Cyproterone acetate 50mg tablets
Each round, white, flat, 9mm tablet is embossed on one side with "BV" in a regular hexagon, and is scored on the other. Each tablet contains 50mg cyproterone acetate.
ANDROCUR is an antiandrogenic hormone preparation. It inhibits the influence of androgens which are also produced - to a slight extent- in the female organism, and also exerts a progestational and antigonadotrophic effect.
Cyproterone acetate inhibits competitively the effect of androgens at androgen-dependent target organs, e.g. it shields the prostate from the effect of androgens originating from the gonads and/or the adrenal cortex.
In the man, under treatment with ANDROCUR, sexual drive and potency are reduced and gonadal function is inhibited. These changes are reversible following discontinuation of the therapy.
In the woman, hirsuitism is reduced, but also androgen-dependent alopecia and elevated sebaceous gland function are reduced. During treatment, ovarian function is reduced.
Following oral administration, cyproterone acetate is completely absorbed over a wide dose range. The ingestion of 50mg of cyproterone acetate gives maximum serum levels of about 140ng/ml at about 3 hours. Thereafter drug serum levels decline during a time interval of typically 24 to 120h, with a terminal half-life of 43.9 ± 12.8h. The total clearance of cyproterone acetate from serum was determined to be 3.5 ± 1.5 ml/min/kg. Cyproterone acetate is metabolised by various pathways, including hydroxylation and conjugation. The main metabolite in human plasma is 15ß-hydroxy derivative.
Some dose parts are excreted unchanged with bile fluid. Most of the dose is excreted in the form of metabolites at a urinary to bilary ratio of 3:7. The renal and bilary excretion was determined to proceed with a half-life of 1.9 days. Metabolites from plasma were 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 unbound. Because protein binding is non-specific, changes in SHBG (sex hormone binding globulin) levels do not affect the pharmacokinetics of cyproterone acetate.
According to the long half-life of the terminal disposition phase from plasma (serum) and the daily intake, an accumulation of cyproterone acetate by a factor of about 3 can be expected in the serum during repeated daily administration.
The absolute bioavailability of cyproterone acetate is almost complete (88% of dose).
Indications in the man
Antiandrogen treatment in inoperable carcinoma of the prostate
Reduction of drive in sexual deviations
Indications in the woman
Severe signs of androgenization, e.g. very severe hirsutism in the female, severe androgenetic alopecia, often attended by severe forms of acne and/or seborrhoea.
Dosage and Administration
Dosage in the man
Antiandrogen treatment in inoperable carcinoma of the prostate
To eliminate the effect of adrenocortical androgens after orchiectomy: 2 tablets once or twice daily (= 100-200mg). Without orchiectomy: 2 tablets twice to three times daily (= 200-300mg).
The tablets are to be taken with some liquid after meals. Treatment should not be interrupted nor the dosage reduced after improvement or remissions have occurred.
To reduce the initial increase of male sex hormones in treatment with LH-RH agonists: Initially 2 tablets ANDROCUR twice daily (= 200mg) alone for 5 - 7 days followed by 2 tablets ANDROCUR twice daily (= 200mg) for 3 - 4 weeks together with an LH-RH agonist in the dosage recommended by the manufacturer.
To eliminate the effect of adrenocortical androgens in treatment with LH-RH agonists: Continuation of the antiandrogen therapy with 2 tablets ANDROCUR once to twice daily (= 100 - 200mg).
Reduction of drive in pathologically altered or increased sexuality
The tablets are to be taken with some liquid after meals. Generally the treatment is started with 1 tablet twice daily. It may be necessary to increase the dose to 2 tablets twice daily or even 2 tablets 3 times daily for a short period of time. When a satisfactory result is achieved, an attempt should be made to maintain the therapeutic effect with the lowest possible dose. Quite often 1/2 a tablet twice daily is sufficient. When establishing the maintenance dose or when discontinuing the preparation, one should not reduce the dosage abruptly, but gradually. To this end, the daily dose should be reduced by 1 tablet or, better,1/2 a tablet, at intervals of several weeks.
To stabilise the therapeutic effect, it is necessary to take ANDROCUR over a protracted period of time, if possible with the simultaneous use of psychotherapeutic measures.
Dosage in the Woman
Pregnant women must not take ANDROCUR. Therefore pregnancy must be excluded before the start of therapy.
In women of childbearing age, the treatment is commenced on the 1st day of the cycle. Only women with amenorrhoea can start the treatment immediately. In this case, the first day of treatment is to be regarded as the 1st day of the cycle and the following recommendations then observed as normal.
Two tablets of ANDROCUR are to be taken daily with some liquid after a meal from the 1st to the 10th day of the cycle (= for10 days). In addition, these women receive a progestogen-oestrogen preparation, e.g. from the 1st to the 21st day of the cycle [1 tablet DIANE-35 daily], to provide the necessary contraceptive protection and to stabilise the cycle.
Women receiving the cyclical combined therapy should keep to a particular time of the day for tablet taking. If more than 12 hours elapse from this time, contraceptive protection in this cycle may be reduced. The use of Androcur and Diane-35 should nevertheless be continued according to the instructions, ignoring the missed tablet or tablets, in order to avoid premature bleeding in this cycle. However, a non-hormonal method of contraception (with the exception of the rhythm and temperature methods) is to be employed additionally for the rest of the cycle.
A 7-day tablet-free interval is observed after 21 days during which time a withdrawal bleeding occurs. Exactly 4 weeks after the first course was started i.e. on the same day of the week, the next cyclical course of combined treatment is started, regardless of whether bleeding has stopped or not. If no bleeding occurs, the treatment must be interrupted and pregnancy must be excluded before tablet taking is resumed.
Following clinical improvement, the daily dose of ANDROCUR during the first 10 days of the combined treatment with Diane-35 can be reduced to 1 or ½ tablet. Perhaps DIANE-35 alone will be sufficient.
With regard to the cyclical combined therapy, attention is drawn to the special notes contained in the product information for Diane-35, the preparation used in combination with ANDROCUR.
In postmenopausal or hysterectomised patients, ANDROCUR may be administered alone. According to the severity of the complaints, the average dose should be 1 to ½ tablet ANDROCUR once daily for 21 days, followed by a 7-day tablet-free interval.
Pregnancy, lactation, liver diseases, a history of jaundice or persistent itching during a previous pregnancy, a history of herpes of pregnancy, Dubin-Johnson syndrome, Rotor syndrome, previous or existing liver tumours (in carcinoma of the prostate only if these are not due to metastases), wasting diseases (with the exception of carcinoma of the prostate), severe chronic depression, previous or existing thromboembolic processes, severe diabetes with vascular changes, sickle-cell anaemia.
In patients with inoperable prostatic carcinoma presenting with a history of thromboembolic processes or suffering from sickle-cell anaemia or from severe diabetes with vascular changes, the risk:benefit ratio must be considered carefully in each individual case before ANDROCUR is prescribed.
With regard to the cyclical combination therapy of severe signs of androgenization, attention is also drawn to the data on contraindications contained in the product information for Diane-35, the preparation is used in addition to ANDROCUR.
Warnings and Precautions
The drive-reducing effect of ANDROCUR can be diminished under the disinhibitory influence of alcohol.
ANDROCUR should not be given before the conclusion of puberty since an unfavourable influence on longitudinal growth and the still unstabilized axes of endocrine function cannot be ruled out.
During treatment, liver function, adrenocortical function and the red blood-cell count should be checked regularly.
Direct hepatic toxicity, including jaundice, hepatitis and hepatic failure, which has been fatal in some cases, has been reported in patients treated with 200 - 300mg 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.
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 included in the differential-diagnostic considerations.
Strict medical supervision is necessary if the patient suffers from diabetes.
A sensation of shortness of breath may occur in individual cases under high-dosed treatment with ANDROCUR. The differential diagnosis in such cases must include the stimulating effect on breathing known for progesterone and synthetic progestogens which is accompanied by hypocapnia and compensated respiratory alkalosis and which is not considered to require treatment.
In extremely rare cases, the occurrence of thromboembolic events has been reported in temporal association with the use of ANDROCUR although a causal relationship seems to be questionable. Rarely cases of osteoporosis have also been reported.
The therapy of sexual deviations with ANDROCUR is usually ineffective in chronic alcoholism.
Before the start of therapy, a thorough general medical and gynaecological examination (including the breasts and a cytological smear of the cervix) should be carried out in women. Pregnancy must be excluded in women of childbearing age.
If, during the combined treatment, persistent or recurrent bleeding occurs at irregular intervals, a gynaecological examination must be carried out to exclude organic disease.
With regard to the necessary additional use of Diane-35, attention is drawn to all the data contained in the product information for this preparation.
Effect on driving and ability to use machinery
It should be pointed out to patients whose occupation demands great concentration (e.g. road users, machine operators) that ANDROCUR can lead to tiredness and diminished vitality and can impair the ability to concentrate.
Preclinical safety data
Investigations into the toxicity following repeated administration of cyproterone acetate gave no indication of specific risks from the use of ANDROCUR.
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).
Experimental investigations into possible sensitising effects of cyproterone acetate have not been carried out.
The temporary inhibition of fertility in male and female rats brought about by daily oral treatment did not in any way indicate that treatment with ANDROCUR leads to spermatozoa or ovocyte damage which could lead to malformations or impairment of fertility in the offspring.
Investigations into embryotoxic or teratogenic effects were not carried out with cyproterone acetate but only in combination with ethinylestradiol. Such investigations produced no effects after treatment during the foetal organogenesis before development of the external genital organs which would indicate a general teratogenic potential in humans. Administration of high doses of cyproterone acetate during the hormone-sensitive differentiation phase of the genital organs (starting roughly on day 45 of gravidity) could cause feminization effects in male foetuses. Observation of male newborn children who had been exposed in the uterus to cyproterone acetate revealed no indications of feminization. However, pregnancy is a contraindication for use of ANDROCUR. Women of child-bearing age should only be treated if reliable contraceptive measures are taken at the same time.
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 relevance of these findings is presently uncertain. Clinical experience to date would not support an increased incidence of hepatic tumours in man. Nor did investigations into the tumorigenicity of cyproterone acetate in rodents reveal any indication of a specific tumorigenic potential. However, it must be borne in mind that sexual steroids can promote the growth of certain hormone-dependent tissues and tumours.
On the whole the available toxicological findings do not raise any objection to the use of ANDROCUR in humans if used in accordance with the directions for the given indications and at the recommended dosages.
Pregnancy and Lactation
Use in Pregnancy
The administration of ANDROCUR during pregnancy is contraindicated.
Use in Lactation
The administration of ANDROCUR during lactation is contraindicated. About 0.2% of the dose is excreted with the breast milk.
Over the course of several weeks, ANDROCUR inhibits spermatogenesis as a result of the antiandrogenic and antigonadotropic actions. Spermatogenesis recovers gradually within a few months of discontinuing the therapy.
In male patients, ANDROCUR occasionally leads to gynaecomastia (sometimes combined with tenderness to touch of the mamillae) which usually regresses after withdrawal of the preparation.
In women, ovulation is inhibited under the combined treatment, so that a state of infertility exists. A feeling of tension in the breasts may occur.
Tiredness and diminished vitality and occasionally temporary inner restlessness or depressive moods can occur.
Changes in body weight are possible.
The requirement for oral antidiabetics or insulin can change.
Acute toxicity studies following single administration showed that cyproterone acetate, the active ingredient of ANDROCUR, can be classified as practically non-toxic. Nor is any risk of acute intoxication to be expected after a single inadvertent intake of a multiple of the dose required for therapy.
Shelf-life: 5 years.
Special precautions for storage:
Store below 25°C.
50 tablets sealed in deep-drawn strips made of polyvinyl chloride film with counter-sealing foil made of aluminium with heat sealable coating.
List of excipients
Polyvidone 25 000
Colloidal anhydrous silica