Cyproterone Acetate 50mg Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Cyproterone Acetate 50mg Tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 50mg cyproterone acetate.
For excipients, see section 6.1 (List of Excipients)
3. PHARMACEUTICAL FORM
Tablet
The tablets are white, round, scored on one side and embossed “50” on the reverse side.
4. CLINICAL PARTICULARS
4.1. Therapeutic indications
Control of libido in severe hypersexuality and/or sexual deviation in the adult male.
Management of patients with prostatic cancer, (a) to suppress "flare" with initial gonadorelin (LHRH) analogue therapy,(b) in long-term palliative treatment where gonadorelin (LHRH) analogues or surgery are contraindicated, not tolerated, or where oral therapy is preferred, and (c) in the treatment of hot flushes in patients under treatment with gonadorelin analogues or who have had orchidectomy.
4.2. Posology and method of administration
For oral administration.
For 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.
Not recommended for adolescents under the age of 18 years.
For management of prostatic cancer:
Adults including the elderly:
Dosage for suppression of "flare" with initial gonadorelin analogue therapy is 300mg/day, which may be reduced to 200mg if the higher dose is not tolerated. For long-term palliative treatment where gonadorelin analogues or surgery are contraindicated, not tolerated, or where oral therapy is preferred the dosage is 200-300mg/day.
For the above two indications the dosage should be divided into 2 - 3 doses per day and taken after meals.
For the treatment of hot flushes in patients under treatment with gonadorelin analogues, or who have had orchidectomy, a 50mg starting dose, with upward titration if necessary within the range 50-150mg/day, is recommended. For this indication the dosage should be divided into 1 - 3 doses per day and taken after meals.
Children:
Not recommended.
4.3 Contraindications
Cyproterone Acetate must not be used in patients with meningioma or a history of meningioma.
In the control of libido in hypersexuality and sexual deviation, the following contraindications apply:
Liver disease, malignant tumours (except for carcinoma of the prostate) and 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. Cyproterone Acetate should not be given to patients under the age of 18 years, or to those whose bone maturation and testicular development are incomplete.
Hypersensitivity to any of the constituents of Cyproterone Acetate 50mg Tablets.
4.4 Special warnings and precautions for use
In all indications:
Direct hepatic toxicity, including jaundice, hepatitis and hepatic failure, which has been fatal in some cases, has been reported in patients treated with 200300 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 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.
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 a patient treated with Cyproterone Acetate is diagnosed with meningioma, treatment with Cyproterone Acetate must be stopped (see section 4.3).
As with other sex steroids, benign and malignant liver changes have been reported in isolated cases.
In very rare cases, liver tumours may lead to life-threatening intra-abdominal haemorrhage. 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 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.
During treatment adrenocortical function should be supervised, since suppression has been observed.
Sperm count and volume of ejaculate are reduced. Infertility is usual, and there may be azoospermia after 8 weeks. There is usually slight atrophy of 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 cyproterone acetate, or in some patients, up to 20 months. Whether 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.
Hypochromic anaemia has been reported rarely during long-term treatment, and blood-counts before and at regular intervals during treatment are advisable.
A negative nitrogen balance is usual at the start of treatment, but does not persist.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.
In the control of libido in hypersexuality or sexual deviation:
Doctors are advised to ensure that the fully informed consent of the patient to receive cyproterone acetate therapy, is witnessed and can be verified.
A spermatogram should be recorded before the start of treatment in patients of reproductive age, as a precaution against the attribution of pre-existing infertility to cyproterone acetate at a later stage. It should be noted that the decline in spermatogenesis is slow, and cyproterone acetate should therefore not be regarded as a male contraceptive.
In the treatment of prostatic cancer:
Patients with a history of thrombosis 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.
In extremely rare cases, the occurrence of thromboembolic events has been reported in temporal association with the use of cyproterone acetate. However a causal relationship has not been established.
It has been found that some patients with severe chronic depression deteriorate whilst receiving cyproterone acetate therapy.
Cyproterone acetate can influence carbohydrate metabolism. Parameters of carbohydrate metabolism should be examined carefully in all diabetics before and regularly during treatment.
4.5 Interaction with other medicinal products and other forms of interaction
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).
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.
In the control of libido in hypersexuality or sexual deviation:
Alcohol can reduce the effect of cyproterone acetate which is ineffective in chronic alcoholics.
4.6. Pregnancy and lactation
Not applicable
4.7. Effects on ability to drive and use machines
Fatigue and lassitude are common in the first few weeks of therapy but usually become much less from the third month. Patients should be warned to take special care when driving or operating machinery.
4.8 Undesirable effects
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.
See also sections 4.4 and 4.7.
4.9. Overdose
There is no specific antidote. Treatment of overdosage should therefore be symptomatic.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Cyproterone acetate acts 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.
In prostatic cancer:
Prostatic carcinoma and its metastases are in general androgen-dependent. Cyproterone acetate exerts a direct anti-androgen action on the tumour and its metastases. It also has progestogenic activity, which exerts a negative feedback effect on the hypothalamic receptors, so leading to a reduction in gonadotrophin release, and hence to diminished production of testicular androgens. Cyproterone acetate may be used alone, or in conjunction with surgery or gonadorelin analogues.
The antigonadotropic effect of cyproterone acetate is also exerted when administered with LHRH analogues. The initial increase of testosterone caused by this class of substances is reduced by cyproterone acetate.
5.2. Pharmacokinetic properties
Following oral administration, cyproterone acetate is completely absorbed over a wide dose range. The ingestion of two 50 mg of cyproterone acetate 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 15 P -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 nonspecific, 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).
5.3 Preclinical safety data
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 (300 mg/day).
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.
6. PHARMACEUTICAL PARTICULARS
6.1. List of excipients
Lactose monohydrate Maize starch Povidone K 25 Magnesium Stearate Colloidal anhydrous silica
6.2.
Incompatibilities
Not applicable.
6.3 Shelf life
36 months
6.4. Special precautions for storage
None
6.5. Nature and contents of container
Packs of blister strips containing 56 or 168 -tablets
6.6. Instructions for use and handling
Not applicable
7. MARKETING AUTHORISATION HOLDER
Stragen UK Limited
Castle Court
41 London Road
Reigate
Surrey
RH2 9RJ
United Kingdom
8. MARKETING AUTHORISATION NUMBER
PL 21844/0001
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
15/08/2009
10 DATE OF REVISION OF THE TEXT
26/02/2010