CYPROTERONE ACETATE

For oral administration only. Control of libido in severe hypersexuality and/or sexual deviation.

Adults and the elderly:

The usual dose is started with one Cyproterone Acetate 50 mg Tablet twice daily. The duration of cyproterone acetate treatment should be defined on an individual basis. When a satisfactory result has been achieved, the therapeutic effect should be maintained with the lowest possible dose.

When changing the dose or when discontinuing cyproterone acetate, this should be done gradually. The daily dose should be divided and taken after the morning and evening meals. The management of patients with prostatic cancer The maximum daily dose is 300 mg Adults and the elderly: To suppress "flare" with initial LHRH Analogue therapy: Initially 2 tablets of Cyproterone Acetate 50 mg Tablets twice daily (200 mg) alone for 5-7 days, followed by 2 tablets of Cyproterone Acetate 50 mg Tablets twice daily (200 mg) for 3-4 weeks together with the LHRH analogue therapy in the dosage recommended by the marketing authorization holder (see SmPC of LHRH analogue)..

In long term palliative treatment where LHRH analogues or surgery are contraindicated, not tolerated, or when oral therapy is preferred: 200-300 mg/day. For the above two indications the dosage should be divided into 2-3 doses per day and taken after meals.

In the treatment of hot flushes in patients under treatment with LHRH analogues or who have had an orchidectomy: 50 mg starting dose with upward titration if necessary within the range 50-150mg/day. For this indication the dosage should be divided into 1-3 doses per day and taken after meals Additional information on special population (applies to all indications) Children and adolescents: Cyproterone acetate is not recommended for use in male children and adolescents below 18 years of age due to lack of data on safety and efficacy.

Cyproterone acetate must not be given before the conclusion of puberty since an unfavourable influence on longitudinal growth and still unstabilised axes of endocrine function cannot be ruled out.

Elderly patients:

There are no data suggesting the need for a dosage adjustment in elderly patients. 8).

Patients with renal impairment:

The use of cyproterone acetate in patients with renal impairment has not been investigated. 2).

The most frequently observed adverse drug reactions (ADRs) in patients receiving cyproterone acetate are decreased libido, erectile dysfunction and reversible inhibition of spermatogenesis. The most serious ADRs in patients receiving cyproterone acetate are hepatic toxicity, benign and malignant liver tumours which may lead to intra-abdominal haemorrhage and thromboembolic events.

4). 4).

Blood and lymphatic system disorders Not known:

Anaemia during long-term treatment Immune system disorders Rare: Hypersensitivity reactions Endocrine disorders Not known: Suppression of adrenocortical function.

Metabolism and nutritional disorders Common:

Changes in bodyweight during long-term treatment (chiefly weight gains in association with fluid retention).

Psychiatric disorders Common:

Depressive moods and restlessness (temporary). 4). 4). 4). Most reported fatal cases were in men with advanced carcinoma of the prostate. Toxicity is dose related and develops, usually, several months after treatment has begun.

Skin & subcutaneous tissue disorders Uncommon:

Rash Not known: Reduction of sebum production leading to dryness of the skin and consequently 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, connective tissue and bone disorders Not known:

Osteoporosis (due to long-term androgen deprivation).

Reproductive system disorders Very common:

Decreased libido, erectile dysfunction, reduced sexual drive and inhibition of gonadal function. These changes are reversible after discontinuation of therapy.

Inhibition of spermatogenesis:

Very common: Sperm count and the volume of ejaculate is reduced. Infertility is usual, and there may be azoospermia after eight 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 three to five months after stopping treatment or in some users up to 20 months.

That spermatogenesis can recover even after very long treatment is uncertain. There is evidence that abnormal sperms, which might give rise to malformed embryos, are produced during treatment.

Gynaecomastia:

Common: Gynaecomastia (sometimes combined with tenderness to touch of the mamillae) which usually regresses after withdrawal of the preparation.

Rare:

Galectorrhoea and tender benign nodules. Symptoms mostly subside after discontinuation of treatment or reduction of dosage.

General and administration site disorders Common:

Hot flushes, sweating, fatigue and lassitude Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

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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/day 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.

g. metastatic disease, in which case cyproterone acetate should be continued only if the perceived benefit outweighs the risk. Very rarely liver tumours, leading in isolated cases to life-threatening intra-abdominal haemorrhage, have been observed after the use of sex steroids, to which class cyproterone acetate belongs.

If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, hepatic tumour should be considered in the differential diagnosis and, if necessary, cyproterone acetate should be withdrawn.

Thromboembolism:

The occurrence of thromboembolic events has been reported in patients using cyproterone acetate, although a causal relationship has not been established. g. deep vein thrombosis, pulmonary embolism, myocardial infraction), 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 cyproterone acetate therapy.

In patients with a history of thromboembolic disorders or suffering from sickle-cell anaemia or severe diabetes with vascular changes, the risk: benefit ratio must be considered carefully in each individual case before cyproterone acetate is prescribed.

In very rare cases, the occurrence of thromboembolic events has been reported in temporal association with the use of cyproterone acetate; a causal relationship seems however questionable.

Chronic depression:

It has been found that some patients with severe chronic depression deteriorate during cyproterone acetate therapy. Such patients should be closely monitored for signs of deterioration and warned to contact their doctor immediately if their depression worsens Breathlessness: Shortness of breath may occur.

Possibly due to the known stimulatory effect of progesterone and synthetic progestogens on breathing, which is accompanied by hypocapnia and compensatory alkalosis, but it is not considered that treatment is required.

Adrenocortical function:

During treatment adrenocortical function should be monitored regularly, as preclinical data suggest a possible suppression due to the corticoid-like effect of Cyproterone Acetate.

Diabetes mellitus:

Strict medical supervision is necessary if the patient suffers from diabetes ascyproterone acetate can influence carbohydrate metabolism. Parameters of carbohydrate metabolism should be examined carefully in all diabetics before and regularly during treatment because the requirement for oral antidiabetics or insulin can change.

Haemoglobin:

Hypochromic anaemia has been found rarely during long term treatment, and blood counts before and at regular intervals during treatment are advisable. Nitrogen balance: a negative nitrogen balance is usual at the start of treatment, but usually does not persist.

Spermatogenesis:

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

1). 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.

Meningiomas:

The occurrence of meningiomas (single and multiple) has been reported in association with use of cyproterone acetate primarily at doses of 25 mg and above. 1). High cumulative doses can be reached with prolonged use (several years) or shorter duration with high daily doses.

Patients should be monitored for meningiomas in accordance with clinical practice. If a patient treated Cyproterone Acetate is diagnosed with meningioma, treatment with Cyproterone Acetate and other cyproterone containing products must be permanently stopped (see section ‘Contraindications’).

There is some evidence that the meningioma risk may decrease after treatment discontinuation of cyproterone.

Anaemia:

Anaemia has been reported during long-term treatment. Therefore, the red blood count should be checked regularly during treatment

Cyproterone acetate must not be used in patients with:

Use in patients known to be hypersensitive to cyproterone acetate or to any of the ingredients of the Cyproterone Acetate Tablets. Cyproterone acetate must not be used in patients with meningioma or a history of meningioma. Additional contraindications for patients being treated for hypersexuality / sexual deviation.

Cyproterone acetate is contraindicated for use in patients with liver diseases (including Dubin-Johnson syndrome and Rotor syndrome) malignant tumours (other than prostatic cancer); wasting diseases (with the exception of inoperable carcinoma of the prostate) (because of transient catabolic action); a history of or existing thrombosis or embolism; severe diabetes with vascular changes; sickle-cell anaemia; severe chronic depression.

Cyproterone acetate should not be given to youths under the age of 18 or to those whose bone maturation and testicular maturation is incomplete.