INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo ANDROCUR 50 mg TABLETS

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

ANDROCUR 50 mg TABLETS

Oral antiandrogen

COMPOSITION
1 Androcur 50 mg tablet contains
cyproterone acetate (6-chloro-17-hydroxy-1alpha,2alpha-methylene-pregna-4,6-diene-3,20-dione-acetate) 50 mg.

PHARMACOLOGICAL CLASSIFICATION
A. 21.12 Hormone inhibitors.

PHARMACOLOGICAL ACTION
Androcur is an antiandrogenic hormone preparation.
The active substance, cyproterone acetate, has three partial effects: an antiandrogenic effect, a progestational effect and an antigonadotropic effect.
Cyproterone acetate blocks the effect of endogenously produced and exogenously administered androgens at the target organs by means of competitive inhibition.
The stimulating effect of male sex hormones on androgen dependent structures and functions is weakened or abolished by cyproterone acetate.
The inherent progestational activity exerts a negative feedback on the hypothalamic receptors so leading to a reduction in gonadotropin release, and hence to diminished production of androgens.

INDICATIONS
•        In men
Reduction of drive in sexual deviations, antiandrogen treatment in inoperable carcinoma of the prostate.
•        In women
Severe signs of androgenisation, eg very severe hirsutism, androgen-dependent severe loss of scalp hair eventually resulting in baldness (severe androgenic alopecia), often attended by severe forms of acne and/or seborrhoea.

CONTRA-INDICATIONS
Pregnancy; lactation; liver disease; 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); depression; previous or existing thromboembolic processes; diabetes with vascular changes; sickle-cell anaemia.
As regards patients with prostatic carcinoma who have a history of thromboembolic processes and/or an existing sickle-cell anaemia, or diabetes with vascular changes, the risk:benefit ratio must be considered carefully in each individual case before the use of Androcur.

DOSAGE AND DIRECTIONS FOR USE
•        In men
O        Reduction of drive in sexual deviations
The individual dosage will be determined by the doctor. The tablets are to be taken with a little liquid after meals.
Generally, 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 three times daily for a short period of time. If a satisfactory result is achieved, one should try to maintain the therapeutic effect with the lowest possible dose. 50 mg per day may be adequate in some patients. 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 half 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.
O        Antiandrogen treatment in inoperable carcinoma of the prostate
After orchidectomy:
2 tablets once to twice daily (= 100-200 mg).
Without orchidectomy:
2 tablets twice to three times daily (= 200-300 mg).
In both cases, the treatment and dosage prescribed by the doctor should not be changed or interrupted after improvement or remissions have occurred.

•        In women
O        For severe signs of androgenisation
Before starting Androcur therapy a thorough general medical and gynaecological examination (including the breasts and a cytological smear of the cervix) should be carried out. Since pregnant women may not take Androcur, pregnancy must be excluded.
<>        In women of child bearing age
For the duration of Androcur therapy women of child-bearing age must also receive a combination oral contraceptive. This will provide the necessary contraceptive protection and will stabilise the menstrual cycle. Dosage and directions for use as per the package insert of that product must be strictly adhered to.
Prior to commencing Androcur treatment it is always necessary for the patient to receive one complete cycle of a combination oral contraceptive.
Extra non-hormonal methods (with the exception of the rhythm and temperature methods) should be employed during the first 3 weeks of the first cycle, which may be shorter than 4 weeks. Subsequent cycles should then be regular.
In the subsequent cycle of the combination oral contraceptive (second cycle) which starts the very next day after completion of the first pack of combination oral contraceptive, Androcur treatment is commenced on the 5th day of the menstrual cycle (1st day of bleeding = 1st day of the menstrual cycle).
2 Androcur 50 mg tablets are to be taken with some liquid after a meal from the 5th to the 14th day of the cycle (ie for ten days).
Every 28 days (the usual duration of a menstrual cycle), the above dosage regimen is to be followed.
Women receiving the cyclical combined Androcur and combination oral contraceptive 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 these two products should nevertheless be continued according to instructions, ignoring the missed tablet or tablets, in order to avoid premature bleeding in this cycle. However, an additional non-hormonal method of contraception (with the exception of the rhythm and temperature methods) is to be employed for the rest of the cycle.
If bleeding fails to occur during the last days of the 28-day cycle, the doctor must be consulted.
Following clinical improvement, the doctor can reduce the daily dose of Androcur 50 mg to 1 or half a tablet daily during the first 10 days of the combination cyclical treatment with the oral contraceptive combination preparation.
<>        In postmenopausal or hysterectomised patients
In postmenopausal or hysterectomised patients in whom the additional administration of a combination oral contraceptive is not required for cycle control or contraception, Androcur may be administered alone. Depending upon the severity of the condition, the average dose should be 1 to half an Androcur 50 mg tablet (= 50-25 mg) once daily for 21 days, followed by a seven day tablet-free interval.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
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).
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 feminisation effects in male foetuses. Observation of male newborn children who had been exposed in the uterus to cyproterone acetate revealed no indications of feminisation. However, pregnancy is a contra-indication for the 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, there is some evidence of genotoxicity as 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 and how these findings relate to the risk of developing benign and malignant liver tumours in humans is presently unknown. 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.
Direct hepatic toxicity, including jaundice, hepatitis and hepatic failure, which has been fatal in some cases, has been reported in patients treated with 200 to 300 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, eg metastatic disease, in which case cyproterone acetate should be continued only if the perceived benefit outweighs the risk.
In rare cases benign, and in even rarer cases malignant, liver tumours leading in isolated cases to life-threatening intraabdominal haemorrhage have been reported after the use of sex steroids to which the substance contained in Androcur 50 mg also belongs. If severe upper abdominal complaints, liver enlargement or signs of intraabdominal haemorrhage occur, a liver tumour should be included in the differential-diagnostic considerations.
Over the course of several weeks, Androcur gradually restricts the man's ability to procreate. This ability is regained within a few months of discontinuing the therapy. In rare cases recovery may be possible under dose reduction.
In male patients, Androcur 50 mg may lead to gynaecomastia (sometimes combined with tenderness to touch of the mamillae) which may regress after withdrawal of the preparation.
In women, ovulation is inhibited under the combined cyclical treatment, so that a state of infertility exists. This is essential because if Androcur were taken during pregnancy, the properties of the preparation could lead to signs of feminisation in male neonates.
A feeling of tension in the breasts may occur.
A high-dosed treatment may reduce the function of the adrenal cortex, particularly the adrenocortical response to stress.
Tiredness and diminished vitality and occasionally temporary inner restlessness or depressive moods can occur. Changes in body-weight are possible.
It should be pointed out to patients whose occupation demands great concentration (eg road users, machine operators) that Androcur 50 mg can lead to tiredness and diminished vitality and can impair the ability to concentrate.
In extremely rare cases, the occurrence of thromboembolic events has been reported in temporal association with the use of Androcur. However, a causal relationship seems to be questionable.
Androcur should be used with caution in cardiovascular disease, ischemic heart disease, cerebrovascular disease and hypertension.
The sexual drive-reducing effect of Androcur can be diminished under the disinhibitory influence of alcohol.
Androcur 50 mg should 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.
During treatment, liver function, adrenocortical function and the red blood-cell count should be checked regularly. In diabetics, carbohydrate metabolism as well should be monitored particularly carefully.
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 compensatory alkalosis and which is not considered to require treatment.
Before the start of therapy in women, a thorough general medical and gynaecological examination (including the breasts and a cytological smear of the cervix) should be carried out. Pregnancy must be excluded in women of child-bearing age.
Attention is drawn to the special notes on side effects, reasons for immediate discontinuation of treatment and all relevant data contained in the package insert of the oral contraceptive combination preparation.
If, during the combined cyclical treatment, slight "unscheduled" bleeding occurs, tablet-taking should not be interrupted. However, if the bleeding is heavy, the patient should consult her doctor.
Haemoglobin and red blood cell counts may decrease on therapy with Androcur.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
See “Side effects and special precautions”. Treatment is supportive and symptomatic.

IDENTIFICATION
White to faintly yellowish, round, flat-sided tablets with bevelled edges. Upper surface: imprinted with BV in an equilateral hexagon; lower surface: scored.

PRESENTATION
Bottles of 20 and 50 tablets.

STORAGE INSTRUCTIONS
Store below 30°C. Keep out of reach of children.

REGISTRATION NUMBER
R/21.12/160

NAME AND BUSINESS ADDRESS OF THE APPLICANT
Schering (Pty) Ltd
(Reg No: 1964/009072/07)
106 Sixteenth Road
Randjespark
Midrand        1685
P O Box 5278
Halfway House        1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT
14 February 1992

SCHERING (PTY) LTD
(Reg No: 1964/009072/07)
Subsidiary of
Schering AG        Germany

Updated on this site: April 2003
Current: January 2005
Source: Pharmaceutical Industry

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