This information is intended for use by health professionals

1. Name of the medicinal product

Cyproterone acetate 50mg tablets

2. Qualitative and quantitative composition

Cyproterone acetate 50mg

For excipients, see 6.1.

3. Pharmaceutical form

Tablet

For oral administration

4. Clinical particulars
4.1 Therapeutic indications

For the management of patients with prostatic cancer

(1) To suppress “flare” with initial LHRH analogue therapy

(2) In long-term palliative treatment where LHRH analogues or surgery are contraindicated, not tolerated, or where oral therapy is preferred

(3) In the treatment of hot flushes in patients under treatment with LHRH analogues or who have had orchidectomy

4.2 Posology and method of administration

For use only in the adult male.

(1) To suppress “flare” with initial LHRH analogue therapy:

300 mg/day which may be reduced to 200 mg if the higher dose is not tolerated

(2) In long-term palliative treatment where LHRH analogues or surgery are contraindicated, not tolerated, or where oral therapy is preferred:

200-300 mg/day

(3) In the treatment of hot flushes in patients under treatment with LHRH analogues or who have had orchidectomy:

50 mg starting dose with upward titration if necessary within the range 50-150 mg/day

Elderly men: The dosage is dependent on the clinical indication and not the age of the patient, although greater monitoring for possible adverse effects may be necessary in the elderly.

4.3 Contraindications

Must not be used in patients with meningioma or a history of meningioma.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Liver disease (including Dubin-Johnson syndrome and Rotor syndrome)

Malignant or wasting diseases (except for prostatic carcinoma for which cyproterone acetate is specifically indicated)

Previous or existing liver tumors (only if these are not due to metastases from carcinoma of the prostate)

Existing thromboembolic processes or a history of thromboembolic disorders

Immaturity: cyproterone acetate should not be given to youths, usually those under 18 years of age, whose bone or testicular maturity is incomplete.

Should not be used by females. Cyproterone acetate, used alone, is absolutely contraindicated in women of child-bearing age.

4.4 Special warnings and precautions for use

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

Cyproterone should be used with caution in patients with severe depressionor sickle cell anaemia.

Thromboembolism: the occurrence of thromboembolic events has been reported in 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 cyproterone acetate therapy.

In patients with a history of thromboembolic processes 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

Chronic depression: It has been found that some patients with severe chronic depression deteriorate whilst taking acetate therapy. Such patients should be closely monitored for signs of deterioration and warned to contact their doctor immediately if their depression worsens.

Liver disease: direct hepatic toxicity, including jaundice, hepatitis and hepatic failure, which has been fatal in some cases, has been reported in patients treated with dosages of cyproterone acetate of 100mg and above. Most reported fatal cases were in men with advanced 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 hepatoxicity 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 very rare cases benign and malignant liver tumours, which may lead to life-threatening intra-abdominal haemorrhage, have been observed after the use of cyproterone acetate. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur a liver tumour should be considered in the differential diagnosis.

Shortness of breath: Shortness of breath may occur under high-dosed treatment with cyproterone acetate. 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: Suppression of corticotropin (ACTH) has been reported. Adrenocortical function should be monitored regularly during treatment as preclinical data suggest a possible suppression due to the corticoid-like effect of cyproterone acetate with high doses.

Diabetes: Strict medical supervision is necessary if the patient suffers from diabetes. Cyproterone acetate can influence carbohydrate metabolism and deleterious effects on some diabetic patients have been reported. Blood sugar levels of diabetic patients should therefore be monitored before and regularly during treatment because the requirement for oral antidiabetics or insulin can change. See also section 4.5.

Anaemia: Rarely, anaemia has been observed; blood counts should be taken initially and at regular intervals during treatment.

Alcohol: Alcohol reduces the effects of cyproterone acetate which is of no value in chronic alcoholics.

Lactose: This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine. Patients who are on a lactose-free diet should take this into consideration.

4.5 Interaction with other medicinal products and other forms of interaction

The effects of cyproterone acetate may be altered by pharmacological interactions with other sex hormones. It is ineffective in chronic alcoholism.

Antidiabetics: 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. As thiazolidinediones (e.g. pioglitazone and rosiglitazone) are substrates of CYP2C8 this can lead to increased blood levels of these antidiabetics may require dose adjustment.

Other interactions: Clinical interaction studies have not been performed. As cyproterone acetate is metabolised by CYP3A4, it is expected that ketoconazole, intraconazole, clotrimazole, ritonavir and other strong inhibitors of CYP3A4 inhibit the metabolism of cyproterone acetate. 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 100 mg three times per day.

Statins: 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 therapeutic cyproterone acetate doses, since they share the same metabolic pathway.

4.6 Fertility, pregnancy and lactation

Cyproterone acetate, used alone, should not be given to females. It is strongly contraindicated in pregnancy or lactation.

4.7 Effects on ability to drive and use machines

Lassitude and fatigue may occur, especially during the first few weeks of therapy, and may interfere with driving or operation of machinery. Patients should be warned to take special care and if affected should not drive or operate machinery.

4.8 Undesirable effects

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.

Neoplasms benign, malignant and unspecified (including cysts and polyps):

Benign and malignant liver tumours which may lead to life threatening intra-abdominal haemorrhage and thromboembolic events. The occurrence of (multiple) meningiomas has been reported in association with longer term use (years) of cyproterone acetate at doses of 25mg/day and above.

Blood and lymphatic system disorders: anaemia during long term treatment

Immune system disorders: hypersensitivity and allergic dermatitis.

Endocrine disorders: Suppression of adrenocortical function.

Metabolism and nutrition disorders: fluctuations in body weight during long term treatment (chiefly weight gains in association with fluid retention)

Psychiatric disorders: depression and restlessness (temporary)

Nervous system disorders: headache, stroke

Cardiac disorders: myocardial infarction

Vascular disorders: Hot flushes, or hypertension. Thromboembolic events, although a causal relationship, has not been established. Fatalities have been reported.

Respiratory, thoracic and mediastinal disorders: pulmonary embolism and dyspnoea.

Gastrointestinal disorders: nausea.

Hepatobiliary disorders: Direct hepatic toxicity (including jaundice, hepatitis and hepatic failure) and liver function disturbances. Occasional reports of benign and malignant liver changes. At doses of 100mg and above, cases with fatal outcome have also been reported. 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. Cholestasis and hepatic cytolysis have been reported.

Skin and subcutaneous tissue disorders: changes in hair pattern (including a reduction and transient patchy loss of body hair, alopecia and hirsutism, increased growth of scalp hair, lightening of hair colour and female type of pubic hair growth), sweating and rash. Cyproterone acetate through its pharmacological activity decreases sebum production and dries the skin. Improvement of existing acne vulgaris has been reported.

Musculoskeletal and connective tissue disorders: osteoporosis may occur (due to long-term androgen deprivation).

Reproductive system and breast disorders: Gynaecomastia (sometimes combined with tenderness to touch of the mamillae) has been reported with a frequency of between 2% and 20%. Although signs usually subside on dosage reduction or treatment discontinuation, there have been reports of permanent enlargement of the breast. Rarely, galactorrhoea and benign breast nodules.

Cyproterone acetate inhibits spermatogenesis, reduces plasma testosterone levels, reduces the volume of ejaculate, causes infertility, suppressed libido, inhibition of gonadal function and impotence. These pharmacological effects are reversible. Abnormal spermatozoa may be produced.

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 3-5 months after stopping cyproterone acetate, 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 cyproterone acetate.

General disorders and administration site conditions: oedema, fatigue and lassitude may occur, especially at the start of treatment, but usually decrease as treatment progresses.

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. Healthcare professionals are asked to report any suspected adverse reactions via:

UK

Yellow Card Scheme

www.mhra.gov.uk/yellowcard.

MT

ADR Reporting, The Medicines Authority, Post-Licensing Directorate, 203 Level 3, Rue D'Argens, GŻR-1368 Gżira; Website: www.medicinesauthority.gov.mt; e-mail: postlicensing.medicinesauthority@gov.mt

4.9 Overdose

There are no reports of ill effects from overdosage. There are no specific antidotes and if treatment is required it should be symptomatic.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Cyproterone acetate is a potent anti-androgen with progestational activity.

Cyproterone acetate competes with testosterone at receptor sites, inhibits the synthesis of testosterone both in tests and the adrenals thus causing a decrease in plasma testosterone levels and suppresses the secretion of gonadotrophins thus preventing a re-elevation of testosterone by a bio-feedback mechanism.

5.2 Pharmacokinetic properties

Cyproterone acetate when given orally is completely or almost completely absorbed. Maximal plasma levels occur two to four hours after ingestion.

There is no evidence of a first-pass effect. The compound is metabolised to the 15-hydroxy analogue.

Distribution and elimination are in two phases, the first phase having a reported half-life of 4.2 hours, and the second approximately 1.6 days.

Ten days after an oral dose of 50 mg, 93% is eliminated, approximately one third in the urine and two thirds in the faeces.

5.3 Preclinical safety data

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. One in vivo consequence of cyproterone acetate treatment was the increased incidence of focal, possibly pre-neoplastic, liver lesions in which cellular enzymes were altered in female rats. The clinical relevant of these findings is presently uncertain.

6. Pharmaceutical particulars
6.1 List of excipients

Lactose

Maize starch

Povidone K 25

Colloidal silicon dioxide

Magnesium stearate

Purified water

6.2 Incompatibilities

None known.

6.3 Shelf life

Three years.

6.4 Special precautions for storage

Do not store above 25°C. Store in the original package.

6.5 Nature and contents of container

Polypropylene containers with press-on tamper-evident lids: 50, 100 and 200 pack sizes.

Blister pack of PVC and aluminium foil: 14, 56 or 168 pack sizes.

6.6 Special precautions for disposal and other handling

No special instructions.

7. Marketing authorisation holder

Wockhardt UK Ltd

Ash Road North

Wrexham

LL13 9UF

United Kingdom

8. Marketing authorisation number(s)

PL 29831/0059

MA154/01001

9. Date of first authorisation/renewal of the authorisation

24/07/2007

10. Date of revision of the text

31/07/2014