In men

-           for the palliative treatment of metastasising or locally advanced, inoperable prostate carcinoma

-           if treatment with LHRH analogues or surgical intervention has proven inadequate, is contraindicated or oral therapy is given preference.

-           initially for the prevention of undesired sequelae and complications which can be caused at the start of treatment with LHRH agonists by the initial increase in serum testosterone.

-           for the treatment of hot flushes, which occur during treatment with LHRH agonists or following an orchiectomy.

-           sexual-drive suppression in the event of hypersexuality and sexual deviations.

Cyproterone acetate 50 mg can be used for sexual-drive suppression in the event of hypersexuality and sexual deviations where other therapies are considered unsuitable.

 

In women

Severe to very severe androgenisation symptoms such as

-           severe forms of increased facial and body hair caused by androgens (severe hirsutism),

-           severe forms of loss of scalp hair (androgenetic alopecia), often associated with severe forms of acne and/or seborrhoea,

 

 

Cyproterone acetate 50 mg is indicated for severe to very severe androgenisation symptoms in women, where satisfactory results could not be obtained with medicinal products containing low-dose cyproterone or with other treatment options.

 

Note: Pregnant women may not take Androcur. Consequently, pregnancy has to be excluded prior to treatment. Androcur has to be combined with a suitable oestrogen or a suitable progestogen-oestrogen combination in fertile women, in order to avoid menstrual-cycle disturbances.

Dosage

The tablets should be taken with some liquid after meals.

 

Use in men

The maximum daily dose is 300 mg.

 

Sex-drive suppression in the event of hypersexuality and sexual deviations

The duration of treatment has to be individually specified. Sometimes, a therapeutic effect can set in after a few weeks; however, it can also take several months until any treatment success is noticed.

 

The initial dose is generally 1 tablet twice daily (= 100 mg). If there has been no improvement after about four weeks, the dose can be increased to two tablets, twice daily (= 200 mg) or temporarily even to two tablets thrice daily (= 300 mg).

 

When a satisfactory treatment result has been reached, it should be attempted to manage with the lowest possible dose. Often, ½ of a tablet twice daily is sufficient (= 50 mg).

 

When adjusting to a maintenance dose and when discontinuing the product, the dose has to be reduced or discontinued gradually. The daily dose should be decreased by 1 tablet (= 50 mg) or better ½ (= 25 mg) of a tablet in intervals of a few weeks each.

 

In order to stabilise the therapeutic effect, it is necessary to administer Androcur 50 mg over a prolonged period, if possible with simultaneous application of psychotherapeutic measures.

 

The duration of treatment with cyproterone acetate should be determined on an individual basis. If a satisfactory outcome is attained, the therapeutic effect should be maintained with the lowest possible dose. A change in dose or discontinuation of cyproterone acetate should be undertaken gradually.

 

Anti-androgen treatment of prostate carcinoma

-           Palliative therapy of metastasising or locally advanced, inoperable prostate carcinoma without orchiectomy or treatment with LHRH agonists

Two tablets 2 to 3 times daily (= 200 to 300 mg).

In the event of improvement or remission, therapy should neither be discontinued nor the dose reduced.

 

-           Initially for the prevention of undesired sequelae and complications which can be caused at the start of treatment with LHRH agonists by the initial increase in serum testosterone

First, 2 tablets alone twice daily for 5 to 7 days (= 200 mg) Androcur 50 mg, then 2 tablets twice daily for 3 to 4 weeks (= 200 mg) Androcur 50 mg together with an LHRH agonist in the dosage designated by the marketing authorisation holder.

The instructions in the package leaflet of the product used during treatment with LHRH agonists are to be followed.

 

-           for the treatment of hot flushes, which occur during treatment with LHRH agonists or following an orchiectomy

The recommended dose is 1 to 3 tablets (50 to 150 mg) daily. It can be increased up to 2 tablets three times daily (= 300 mg), when required.

 

Use in women

 

Women of childbearing age with a regular menstrual cycle

Treatment is started in sexually mature women on day 1 of their cycle (first day of menstruation = first day of the cycle).

Two tablets of Androcur (= 100 mg) are to be taken daily from day 1 to day 10 of the cycle, if possible at a specific time, in order to reduce the risk of forgetting to take them. In addition, a suitable oestrogen or suitable progestogen-oestrogen combination with the lowest possible content of ethinyl oestradiol, such as 30 or 35 µg, has to be used each day from day 1 to day 21 of the menstrual cycle, in order to stabilise the cycle of the patient and to provide the necessary contraceptive protection

This is followed by a seven-day break, during which withdrawal bleeding occurs. Four weeks after having started taking the tablets, i.e. on the same day of the week, the next combined treatment is started, irrespective of whether the bleeding has already stopped or is still ongoing. If there has not been any bleeding, pregnancy has to be ruled out prior to continuing treatment.

 

After clinical improvement, the daily Androcur dose can be reduced during the first 10 days of combination treatment to 1 (= 50 mg) or ½ tablet (= 25 mg), or combination treatment continued with Androcur 10 mg tablets. Perhaps even an anti-androgenic progestogen-oestrogen combination alone will suffice.

 

Since women may not become pregnant while receiving Androcur 50 mg, they must properly adhere to the treatment regimen (see above). Conception protection can be expected only if there has been no deviation from a 24‑hour schedule of use.

 

Women of childbearing age with an irregular menstrual cycle or amenorrhoea

After pregnancy has been ruled out, treatment may begin immediately according to prescription. As opposed to women of childbearing age who have a regular menstrual cycle, there is no reliable protection against pregnancy as of day 1 of treatment.

Up to day 14 of taking a daily contraceptive, additional mechanical contraception (e.g. by using a condom) will have to be used. Day 1 of treatment will be regarded as day 1 of the menstrual cycle. Further treatment follows as described for women with a regular menstrual cycle. During the tablet-free break, there will probably be withdrawal bleeding.

 

Reaction to missed tablets

If pregnancy is suspected, or after a lengthy tablet-free break, the treatment may only be restarted after pregnancy has been ruled out (see section 4.4).

 

Women, who are taking the oral contraceptive concomitantly with Androcur tablets, should take the tablets at a specific time.

 

If Androcur 50 mg and (or) the oestrogen or the progestogen-oestrogen combination have been missed, they must be taken within 12 hours of the usual time. The contraceptive effect becomes questionable if more than 36 hours have elapsed since the previous administration. Forgetting to take Androcur 50 mg can result in reduced efficacy and intermenstrual bleeding. The missed Androcur tablet(s) shall not be taken (a double dose may not be taken to make up for the forgotten tablet(s)). The oestrogen or progestogen-oestrogen combination shall be continued on schedule to avoid premature withdrawal bleeding. Following the usual seven-day, tablet-free break, the combination treatment is then to be restarted as prescribed.

 

If, however, withdrawal bleeding does not occur during the break, pregnancy has to be reliably excluded prior to starting the tablets again.

 

The advice and recommendations contained in the package leaflet and in the summary of product characteristics of the oestrogen or the progestogen-oestrogen combination, being used, have to be followed (above all with regard to the reliability of contraceptives and recommendations in the event of forgetting to take the tablets).

 

Post-hysterectomy or post-menopausal women

Androcur 50 mg may be administered alone to patients who have had a hysterectomy or have gone through menopause. Depending upon the severity of the complaints, the dose is ½ to 1 tablet (= 25 to 50 mg) daily, according to the tablet-taking schedule of 21 days and a 7‑day break.

 

The risks and benefits of treatment with Androcur 50 mg should be re-evaluated at the start of the menopause. Long-term treatment (over the course of years) with Androcur 50 mg should be avoided (see section 4.4 Meningiomas).

 

Additional information on special populations

 

Children and adolescents

Androcur 50 mg should not be used in male children and adolescents younger than 18 years of age, since no data on efficacy and tolerability exist for this age group.

The safety and efficacy of Androcur 50 mg in female children and adolescents under 18 years has not been investigated.

Androcur 50 mg may not be used in male and female patients prior to the end of puberty, since an undesirable effect on the endocrine system and growth in length cannot be ruled out.

 

Geriatric Patients

The pharmacokinetics of cyproterone acetate in elderly patients has not been investigated.

 

Patients with liver disease

The use of Androcur 50 mg is contraindicated in patients with liver disease for as long as the liver values have not returned to normal.

 

Patients with renal impairment

The pharmacokinetics of cyproterone acetate in patients with renal impairment has not been investigated.

 

Method of administration

Oral use

The following contraindications shall apply when indicated for ‘sex-drive suppression in the event of hypersexuality and sexual deviations’ in men - Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, - liver diseases, - Dubin-Johnson syndrome, Rotor syndrome, - presence or history of liver tumours, - known or suspected malignant diseases, - presence or history of meningiomas, - severe chronic depression, - history or presence of thromboembolic events, - severe diabetes mellitus with vascular changes, - sickle cell disease, - adolescents before the end of puberty and children (see section 4.2). The following contraindications shall apply when indicated for ‘palliative treatment of advanced prostate carcinoma’ in men - Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, - liver diseases, - Dubin-Johnson syndrome, Rotor syndrome, - existing or history of liver tumours (only if they have not been caused by metastases of the prostate carcinoma), - known or suspected malignant diseases (other than advanced prostate carcinoma), - presence or history of meningiomas, - severe chronic depression, - presence of thromboembolic events, - adolescents before the end of puberty and children (see section 4.2). The following contraindications shall apply when indicated for ‘severe to very severe signs of androgenisation’ (see section 4.1) in women - Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, - during pregnancy, - whilst breastfeeding, - diagnostically inconclusive vaginal bleeding, - liver diseases, - Dubin-Johnson syndrome, Rotor syndrome, - idiopathic pregnancy or severe pruritus during pregnancy or respectively Pemphigoid gestationis in the medical history, - history or presence of liver tumours, - known or suspected malignant diseases, - presence or history of meningiomas, - severe chronic depression, - history or presence of thromboembolic events, - severe diabetes mellitus with vascular changes. - sickle cell disease, - adolescents before the end of puberty and children (see section 4.2). Additionally, the information concerning contraindications and reasons to discontinue the oestrogen or progestogen-oestrogen combination immediately, which is contained in the respective package leaflets and summary of product characteristics, have to be followed when treating severe signs of androgenisation with combination therapy.

In patients with advanced prostate carcinoma, the benefits have to be weighed carefully against the risks of using this product on an individual basis, if thromboembolic processes, severe Diabetes mellitus with vascular changes or sickle-cell disease have been diagnosed in the past.

 

Thromboembolic events (men and women)

The occurrence of thromboembolic events has been reported in patients using Androcur 50 mg. 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 malignant diseases are at increased risk of further thromboembolic events.

 

Adrenal cortex (men and women)

The adrenocortical function should be checked regularly during treatment, since preclinical results indicate suppression due to the corticoid-like effect of Androcur 50 mg (see section 5.3).

 

Liver (men and women)

Direct hepatotoxic reactions, such as jaundice, hepatitis and liver failure have been reported in patients treated with Androcur. Cases with fatal outcome have also been reported at doses of 100 mg and more. Most of the reported fatalities were men with advanced prostate carcinoma. Toxicity is dose dependent and generally develops several months after the start of treatment.

Liver function should be checked prior to the start of treatment, at regular intervals during treatment, as well as whenever symptoms or signs suggest hepatotoxicity. As a rule, Androcur should be discontinued (men and women), if the suspicion of hepatotoxicity has been confirmed, the exception being, that the hepatotoxicity can be explained by another cause, such as metastases (in men). In this case, treatment with Androcur should only be continued, if the expected benefit outweighs the risk.

 

Benign and malignant liver tumours (in very rare cases in men), which may lead to life-threatening intra-abdominal haemorrhage, have been observed as a result of using Androcur 50 mg. A liver tumour should be considered in the differential diagnosis when severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur. If necessary, therapy should be discontinued.

 

Meningioma (men and women):

In connection with the use of cyproterone acetate the occurrence of meningiomas (single and multiple) has been reported mainly at doses of 25 mg per day and above. The risk of meningioma increases with increasing cumulative doses of cyproterone acetate (see section 5.1). High cumulative doses can be attained by long-term use (several years) or in cases of shorter duration with high daily doses. Patients should be monitored for meningioma in accordance with clinical practice.

If a patient treated with Androcur 50 mg is diagnosed with meningioma, treatment with Androcur 50 mg and other medicinal products containing cyproterone acetate must be permanently discontinued (see section ”Contraindications”).

There is some evidence to indicate that the risk for meningioma may reduce following cessation of treatment with cyproterone acetate.

 

Carbohydrate metabolism (men and women)

There have been reports of increased blood sugar levels in diabetics treated with Androcur 50 mg. Carbohydrate metabolism should be monitored carefully in patients with Diabetes mellitus before and regularly during treatment with Androcur 50 mg since the required dose of oral antidiabetic drugs or insulin can change. See also section 4.3.

 

Breathing (men and women)

The feeling of being short of breath may occur during high-dosed administration of Androcur (common in men). In the differential diagnosis of such cases, the stimulatory effect of progesterone and synthetic progestogens on breathing should be considered, which is accompanied by hypocapnea and compensatory alkalosis, and which is not considered to require treatment.

 

Erythropoiesis (men)

Cases of anaemia have occurred during treatment with Androcur 50 mg. Therefore, the erythrocyte count in men has to be monitored regularly during treatment.

 

Other conditions (men)

When using Androcur 50 mg to suppress the sexual drive in hypersexuality and sexual deviations, the simultaneous use of alcohol makes it possible to diminish the libido-suppressing effect, due to its disinhibitory effect.

 

Reproductive system and changes in the breast (men)

In the course of treatment for several weeks, spermatogenesis is often inhibited due to the anti-androgenic and anti-gonadotropic effect of cyproterone acetate. Likewise, the volume of ejaculate is reduced. The inhibition of spermatogenesis, which slowly develops during treatment, and which is generally associated with infertility, is reversible following discontinuation. Within a few months, sometimes up to 20 months after ending therapy, spermatogenesis gradually normalises itself, reverting to its previous state prior to using Androcur. Even the effect on the ejaculate is completely reversible. Libido impairment and erectile dysfunction are very common. It is advisable in men of reproductive age, for whom fertility could be important once medication has been completed, to have at least one spermiogram check carried out prior to treatment as a precautionary measure. This can be used best to respond to any unfounded allegations about subsequent infertility being a result of anti-androgen therapy.

Gynaecomastia is common in treated men, which usually regresses after discontinuation of treatment or reduction of dosage.

 

Adverse effects (women)

Pain, tension or enlargement of the breasts commonly occurs at the start of treatment. Loss of libido can occasionally be observed. Irregular gynaecological bleeding and amenorrhoea are very common.

 

Hepatotoxic reactions (hepatitis, liver failure) are very rare. Little is known about the hepatotoxic mechanism of cyproterone acetate. Possibly, it is a direct hepatotoxic effect of the medicinal product; it is more probably caused, however, by a hypersensitivity reaction to a metabolite of cyproterone acetate.

 

Presently available data indicate that the undesirable effects of cyproterone acetate occur more commonly in elderly patients, who are being treated with high doses over an extended period due to malignant diseases. For this reason, liver-function monitoring is absolutely necessary in these patients. Treatment with cyproterone acetate has to be discontinued, should pathological liver function values appear.

 

Additional instructions for use (women)

Before starting treatment, a thorough gynaecological examination (including an examination of the breasts and a cytological cervical smear) must be conducted following the differential diagnosis of androgenisation signs and symptoms. Pregnancy has to be ruled out in the sexually mature due to the risk of feminising male foetuses.

 

Combination treatment results in infertility because of the ovulation-inhibiting effect. After discontinuation, the menstrual cycle readjusts to its previous rhythm.

Treatment has to be stopped immediately if pregnancy does occur during combined therapy through compliance errors, medicinal product interactions, etc. The absence of a withdrawal bleed during the seven-day break may be an indication of pregnancy. Therefore, combination treatment may only be resumed when it is certain that there is no pregnancy.

 

Tablet-taking should not be interrupted should irregular bleeding occur during the three-week combined treatment. However, if bleeding is persistent or recurrent at irregular intervals, a gynaecological examination is required to exclude organic disease.

 

Additionally with regard to combination treatment, special references have to be followed, which are contained in the respective package leaflets and summary of product characteristics of the oestrogen or progestogen-oestrogen combination used.

 

Treatment of hypersexuality and sexual deviations (men)

Sexual deviations are in need of treatment if psychological strain is present. The patient's request is required for treatment.

Given that sexual and androgenic activities are not necessary analogous, suppression of the androgenic activity will not always be accompanied by a suppression of the sexual drive.

 

As a matter of principle, psychiatric, psychotherapeutic and socio-therapeutic measures will be necessary. Suppressing sexuality through treatment with cyproterone-acetate tablets can be advantageous, when these measures are adopted.

 

Patients with organic brain damage or a mental disorder, who suffer from deviant sexual behaviour, are usually therapy-resistant.

 

In the event of possible fertility disorders, it is advisable to have a spermiogram done before starting treatment.

 

Lactose warning (men and women)

Patients with the rare hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take Androcur 50 mg.

Although clinical interaction studies have not been performed, it is expected that ketoconazole, itraconazole, clotrimazole, ritonavir and other strong inhibitors of CYP3A4 inhibit the metabolism of cyproterone acetate, since this medicinal product is metabolised by CYP3A4. On the other hand, inducers of CYP3A4 such as rifampicin, phenytoin, and products containing St. John's wort may reduce the level of cyproterone acetate.

In‑vitro inhibition studies confirm a potential inhibition of the cytochrome P450 enzymes, CYP2C8, 2C9, 2C19, 3A4 and 2D6, at high therapeutic doses of 100 mg cyproterone acetate three times per day.

 

The risk of statin-related myopathy or rhabdomyolysis may be increased, when such HMG‑CoA inhibitors (statins), which are primarily metabolised by CYP3A4, are co-administered with high therapeutic doses of cyproterone acetate, since they are subject to the same metabolic pathway.

 

Additionally, the information concerning interactions, which is contained in the respective package leaflets and summary of product characteristics of the oestrogen or progestogen-oestrogen combination used, have to be followed when treating severe signs of androgenisation with combination therapy.

The use of Androcur 50 mg is contraindicated during pregnancy and lactation (see section 4.3).

 

Pregnancy

Administration of CPA during the hormone-sensitive differentiation phase of the genital organs caused signs of feminisation in male foetuses following high doses in animal studies. Animal studies on embryo-toxicity revealed no evidence of teratogenicity.

 

Based on 100,000 woman-years of CPA exposure, there were 0.2 cases reported, in which male foetuses were exposed in utero to CPA. In the majority of these cases, the women involved had taken 2 mg CPA per day during the first trimester of pregnancy. In isolated cases, 100 mg CPA were taken per day up to the second trimester or respectively 2 mg CPA per day up to the third trimester of pregnancy. None of the male neonates in these cases showed any signs of feminisation. Nonetheless, gravidity is a contraindication for the use of Androcur 50 mg.

 

 

Breastfeeding

CPA passes into breast milk. About 0.2% of the maternal dose can be transferred to the nursing infant.

Androcur 50 mg can cause fatigue and decreased vitality and may impair the ability to concentrate. Androcur 50 mg can, even under normal conditions of use, alter the ability to react to such an extent, that the ability to participate actively in traffic and to operate machinery is impaired.

 

Men

The most commonly reported adverse drug reactions, (ADRs) in male patients taking Androcur 50 mg are decreased libido, erectile dysfunction and reversible inhibition of spermatogenesis.

 

The most serious adverse drug reactions involved hepatotoxic reactions, benign and malignant liver tumours, which may cause intra-abdominal haemorrhage, and thromboembolic events.

 

Women

The most commonly reported adverse drug reactions, (ADRs) in female patients taking Androcur 50 mg are breakthrough bleeding, weight gain and depressive mood.

The most serious adverse drug reactions involved hepatotoxic reactions, benign and malignant liver tumours, which may cause intra-abdominal haemorrhage, and thromboembolic events.

 

The following table lists the adverse drug reactions, which have been reported in connection with Androcur 50 mg. Adverse drug reactions, which were only reported as post-marketing data and for which frequency cannot be estimated, are listed under the frequency category, ‘frequency not known’.

 

The following categories are used to rank adverse drug reactions by frequency of occurrence

Very common       (≥ 1/10)
Common              (≥ 1/100 to < 1/10)
Uncommon           (≥ 1/1,000 to < 1/100)
Rare                     (≥ 1/10,000 to < 1/1,000)
Very rare              (< 1/10,000)
Not known           (frequency cannot be estimated from the available data)

 

The most appropriate MedDRA term has been used to describe a particular reaction. Synonyms and related conditions are not listed but should also be considered.

 

System Organ Class, MedDRA	Very common	Common	Uncommon	Rare	Very rare	Frequency not known
Neoplasms Benign, Malignant and Unspecified (incl. cysts and polyps)				Meningioma	Benign and malignant liver tumours (men)*	Benign and malignant liver tumours (women)*
Investigations			Prolactin levels slightly increased		Decreased cortisol levels
Blood and lymphatic system disorders						Anaemia (men)*
Respiratory, thoracic and mediastinal disorders		Shortness of breath (men)*				Shortness of breath (women)*
Skin and subcutaneous tissue disorders			Rash (men)			Rash (women) Dry skin
Musculoskeletal, connective tissue and bone disorders						Osteoporoses (men)
Metabolism and nutrition disorders		Weight gain or weight loss (men)				Weight gain (women) Weight loss (women) Rise in blood sugar in diabetics (men and women)*
Vascular disorders						Thromboembolic events (men and women)*
General disorders and administration site conditions		Fatigue (men) Hot flushes (men), Sweating (men)				Fatigue (women)
Immune system disorders				Hypersensitivity reactions (men)		Hypersensitivity reactions (women)
Hepatobiliary disorders		Hepatotoxic reactions, such as jaundice, hepatitis, liver failure (men)*				Hepatotoxic reactions, such as jaundice, hepatitis, liver failure (women)*
Reproductive system and breast disorders	Reversible inhibition of spermatogenesis (men)	Gynaecomastia (men)	Tenderness to touch of the mamillae (men)			Inhibition of ovulation (women) Pain and tension in the breast (women) Enlargement of the breasts (women) Spotting (women)* Irregular gynaecological bleeding (women) Amenorrhea (women)
Psychiatric disorders	Decreased libido (men) Erectile dysfunction (men)	Depressive moods (men) Transient restlessness (men) Lassitude				Depressive moods (women) Transient restlessness (women) Decreased libido (women) Increased libido (women)
Gastrointestinal disorders						Intra-abdominal haemorrhage (men and women)*

^§        See section 4.3

*        For further information see section 4.4

 

Stomach complaints, dizziness, headache and nausea have been commonly reported primarily in women in connection with medicinal products, which contain cyproterone acetate as their active ingredient.

 

The occurrence of meningiomas (single and multiple) has been reported in connection with the use of cyproterone acetate (see section 4.4).

 

Isolated cases of anaemia and a reduction in endogenous cortisol production were observed with high-dose treatment with cyproterone acetate (see section 4.4).

 

Treatment with Androcur diminished sexual drive and potency, and inhibited gonadal function in male patients. These changes are reversible after discontinuing treatment.

 

Spermatogenesis is inhibited as a result of the anti-androgenic and anti-gonadotropic effect in men during the course of several weeks of treatment. Spermatogenesis gradually re-establishes itself within a few months after discontinuation of therapy (see section 4.4).

 

Gynaecomastia is common in treated men. It is uncommonly associated with the nipples being more sensitive to touch. These changes mostly revert to their previous state after the end of treatment.

 

As is the case with other anti-androgenic active substances, the long-term use of Androcur can also, in very rare cases, cause osteoporosis in men.

 

The ovarian function is inhibited in women during combined treatment with a suitable oestrogen or a suitable progestogen-oestrogen combination with the intention that infertility will continue throughout treatment.

 

With regard to the necessary combination treatment in women, the special references to adverse drug reactions have to be followed, which are contained in the respective package leaflets and summary of product characteristics of the oestrogen or progestogen-oestrogen combination used.

 

Androcur causes a negative nitrogen balance at the start of treatment, which, however, equalises itself during the course of use. As a precautionary measure due to this initial catabolic effect, Androcur 50 mg should not be given if there are known or suspected malignant diseases (exception: prostate carcinoma) (see section 4.3).

 

A tendency toward a slight increase in prolactin levels was occasionally observed at high doses of CPA.

 

Dry skin can occur due to decreased secretion of the sebaceous glands.

 

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:

 

To report any side effect(s):

The National Pharmacovigilance Centre (NPC).

SFDA Call Center: 19999

E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa

There are no indications pointing toward serious adverse health effects resulting from an overdose of Androcur 50 mg. Studies on acute toxicity after single-dose administration have shown, that cyproterone acetate, the active component of Androcur 50 mg, has to be classified as virtually non-toxic. Similarly, acute intoxication is not to be expected following a single accidental ingestion of multiple treatment doses.

Pharmacotherapeutic group: Anti-androgen, pure, cyproterone; ATC Code: G03 HA01

 

CPA has an anti-androgen, a progestogenic, and an anti-gonadotropic effect. These three partial effects are identifiable in animals and humans.

 

Endocrine pharmacological investigations in animals

 

Anti-androgenic effect

CPA prevents the effect of endogenous and exogenous androgens on the target organs by competitive inhibition. This blocks the translocation of the DHT-receptor complex into the nucleus. In‑vitro cell-culture experiments, testing the effect of CPA on the androgen receptor functions, show CPA to have a high anti-androgenic potency. Additionally, in some in‑vitro test systems, there is a slight partial agonist effect of CPA at the androgen receptor. The stimulatory effect of male sex hormones on androgen-dependent structures and functions is weakened or cancelled by CPA: In animals CPA leads to dose-dependent atrophy of the accessory sex glands, i.e., prostate, seminal vesicles and preputial glands. It affects testicular function: Spermatogenesis is inhibited dose-dependently. Similarly in humans, CPA inhibits the libido in dogs, rabbits, pigs and monkeys.

In rats, the onset of puberty can be prevented or delayed. CPA inhibits the physiological epiphyseal plate closure and bone maturation.

It affects the sebaceous gland function; the thickness of the epidermis decreases.

Treating pregnant animals with CPA results in developmental disorders in male foetuses. Testosterone-dependent differentiation processes are affected: there are more or less prominent signs of feminisation as a result.

 

Progestogenic effect

The Clauberg test (in rabbits) proved the potency of CPA to be 100-fold greater following subcutaneous administration than that of progesterone. In testing for progestogenic effects in rats, CPA is about as potent as progesterone following subcutaneous administration.

 

Anti-gonadotropic effect

As do all potent progestogens, CPA has anti-gonadotropic properties, which manifest themselves in males by inhibiting testicular growth and in females by inhibiting ovulation.

 

Endocrine pharmacological investigations in humans

 

Anti-androgenic effect

CPA inhibits competitively the effect of androgens at their target organs. The following associated effects, among others, have been described in humans: inhibition of sexual drive, reduction of sebaceous gland activity, influence on hair growth, prevention of androgenic growth impulses to the prostatic tissue, inhibition of premature adolescent developmental processes, including bone.

 

Progestogenic effect

CPA is a potent progestogen. According to the Kaufmann assay, it causes endometrial transformation from a total dose of 20 to 30 mg.

 

Anti-gonadotropic effect

As a potent progestogen, CPA has a central inhibitory effect. On account of this anti-gonadotropic effect there is no counter-regulatory increase in LH secretion, although androgens are blocked by the anti-androgenic effect of CPA also at the receptors in the hypothalamus, at which they exert their negative feedback.

Rather, the LH secretion and that of the FSH are inhibited by the progestogenic partial effect of CPA. As a result, there is a decrease of testosterone and oestrogens in plasma.

This central inhibitory effect of CPA also comes into play in combination with LHRH-agonists. The initial increase in testosterone, caused by this group of substances, is diminished by CPA.

 

Further effects on endocrine parameters

CPA causes the concentration of testosterone and estrogens to decline.

No significant influence on 17‑ketosteroids and 17‑ketogenic steroids has been found. Cortisol secretion remained unchanged or decreased. The function of the hypothalamic-pituitary-adrenal axis (HPA axis) was largely unaffected in adults. The evaluation of all results suggests that the reactivity of the system is usually not affected.

 

Meningioma

Based on a French epidemiological cohort study, a cumulative dose-dependent relationship was observed between cyproterone acetate and meningiomas. This study was based on data from the French health insurance (CNAM) and included a population of 253,777 women, who were taking tablets of 50-100 mg cyproterone acetate. The incidence of meningioma treated by surgery or radiation therapy was compared between women exposed to high-dose cyproterone acetate (cumulative dose ³ 3g) and women with only low exposure to cyproterone acetate (cumulative dose < 3 g). A correlation was revealed between the cumulative dose and occurrence.

 

Cumulative dose of cyproterone acetate	Incidence rate (in patient years)	HRadj (95% CI)a
Mild exposure (< 3 g)	4.5/100,000	Ref.
Exposure up to ³ 3 g	23.8/100,000	6.6 [4.0-11.1]
12 to 36 g	26/100,000	6.4 [3.6-11.5]
36 to 60 g	54.4/100,000	11.3 [5.8-22.2]
more than 60 g	129.1/100,000	21.7 [10.8-43.5]

*Adjusted according to age as a time-dependent variable and oestrogen at start of application

 

A cumulative dose of, for example, 12 g may correspond to one year of treatment with 50 mg/day for 20 days per month

Systemic toxicity

Preclinical data reveal no specific hazard for humans based on conventional studies on chronic toxicity.

 

Toxicity to reproduction

The temporary inhibition of fertility in male rats, as a result of daily oral treatment, revealed no evidence that germ cells are damaged in ways that could lead to maldevelopment or fertility disorders in the offspring.

 

Genotoxicity/carcinogenicity

Recognised first-line tests of genotoxicity gave no indication of a mutagenic effect when conducted with CPA. However, further tests showed that CPA was capable of producing adducts with DNA (and an increase in DNA repair activity) in liver cells from rats, monkeys and humans. This DNA-adduct formation occurred at systemic exposures that might be expected to occur in the recommended dose regimen. One consequence of in‑vivo cyproterone acetate treatment was the increased incidence of focal, possibly pre-neoplastic, liver lesions in which cellular enzymes were altered in female rats and an increased mutation frequency in transgenic rats, carrying a bacterial gene as a mutation marker.

The clinical significance of these findings is currently uncertain. Clinical experience to date and carefully conducted epidemiological studies do not support an increased incidence of hepatic tumours in humans.

Investigations into the tumourigenicity of CPA in rodents did not reveal any results that fundamentally differed from those obtained with other steroid hormones. It must be borne in mind, however, that sex steroids can promote the growth of certain hormone-dependent tissue and tumours.

Overall, there is nothing in the available data to contradict the use of Androcur 50 mg in humans, if this use is in accordance with labelled indications and the recommended dosage.

In experimental studies in rats and dogs, high doses caused corticoid-like effects on the adrenal glands, which could point to similar effects in humans at the highest dose (300 mg/day).

 

 

Systemic toxicity

Preclinical data reveal no specific hazard for humans based on conventional studies on chronic toxicity.

 

Toxicity to reproduction

The temporary inhibition of fertility in male rats, as a result of daily oral treatment, revealed no evidence that germ cells are damaged in ways that could lead to maldevelopment or fertility disorders in the offspring.

 

Genotoxicity/carcinogenicity

Recognised first-line tests of genotoxicity gave no indication of a mutagenic effect when conducted with CPA. However, further tests showed that CPA was capable of producing adducts with DNA (and an increase in DNA repair activity) in liver cells from rats, monkeys and humans. This DNA-adduct formation occurred at systemic exposures that might be expected to occur in the recommended dose regimen. One consequence of in‑vivo cyproterone acetate treatment was the increased incidence of focal, possibly pre-neoplastic, liver lesions in which cellular enzymes were altered in female rats and an increased mutation frequency in transgenic rats, carrying a bacterial gene as a mutation marker.

The clinical significance of these findings is currently uncertain. Clinical experience to date and carefully conducted epidemiological studies do not support an increased incidence of hepatic tumours in humans.

Investigations into the tumourigenicity of CPA in rodents did not reveal any results that fundamentally differed from those obtained with other steroid hormones. It must be borne in mind, however, that sex steroids can promote the growth of certain hormone-dependent tissue and tumours.

Overall, there is nothing in the available data to contradict the use of Androcur 50 mg in humans, if this use is in accordance with labelled indications and the recommended dosage.

In experimental studies in rats and dogs, high doses caused corticoid-like effects on the adrenal glands, which could point to similar effects in humans at the highest dose (300 mg/day).

Lactose monohydrate

Maize starch

Povidone K25

Colloidal anhydrous silica

Magnesium stearate (Ph. Eur.)

 

Not applicable.

4 years

Store below 25°C.

Blister packs made of polyvinyl chloride and hardened aluminium.

 

Pack with 20 tablets

Pack with 50 tablets

Pack with 100 tablets

Hospital packs with 250 tablets

 

Not all pack sizes may be marketed

No special requirements.