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.
Kebirterona must not be used in patients with:
| Liver diseases (including Dubin-Johnson syndrome and Rotor syndrome) Malignant tumours (except for carcinoma of the prostate) Previous or existing liver tumours 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. |
Kebirterona should not be given to youths under 18 or to those whose bone maturation and testicular development are incomplete.
None known
The most frequently observed adverse drug reactions (ADRs) in patients receiving Kebirterona are decreased libido, erectile dysfunction and reversible inhibition of spermatogenesis.
The most serious ADRs in patients receiving Kebirterona 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)
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
| Very rare: | Benign and malignant liver tumours which may lead to life-threatening intra-abdominal haemorrhage. |
| Not known: | 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 | |
| Not known: | Anaemia during long-term treatment. |
| Immune system disorders | |
| Rare: | Hypersensitivity reactions may occur. |
| Endocrine disorders | |
| Not known: | Suppression of adrenocorticol function. |
| Metabolism and nutrition 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). |
| Vascular disorders | |
| Not known: | Thromboembolic events, although a causal relationship has not been established. |
| Respiratory, thoracic and mediastinal disorders | |
| Common: | Dyspnoea. |
| Hepato-biliary disorders | |
| Common: | Direct hepatic toxicity, including jaundice, hepatitis and hepatic failure has been observed in patients treated with Kebirterona. 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. |
| Skin and subcutaneous tissue disorders | |
| 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. |
| Musculoskeletal and connective tissue disorders | |
| Not known: | Osteoporosis (due to long-term androgen deprivation). |
| Reproductive system disorders 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 Kebirterona, 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 Kebirterona. 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. General disorders and administration site conditions | |
| 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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Systemic toxicity
Preclinical data reveal no specific risk for humans based on conventional studies of repeated dose toxicity beyond those discussed in other sections of the SPC.
Experimental investigations produced corticoid-like effects on the adrenal glands in rats and dogs following higher dosages, which could indicate similar effects in humans at the highest given dose (300mg/day).
Genotoxicity and carcinogenicity
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 the DNA-adduct level in the dog liver cells was extremely low.
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.
In long-term carcinogenicity studies in rats cyproterone acetate increased the incidence of liver tumours including carcinomas at high doses which concomitantly caused liver toxicity and exceeded the maximum human dose. Further investigations into rodents at lower, non-hepatotoxic doses revealed benign liver proliferations similar to effects described for other steroid hormones. However, it must be borne in mind that sex steroids can promote the growth of certain hormone dependent tissues and tumours.
Control of libido in severe hypersexuality and/or sexual deviation in the adult male.
Pharmacotherapeutic group: sex hormones and modulators of the genital system, antiandrogens, plain, ATC code: G03HA01
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).
Liver: Direct hepatic toxicity, including jaundice, hepatitis and hepatic failure, has been observed in patients treated with Kebirterona. 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, Kebirterona should be withdrawn, unless the hepatotoxicity can be explained by another cause, e.g. metastatic disease, in which case Kebirterona 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 Kebirterona. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, a liver tumour should be considered in the differential diagnosis.
Thromboembolic events: The occurrence of thromboembolic events has been reported patients using Kebirterona, 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 Kebirterona therapy.
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 Kebirterona is diagnosed with meningioma, treatment with Kebirterona must be stopped.
Shortness of breaths: Shortness of breath may occur under high-dosed treatment with Kebirterona. 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, as preclinical data suggest a possible suppression due to the corticoid-like effect of Kebirterona with high doses.
Diabetes mellitus: Strict medical supervision is necessary if the patient suffers from diabetes as Kebirterona 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.
Anaemia: Anaemia has been reported during long-term treatment. Therefore, the red blood count should be checked regularly during treatment.
Lactose: Kebirterona contains 105.5 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.
Spermatogenesis: A spermatogram should be recorded before starting treatment in patients of procreative age, as a guard against attribution of pre-existing infertility to Kebirterona at a later stage. It should be noted that the decline in spermatogenesis is slow, and Kebirterona 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 Kebirterona treatment is witnessed and can be verified.
Fatigue and lassitude are common - patients should be warned about this and if affected should not drive or operate machinery.
Posology
Adults
Generally, treatment is started with 1 tablet Kebirterona 50 mg twice daily, after the morning and evening meals. When a satisfactory result has been achieved, one should try to maintain the therapeutic effect with the lowest possible dose. When establishing the maintenance dose or when discontinuing the preparation, it is recommended to reduce the dose gradually.
Additional information on special populations
Paediatric population
Kebirterona is not recommended for use in male children and adolescents below 18 years of age due to a lack of data on safety and efficacy.
Kebirterona must not be given before the conclusion of puberty since an unfavourable influence on longitudinal growth and the still unstabilised axes of endocrine function cannot be ruled out.
Older people
There are no data suggesting the need for a dosage adjustment in elderly patients.
Patients with hepatic impairment:
The use of Kebirterona is contraindicated in patients with liver diseases.
Patients with renal impairment:
The use of Kebirterona in patients with renal impairment has not been investigated. There are no data suggesting the need for dosage adjustment in patients with renal impairment.
Method of administration
The tablets are to be taken with some liquid after meals.
For oral administration.
No special requirements.
