Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Bayer plc, 400 South Oak Way, Reading, RG2 6AD
Androcur must not be used in patients with:
Androcur should not be given to youths under 18 or to those whose bone maturation and testicular development are incomplete.
Direct hepatic toxicity, including jaundice, hepatitis and hepatic failure, has been observed in patients treated with Androcur. At dosages of 100mg and above, cases with fatal outcome have also been reported. 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 If hepatotoxicity is confirmed, Androcur should be withdrawn, unless the hepatotoxicity can be explained by another cause, e.g. metastatic disease, in which case Androcur should be continued only if the perceived benefit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 Androcur. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, a liver tumour should be considered in the differential diagnosis.
The occurrence of thromboembolic events has been reported patients using Androcur, 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.
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. The risk of meningioma increases with increasing cumulative doses of cyproterone acetate (see section 5.1). 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 with Androcur is diagnosed with meningioma, treatment with Androcur 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.
Shortness of breath may occur under high-dosed treatment with Androcur. 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.
During treatment adrenocortical function should be checked regularly, as preclinical data suggest a possible suppression due to the corticoid-like effect of Androcur with high doses (see section 5.3).
Strict medical supervision is necessary if the patient suffers from diabetes as Androcur 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. See also section 4.5.
Anaemia has been reported during long-term treatment. Therefore, the red blood count should be checked regularly during treatment.
Androcur contains 108.75 mg 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.
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.
Doctors are advised to ensure that the fully informed consent of the patient to Androcur treatment is witnessed and can be verified.
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).
Alcohol appears to reduce the effect of Androcur which is of no value in chronic alcoholics.
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 most frequently observed adverse drug reactions (ADRs) in patients receiving Androcur are decreased libido, erectile dysfunction and reversible inhibition of spermatogenesis.
The most serious ADRs in patients receiving Androcur are hepatic toxicity, benign and malignant liver tumours which may lead to intra-abdominal haemorrhage and thromboembolic events.
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 ≥1:1,000
rare: incidence <1:1,000 but ≥1:10,000
very rare: incidence <1:10,000
not known (cannot be estimated from available data)
Rare: Meningioma. The occurrence of meningiomas (single and multiple) has been reported in association with use of cyproterone acetate (see section 4.4).
Very rare: Benign and malignant liver tumours which may lead to life-threatening intra abdominal haemorrhage (see section 4.4).
Not known: Anaemia during long-term treatment (see section 4.4).
Rare: Hypersensitivity reactions may occur.
Not known: Suppression of adrenocorticol function.
Common: Changes in bodyweight during long term treatment (chiefly weight gains in association with fluid retention)
Common: Depressive moods and restlessness (temporary).
Not known: Thromboembolic events, although a causal relationship has not been established (see section 4.4).
Common: Dyspnoea (see section 4.4).
Common: Direct hepatic toxicity, including jaundice, hepatitis and hepatic failure has been observed in patients treated with Androcur. At dosages of 100 mg 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.
Uncommon: Rash
Not known: 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.
Not known: Osteoporosis (due to long-term androgen deprivation).
Inhibition of spermatogenesis:
Very common: Sperm count and the volume of ejaculate are 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:
Common: Gynaecomastia (sometimes combined with tenderness to touch of the mamillae) which usually regresses after withdrawal of the preparation.
Rare: Galactorrhoea and tender benign nodules have been reported.
Symptoms mostly subside after discontinuation of treatment or reduction of dosage.
Common: Hot flushes, sweating, fatigue and lassitude.
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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
None known.
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