg.

For a full list of excipients, see 6.1.

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.

Children:

Androcur should not be given to youths under 18.

For oral administration.

Androcur must not be used in patients with:

Hypersensitivity to any of the components of Androcur

Liver diseases

Malignant tumours (except for carcinoma of the prostate)

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

Meningioma or a history of meningioma.

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

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 If hepatotoxicity is confirmed, cyproterone acetate should normally be withdrawn, unless the hepatotoxicity can be explained by another cause, e.g. metastatic disease, in which case cyproterone acetate should be continued only if the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. See also section 4.3.

Meningiomas:

The occurrence of (multiple) meningiomas has been reported in association with longer term use (years) of cyproterone acetate at doses of 25 mg/day and above. If a patient treated with Androcur is diagnosed with meningioma, treatment with Androcur must be stopped (see section 4.3).

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. See also section 4.5.

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. See also section 4.4. 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.

Not applicable

Fatigue and lassitude are common - patients should be warned about this and if affected should not drive or operate machinery.

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

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

The occurrence of (multiple) meningiomas has been reported in association with longer term use (years) of cyproterone acetate at doses of 25 mg/day and above.

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. See also section 4.4.

Respiratory, thoracic and mediastinal disorders

Dyspnoea may occur (see section 4.4).

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. See also section 4.4.

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.

There have been no reports of ill-effects from overdosage, which it is, therefore, generally unnecessary to treat. There are no specific antidotes and if treatment is required it should be symptomatic.

Cyproterone acetate acts as an antiandrogen by blocking androgen receptors. It also has progestogenic activity, which exerts a negative feedback effect on hypothalamic receptors, so leading to a reduction in gonadotrophin release, and hence to diminished production of testicular androgens. Sexual drive and potency are reduced and gonadal function is inhibited.

An occasional tendency for the prolactin levels to increase slightly has been observed under higher doses of cyproterone acetate.

Following oral administration, cyproterone acetate is completely absorbed over a wide dose range. The ingestion of two cyproterone acetate 50 mg tablets gives maximum serum levels of about 285 ng/ml at about 3 hours. Thereafter, drug serum levels declined during a time interval of typically 24 to 120 h, with a terminal half-life of 43.9 ± 12.8 h. The total clearance of cyproterone acetate from serum is 3.5 ± 1.5 ml/min/kg. Cyproterone acetate is metabolised by various pathways, including hydroxylations and conjugations. The main metabolite in human plasma is the 15ß-hydroxy derivative.

Some drug is excreted unchanged with bile fluid. Most of the dose is excreted in the form of metabolites at a urinary to biliary ratio of 3:7. The renal and biliary excretion proceeds with a half-life of 1.9 days. Metabolites from plasma are eliminated at a similar rate (half-life of 1.7 days).

Cyproterone acetate is almost exclusively bound to plasma albumin. About 3.5 - 4 % of total drug levels are present unbound. Because protein binding is non-specific, changes in SHBG (sex hormone binding globulin) levels do not affect the pharmacokinetics of cyproterone acetate.

The absolute bioavailability of cyproterone acetate is almost complete (88 % of dose).

Recognised first-line tests of genotoxicity gave negative results when conducted with cyproterone acetate. However, further tests showed that cyproterone acetate was capable of producing adducts with DNA (and an increase in DNA repair activity) in liver cells from rats and monkeys and also in freshly isolated human hepatocytes. This DNA-adduct formation occurred at exposures that might be expected to occur in the recommended dose regimens for cyproterone acetate. In vivo consequences of cyproterone acetate treatment were the increased incidence of focal, possibly preneoplastic, liver lesions in which cellular enzymes were altered in female rats, and an increase of mutation frequency in transgenic rats carrying a bacterial gene as target for mutation. The clinical relevance of these findings is presently uncertain. Clinical experience to date would not support an increased incidence of hepatic tumours in man. However, it must be borne in mind that sex steroids can promote the growth of certain hormone dependent tissues and tumours.

Lactose

Maize starch

Povidone 25 000

Silicon dioxide (aerosil) (E551)

Magnesium stearate (E572)

None known

5 years

No special precautions for storage

PVC/Aluminium blister pack.

Pack size: 56 tablets

Keep out of the reach of children.

Bayer plc

Bayer House

Strawberry Hill

Newbury

Berkshire RG14 1JA

United Kingdom

Trading as Bayer plc, Bayer Schering Pharma

PL00010/0519

Date of first authorisation: 01 May 2008

9 September 2009