Consumer medicine information

Cyprostat

Cyproterone acetate

BRAND INFORMATION

Brand name

Cyprostat 50 mg

Active ingredient

Cyproterone acetate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Cyprostat.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Cyprostat.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Cyprostat against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

WHAT CYPROSTAT IS USED FOR

Cyprostat is an anti-androgen medicine.

Androgens such as testosterone are natural male sex hormones which are also produced, to a slight extent, in females.

MEN:
In men, androgens may help cancer cells to grow in some types of prostate cancer. By blocking these hormones, Cyprostat may slow or stop the growth of cancer. Cyprostat may also be used in combination with other medicines or following surgical removal of the testes to treat side effects such as “hot flushes” or “sweats” and to prevent any initial worsening of the disease.

Cyprostat is also used to reduce abnormal sex drive in men.

WOMEN:
In women, androgens may increase hair growth, loss of scalp hair and secretion of oil from the sweat glands. By blocking these hormones, Cyprostat may slow or stop excessive hairiness, loss of scalp hair, acne, oily skin and dandruff.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is available only with a doctor’s prescription.

BEFORE YOU TAKE CYPROSTAT

When you must not take it

Do not take Cyprostat if you have an allergy to:

  • cyproterone acetate, the active ingredient in Cyprostat
  • any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Cyprostat should not be taken by children and adolescents below 18 years of age or girls who have not completed puberty.

Do not take this medicine if you are pregnant or suspect you may be pregnant. It may affect your developing baby if you take it during pregnancy.

Do not breastfeed if you are taking this medicine. The active ingredient in Cyprostat passes into breast milk and there is a possibility that your baby may be affected.

Do not take Cyprostat if you have any of the following medical conditions:

  • liver disease, previous or existing liver tumours unless they are caused by metastases from prostate cancer (your doctor would have told you if you have this)
  • Dubin-Johnson or Rotor syndrome (your doctor would have told you if you have either of these conditions)
  • history of jaundice (yellow skin or eyes), herpes or persistent itching during a previous pregnancy
  • previous or existing benign brain tumour (meningioma)
  • wasting disease (a disease causing muscle loss or loss of strength, with the exception of prostate cancer)
  • severe and persistent depression
  • previous or existing conditions relating to formation of blood clots
  • severe diabetes with blood vessel changes
  • sickle-cell anaemia (your doctor would have told you if you have this)

Cyprostat tablets contain lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking Cyprostat.

Do not take this medicine after the expiry date printed on the pack and blister. The expiry date is printed on the carton and on each blister after “EXP” (e.g. 11 18 refers to November 2018). The expiry date refers to the last day of that month. If it has expired return it to your pharmacist for disposal.

Do not take this medicine if the packaging is torn or shows signs of tampering. If the packaging is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any medical conditions, especially the following:

  • diabetes
  • history of blood clotting or sickle cell anaemia
  • osteoporosis, a family history of osteoporosis or risk factors for developing osteoporosis (such as smoking, a diet low in calcium, poor mobility, a slight build or treatment with steroid medicines)

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding. If taken during pregnancy, Cyprostat may lead to signs of feminisation in the male foetus. Therefore, your doctor will check that you are not pregnant before you start taking Cyprostat. Women should use a reliable form of contraception while taking Cyprostat.

Tell your doctor if fertility after treatment is important. For men it is recommended that a sperm count is taken to establish fertility before commencing Cyprostat. It can take 3-20 months for fertile sperm production to be re-established after stopping this medicine. The long-term effects of Cyprostat on female fertility are not known.

If you have not told your doctor about any of the above, tell them before you start taking Cyprostat.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Cyprostat may interfere with each other. These include:

  • phenytoin, a medicine used to treat epilepsy
  • medicines used to treat fungal infections, including ketoconazole, itraconazole, clotrimazole
  • ritonavir, a medicine used in the treatment of HIV
  • rifampicin, an antibiotic used to treat infections such as tuberculosis and leprosy
  • St John's wort, a herbal remedy used to treat mood disorders
  • Statins (HMGCoA inhibitors), medicines used to lower cholesterol levels in people with or at risk of cardiovascular disease
  • medicines used to treat diabetes

These medicines may be affected by Cyprostat, or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines.

Your doctor and pharmacist may have more information on medicines to be careful with or avoid while taking this medicine.

HOW TO TAKE CYPROSTAT

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions printed on the pharmacist label, ask your doctor or pharmacist for help.

How much to take

Your doctor will advise of the most suitable dose for you to take.

Do not alter the dose yourself. Your doctor will advise you if changing the dose is necessary.

MEN:

Prostate cancer
The usual daily dose is 50-300 mg of Cyprostat. Your doctor may request you take Cyprostat with other medicines and/or change your dose during treatment.

Reduction of abnormal sex drive
Generally treatment is started with 50 mg of Cyprostat twice daily and may be increased to 100 mg twice daily or three times daily before reducing gradually to the lowest effective dose. Your doctor may change your dose during treatment.

WOMEN:

If you are of childbearing age, you should commence your tablet taking on the 1st day of your cycle (= 1st day of bleeding). If you have no menstrual periods (amenorrhoea) your treatment can start immediately. In this case, the first day of treatment is to be regarded as the 1st day of the cycle.

Starting from day 1 take 50-100 mg (as advised by your doctor) of Cyprostat daily from the 1st to the 10th day of the cycle (= for 10 days). Additionally, your doctor will advise the most appropriate contraceptive for you to take to provide the necessary contraceptive protection and to stabilise your cycle.

Your doctor will re-evaluate your treatment when you reach menopause. Long-term use (years) of Cyprostat should be avoided.

If you are postmenopausal or have had a hysterectomy, Cyprostat may be administered alone. The usual dose is 25-50 mg of Cyprostat once daily for 21 days, followed by a 7-day tablet-free interval.

Shortness of breath may occur at high doses.

How to take it

Swallow the tablets whole with some liquid after meals.

When to take it

Take your medicine after meals at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

Missed Cyprostat tablets may diminish the effectiveness of treatment and may lead to breakthrough bleeding in women.

How long to take it

Continue taking your medicine for as long as your doctor tells you. This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are also taking an oral contraceptive and more than 12 hours has elapsed from the time Cyprostat was due to be taken, note that contraceptive protection in this cycle may be reduced and thus there is an increased risk of becoming pregnant.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre on 13 11 26 for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Cyprostat. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

WHILE YOU ARE TAKING CYPROSTAT

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Cyprostat.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

Keep all of your doctor’s appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Your doctor will check your liver function during treatment with Cyprostat and whenever any symptoms or signs suggesting liver problems are observed.

If you have diabetes, your doctor will monitor you to ensure that you receive the appropriate dose of oral antidiabetic or insulin whilst taking Cyprostat.

Your doctor will also check your red-blood cell count to ensure you do not become anaemic during treatment with Cyprostat.

If you are a female taking an oral contraceptive during treatment, tell your doctor if your period does not occur during the tablet-free/ placebo interval. Your doctor may need to check whether you are pregnant before you can continue treatment.

If you are a male taking Cyprostat to reduce abnormal sex drive, you should consider additional measures such as therapy or counselling in order to take advantage of the period of reduced drive. These measures may assist in achieving personal and social re-orientation.

Things you must not do

Do not take Cyprostat to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor. If you stop taking it suddenly, your condition may worsen or you may have unwanted side effects.

Things to be careful of

Be careful driving or operating machinery until you know how Cyprostat affects you. This medicine may cause tiredness and can impair the ability to concentrate. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Be careful when drinking alcohol while you are taking this medicine. If you drink alcohol, tiredness and the ability to concentrate may be worse. Alcohol may prevent Cyprostat from working as well as it should in reducing abnormal sex drive.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Cyprostat.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • tiredness, fatigue
  • weight change
  • headache
  • depressive mood
  • nausea and other gastrointestinal complaints
  • decreased sexual drive
  • breast pain, change in breast size, breast swelling and/or tenderness
  • breast enlargement in men
  • menstrual cycle irregularity, spotting
  • hot flushes, sweating
  • shortness of breath
  • osteoporosis

If you were fertile before treatment, Cyprostat will normally prevent sperm production in men and ovulation in women. In men, fertility is usually regained within a few months of discontinuing therapy. The long term effects on female fertility are not known.

In men Cyprostat will also normally result in the inability to get or maintain an erection (impotence). This ability is usually also regained within a few months of discontinuing therapy.

The above includes the more common side effects of your medicine.

Use of cyproterone acetate has been linked to the development of meningioma (generally benign tumour). The risk increases when used for several years, or with high doses (25 mg per day and above).

Tell your doctor immediately if you notice any of the following:

  • changes in vision (e.g. seeing double or blurriness),
  • hearing loss or ringing in the ears,
  • loss of smell,
  • headaches that worsen with time,
  • memory loss,
  • seizures,
  • weakness in your arms or legs

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • yellowing of the skin and/or eyes, light coloured bowel motions, dark coloured urine
  • severe upper abdominal pain
  • vomiting blood or material that looks like coffee grounds, bleeding from the back passage, black sticky bowel motions (stools) or bloody diarrhoea
  • sudden severe headache, loss of vision, loss of coordination, slurred speech, shortness of breath, chest pain, numbness, heat or swelling in the arms and legs

The above list includes serious side effects that may require medical attention or hospitalisation. Serious side effects are rare.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may happen in some people.

AFTER TAKING CYPROSTAT

Storage

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack, they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 30 °C.

Do not store Cyprostat or any other medicine in the bathroom, near a sink, or on a window-sill.

Do not leave it in the car. Heat and damp can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Return any unused medicine to your pharmacist.

PRODUCT DESCRIPTION

What it looks like

Cyprostat 50 mg tablets are white, round tablets, scored on one side with “BV” marking in a hexagon on the other side, presented in blisters containing 20 or 50 tablets.

Ingredients

Active ingredients per tablet:

  • Cyprostat 50 - 50 mg of cyproterone acetate

Inactive ingredients:

  • Lactose monohydrate
  • corn starch
  • povidone
  • magnesium stearate
  • aerosil

Supplier

Made in France for:

Bayer Australia Limited
ABN 22 000 138 714
875 Pacific Highway
Pymble, NSW 2073

Australian Registration Number

Cyprostat 50 mg tablets:
AUST R 156921

Date of preparation

19 November 2020

See TGA website (www.ebs.tga.gov.au) for latest Australian Consumer Medicine Information.

© Bayer Australia Ltd

All rights reserved

® Registered Trademark of the Bayer Group, Germany

Published by MIMS January 2021

BRAND INFORMATION

Brand name

Cyprostat 50 mg

Active ingredient

Cyproterone acetate

Schedule

S4

 

1 Name of Medicine

Cyproterone acetate.

2 Qualitative and Quantitative Composition

Cyprostat 50 mg tablets.

Each Cyprostat 50 mg tablet contains 50 mg cyproterone acetate.

Excipients with known effect.

Sugars as lactose monohydrate.
For a full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Cyprostat 50 mg tablets.

Round, white, scored tablets marked with "BV" inside a hexagon.

4 Clinical Particulars

4.1 Therapeutic Indications

Women.

Moderately severe to severe signs of androgenisation.

Moderately severe/ severe forms of hirsutism.
Moderately severe/ severe androgen dependent loss of scalp hair (moderately severe/ severe androgenic alopecia).
Moderately severe/ severe forms of acne and/or seborrhoea associated with other features of androgenisation.
Cyproterone acetate inhibits the influence of male sex hormones which are also produced by the female. It is thus possible to treat diseases in women caused either by increased production of androgens or a particular sensitivity to these hormones. Hirsutism and alopecia may be expected to recur over a period of time after cessation of treatment.
If Cyprostat 50 mg is taken during pregnancy, the properties of the preparation may lead to signs of feminisation in the male foetus. Therefore, in women of childbearing potential, pregnancy must be excluded at the commencement of treatment and ethinyloestradiol taken as well to ensure contraception. This also promotes regular menstruation.

Men.

Reduction of drive in sexual deviations.

Cyprostat 50 mg reduces the force of the sexual urge in men with sexual deviations. Whilst under treatment the man can control himself better in a predisposing stimulatory situation, but there is no influence on any deviating direction of sexual drive. Abnormal patterns of sexual behaviour require treatment when they are distressing to the patient. A prerequisite for therapy is the desire by the patient for treatment.
Cyprostat 50 mg therapy should be supplemented by psychotherapeutic and sociotherapeutic measures in order to exploit the period of reduced drive for personal and social reorientation.

Inoperable prostatic carcinoma.

To suppress "flare" with initial LHRH analogue therapy.
In long-term palliative treatment where LHRH analogues or surgery are ineffective, not tolerated, contraindicated or where oral therapy is preferred.
In the treatment of hot flushes in patients treated with LHRH analogues or who have had orchidectomy.

4.2 Dose and Method of Administration

Cyprostat 50 mg tablets should be taken with some liquid after a meal.

Women.

Pregnant women must not take Cyprostat 50 mg. Therefore, pregnancy must be excluded before the start of therapy.
In women of childbearing potential, the treatment is commenced on the 1st day of the cycle (1st day of bleeding). Only women with amenorrhoea or menstrual bleeding at very irregular intervals can start 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.
For hirsutism secondary to female androgenisation; the usual starting dose should be 1 tablet of Cyprostat 50 mg taken daily for 10 days per month (from the 1st to the 10th day of the cycle). Once a satisfactory response has been attained it is usually possible to reduce the dose further. Doses as low as 10 mg a day for 10 days per month have been shown to be adequate for maintenance therapy in this condition.
For other severe signs of androgenisation; 2 tablets of Cyprostat 50 mg are to be taken daily from the 1st to the 10th day of the cycle (= for 10 days).
In addition, these women should receive a progestogen oestrogen containing preparation to provide the necessary contraceptive protection and to stabilise the cycle. An appropriate combined oral contraceptive preparation should be commenced on day 1 of the cycle as directed.
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. Attention is drawn to the special notes (especially on contraceptive reliability and to the missed tablet recommendations) in the product information for the combined oral contraceptive preparation being taken in conjunction with Cyprostat 50 mg. If bleeding fails to occur after this cycle, pregnancy must be excluded before tablet taking is resumed.
Missed Cyprostat 50 mg tablets may diminish the therapeutic efficacy and may lead to intermenstrual bleeding. The missed Cyprostat 50 mg tablet should be disregarded (no double dose should be taken to make up for the missed tablet) and tablet taking resumed at the regular time together with the combined oral contraceptive preparation.
A withdrawal bleeding usually occurs during the tablet free interval or whilst taking the 7 day placebo tablets. Exactly 4 weeks after the first course of treatment 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 during the tablet free or 7 day placebo tablet interval, the possibility of pregnancy must be excluded before restarting tablet taking.
Following clinical improvement, the daily dose of Cyprostat 50 mg may be reduced to 1 or 1/2 tablet during the 10 days on which it is given in each treatment cycle. The dose regimen for the combined oral contraceptive preparation remains unchanged. Re-evaluate the treatment with Cyprostat 50 mg at the start of the menopause. Long-term use (years) of Cyprostat 50 mg should be avoided (see Section 4.4 Special Warnings and Precautions for Use, Meningioma).
In postmenopausal or hysterectomised patients Cyprostat 50 mg may be administered alone. According to the severity of the complaints, the average dose should be 1/2 to 1 tablet Cyprostat 50 mg once daily for 21 days, followed by a 7 day tablet free interval.
The length of treatment depends on the severity of the pathological signs of androgenisation and response to treatment. Treatment is usually carried out over several months initially. Acne and seborrhoea usually respond sooner than hirsutism or alopecia. Hirsutism and alopecia are likely to recur when treatment is stopped.

Men.

The maximum daily dose is 300 mg.

Reduction of drive in sexual deviations.

The individual dose will be determined by the response. Generally, treatment is started with one 50 mg tablet twice daily. It may be necessary to increase the dose to two 50 mg tablets twice daily, or even two 50 mg tablets three times daily for a short period of time. The duration of cyproterone acetate treatment should be defined on an individual basis. If a satisfactory result is achieved, the therapeutic effect should be maintained with the lowest possible dose. Quite often 1/2 tablet twice daily is sufficient. When establishing the maintenance dose or when discontinuing the preparation, the dosage should not be reduced abruptly, but gradually. To this end, the daily dose should be reduced by 1 tablet or, better, 1/2 tablet, at intervals of several weeks.
To stabilise the therapeutic effect it is necessary to take Cyprostat 50 mg over a protracted period of time, if possible with the simultaneous use of psychotherapeutic measures.

Inoperable prostatic carcinoma.

To reduce the initial increase of male sex hormones ('flare') in treatment with LHRH agonists.

Initially 100 mg (2 tablets Cyprostat 50 mg) twice daily alone for 5-7 days, then 100 mg (2 tablets Cyprostat 50 mg) twice daily for 3-4 weeks together with an LHRH agonist in the dosage recommended by the manufacturer.

In long-term palliative treatment of advanced prostate cancer in patients who have not had an orchiectomy.

100 mg (2 tablets Cyprostat 50 mg) two to three times daily. Treatment should not be interrupted nor the dosage reduced after improvement or remissions have occurred.

To treat hot flushes in patients under treatment with LHRH analogues or who have had orchiectomy.

50 mg once to three times daily with upward titration to 100 mg three times daily if necessary.

Paediatric use.

Cyprostat is not recommended for use in female patients before conclusion of puberty. There are no data suggesting the need for dosage adjustment in female patients who have completed puberty.
Cyprostat 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.
Cyprostat 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.

Use in the elderly.

There are no data suggesting the need for dosage adjustment in elderly patients.

Patients with hepatic impairment.

The use of Cyprostat is contraindicated in patients with liver diseases.

Patients with renal impairment.

There are no data suggesting the need for dosage adjustment in patients with renal impairment.

4.3 Contraindications

Contraindications in women.

Pregnancy.
Lactation.
Liver diseases.
Dubin Johnson syndrome, Rotor syndrome.
History of jaundice or persistent pruritus during a previous pregnancy.
History of herpes of pregnancy.
Previous or existing liver tumours.
Presence or history of meningioma.
Wasting diseases.
Severe chronic depression.
Previous or existing thromboembolic processes.
Severe diabetes with vascular changes.
Sickle cell anaemia.
Hypersensitivity to any of the components of Cyprostat 50 mg.
With regard to the cyclical combined therapy of severe signs of androgenisation, attention is also drawn to the data on contraindications contained in the product information for the progestogen/ oestrogen containing preparation used in addition to Cyprostat 50 mg.

Contraindications in men.

Reduction of drive in sexual deviations.

Liver diseases.
Dubin Johnson syndrome, Rotor syndrome.
Previous or existing liver tumours.
Presence or history of meningioma.
Wasting diseases.
Severe chronic depression.
Previous or existing thromboembolic processes.
Severe diabetes with vascular changes.
Sickle cell anaemia.
Hypersensitivity to any of the components of Cyprostat 50 mg.

Inoperable carcinoma of the prostate.

Liver diseases.
Dubin Johnson syndrome, Rotor syndrome.
Previous or existing liver tumours (only if these are not due to metastases from carcinoma of the prostate).
Presence or history of meningioma.
Wasting diseases (with the exception of inoperable carcinoma of the prostate).
Severe chronic depression.
Existing thromboembolic processes.
Hypersensitivity to any of the components of Cyprostat 50 mg.
Cyprostat 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.

4.4 Special Warnings and Precautions for Use

During treatment, liver function, adrenocortical function and red blood cell count should be checked regularly.
The long term effects on female fertility are not known with certainty.
In men of procreative age, for whom fertility could be important after conclusion of the medication, it is advisable to make at least one control spermatogram as a precaution before the start of treatment in order to counter any unjustified claims of later infertility as a result of the antiandrogen therapy. Spermatogenesis has taken 3-20 months to return to normal after discontinuing therapy.
As with other antiandrogenic treatments, in male patients long-term androgen deprivation with Cyprostat may lead to osteoporosis.

Use in hepatic impairment.

Liver.

Direct hepatic toxicity, including jaundice, hepatitis and hepatic failure has been observed in patients treated with cyproterone acetate. At dosages of 100 mg and above, cases with fatal outcome have 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. Liver function tests should be performed pretreatment, at regular intervals during treatment and whenever any symptoms or signs suggestive of hepatotoxicity occur. If hepatotoxicity is confirmed, Cyprostat should be withdrawn, unless hepatotoxicity can be explained by another cause, e.g. metastatic disease, in which case Cyprostat should be continued only if the perceived benefit outweighs the risk.
Cases of benign and malignant liver tumours which may lead to life threatening intra-abdominal haemorrhage have been observed after the use of Cyprostat. 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.

Meningioma.

The occurrence of meningiomas (single and multiple) has been reported in association with long-term use (years) of cyproterone acetate at doses of 25 mg/day and above. The risk of meningioma increases with increasing cumulative doses of cyproterone acetate. If a patient treated with Cyprostat is diagnosed with meningioma, treatment with cyproterone containing products, including Cyprostat must be permanently stopped (see Section 4.3 Contraindications).

Diabetes.

Strict medical supervision is necessary if the patient suffers from diabetes, because the requirement for oral antidiabetics or insulin can change during Cyprostat treatment (see Section 4.3 Contraindications).

Shortness of breath.

A sensation of shortness of breath may occur under high dose treatment with Cyprostat 50 mg. 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.

Thromboembolic events.

The occurrence of thromboembolic events has been reported in patients using Cyprostat 50 mg although a causal relationship has not been established. Patients with previous arterial or venous thrombotic/ thromboembolic events (e.g. deep venous thrombosis, pulmonary embolism, myocardial infarction) or with a history of cerebrovascular accidents or with advanced malignancies are at increased risk of further thromboembolic events.

Adrenocortical function.

During treatment adrenocortical function should be checked regularly, as preclinical data suggest a possible suppression due to the corticoid like effect of Cyprostat with high doses.

Anaemia.

Anaemia has been reported during treatment with Cyprostat. Therefore, the red blood cell count should be checked regularly during treatment.

Other conditions.

Cyprostat tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Specifically to be observed in women.

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. Serious organic causes of androgenisation, e.g. Cushing's syndrome, ovarian tumours, adrenal carcinoma and adrenogenital syndrome should be excluded. Pregnancy must be excluded at the time of commencing treatment in women of childbearing potential. If, during the combined treatment, spotting occurs during the 3 weeks in which the tablets are being taken, tablet taking should not be interrupted. However, if persistent or recurrent bleeding occurs at irregular intervals, a gynaecological examination must be carried out to exclude organic diseases.
With regard to the additional use of a combined oral contraceptive preparation, attention is drawn to all the data contained in the product information for this product.

Specifically to be observed in men.

The sexual drive reducing effect of Cyprostat 50 mg can be diminished under the influence of alcohol.
In patients with inoperable carcinoma of the prostate presenting with a history of thromboembolic processes or suffering from sickle cell anaemia or from severe diabetes with vascular changes, a careful risk/ benefit evaluation must be carried out in each individual case before Cyprostat 50 mg is prescribed.

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

See Section 4.2 Dose and Method of Administration.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The requirement for oral antidiabetics or insulin can change.
Although clinical interaction studies have not been performed, since this drug 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, e.g. rifampicin, phenytoin and products containing St. John's wort, may reduce the levels of cyproterone acetate.
The risk of statin associated myopathy or rhabdomyolysis may be increased when those HMGCoA inhibitors (statins), which are primarily metabolised by CYP3A4, are coadministered with high therapeutic cyproterone acetate doses since they share the same metabolic pathway.
Based on in vitro CYP450 studies, the recommended clinical doses are likely to inhibit CYP2C8, and an inhibition of the CYP 2C9, 2C19, 3A4 and 2D6 is also possible at high therapeutic cyproterone acetate doses of 3 times 100 mg per day.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

See Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties.
(Category D)
The use of Cyprostat 50 mg is contraindicated during pregnancy (see Section 4.3 Contraindications).
Administration of cyproterone acetate during the hormone sensitive differentiation phase of the genital organs (after approx. day 45 of pregnancy) could lead to signs of feminisation in male fetuses.
 The use of Cyprostat 50 mg is contraindicated during lactation as small amounts of cyproterone acetate are excreted in human milk (see Section 4.3 Contraindications).

4.7 Effects on Ability to Drive and Use Machines

It should be pointed out to patients whose occupation demands great concentration (e.g. road users, machine operators) that Cyprostat 50 mg can lead to tiredness and diminished vitality and can impair the ability to concentrate (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Adverse reactions reported in clinical trials.

The following adverse reactions have been reported at the approximate frequencies (not necessarily implicating a causal relationship) indicated below.
Very common: ≥ 1/10; common: ≥ 1/100 and < 1/10; uncommon: ≥ 1/1,000 and < 1/100; rare: ≥ 1/10,000 and < 1/1,000; very rare: < 1/10,000.

General.

Very common: tiredness, weight increase.
Common: headache, depressive moods.

Cardiovascular.

Common: thrombotic phenomena.

Gastrointestinal.

Common: nausea and other gastrointestinal complaints.

Reproductive.

Very common: diminished libido.
Common: mastodynia, irregular menstrual cycles.

Skin.

Rare: rash.
The most commonly reported adverse drug reactions (ADRs) in female patients receiving Cyprostat are spotting, weight increase and depressed mood.
The most frequently observed ADRs in male patients receiving Cyprostat are decreased libido, erectile dysfunction and reversible inhibition of spermatogenesis.
The most serious ADRs in patients receiving Cyprostat are hepatic toxicity, benign and malignant liver tumours which may lead to intra-abdominal haemorrhage, and thromboembolic events.
Over the course of several weeks Cyprostat 50 mg gradually impairs spermatogenesis as a result of the antiandrogenic and antigonadotropic actions. Spermatogenesis recovers gradually within several months of discontinuing therapy.
In male patients Cyprostat 50 mg occasionally leads to gynaecomastia (sometimes combined with tenderness to touch of the breast) which usually regresses after withdrawal of the preparation or reduction of the dose.
As with other antiandrogenic treatments, in male patients long-term androgen deprivation with Cyprostat 50 mg may lead to osteoporosis.
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.
In individual cases, disturbances of liver function, some of them severe, have been reported with high dose Cyprostat 50 mg treatment.
Changes in bodyweight are possible.
Other adverse events reported at a low incidence were dysmenorrhoea, vaginal discharge, skin discolouration, striae.

Post-marketing information.

The following adverse effects have been reported in users of cyproterone acetate and are based on postmarketing data and cumulative experience with Cyprostat. The most appropriate MedDRA term to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed, but should be taken into account as well. See Table 1.
The ADRs identified only during postmarketing surveillance and for which a frequency could not be estimated are: anaemia*, meningiomas, intra-abdominal haemorrhage*, rash, menstrual spotting*, thromboembolic events*#.
In male patients under treatment with Cyprostat 50 mg, sexual drive and potency are reduced and gonadal function is inhibited. These changes are reversible after discontinuation of therapy.
Meningiomas have been reported in association with long-term use (several years) of Cyprostat doses of 25 mg and above (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reportingproblems (Australia).

4.9 Overdose

There is no clinical experience in overdose. Assessment and symptomatic treatment should be initiated as required.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Cyprostat 50 mg is an antiandrogenic hormone preparation.
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. Prostatic carcinoma and its metastases are, in general, androgen dependent, cyproterone acetate therefore exerts a direct antiandrogenic action on the tumour and its metastases.
Cyproterone acetate in addition has a progestogenic action exerting a negative feedback effect centrally on the hypothalamic receptors, so leading to a reduction in gonadotropin release and, hence to diminished production of testicular androgens. Treatment with cyproterone acetate in men results in a reduction of sexual drive and potency and inhibition of gonadal function. These changes are reversible following discontinuation of the therapy.
The antigonadotropic effect of cyproterone acetate is also exerted when the substance is combined with LHRH agonists. The initial increase of testosterone provoked by this substance group is decreased by cyproterone acetate.
In women, hirsutism is diminished, but also androgen dependent loss of scalp hair and elevated sebaceous gland function are reduced. During the treatment ovarian function is inhibited.
Prolactin levels can increase slightly under higher doses of cyproterone acetate. Studies showed increased prolactin levels up to 20 nanogram/mL (normal range 5-15 nanogram/mL). There are no data for periods longer than 6 months.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration, cyproterone acetate is completely absorbed over a wide dose range.
The ingestion of 50 mg of cyproterone acetate gives maximum serum levels of about 140 nanogram/mL at about 3 hours. Thereafter, drug serum levels declined during a time interval of typically 24 to 120 hours, with a terminal half-life of 43.9 ± 12.8 hours. The total clearance of cyproterone acetate from serum was determined to be 3.5 ± 1.5 mL/minute/kg. The absolute bioavailability of cyproterone acetate is unknown. Relative bioavailability was calculated, in a study of eight young women, from a dose corrected comparison of area under the curves of serum levels after 100 mg oral and 300 mg intramuscular depot administration and was found to be 80 ± 30% when averaged over all volunteers (range 23%-119%).

Distribution.

The major part of circulating cyproterone acetate is bound to serum albumin. In a study in 15 women receiving 2 mg cyproterone acetate in combination with 35 microgram ethinyloestradiol, the free fraction of cyproterone acetate was about 3.5-4%. Because protein binding is nonspecific, changes in SHBG (sex hormone binding globulin) levels do not affect the pharmacokinetics of cyproterone acetate.

Metabolism.

Cyproterone acetate is metabolised by various pathways, including hydroxylations and conjugations. The main metabolite in human plasma is the 15β-hydroxy derivative. Some dose parts are excreted unchanged with bile fluid. Phase 1 metabolism of cyproterone acetate is mainly catalysed by the cytochrome P450 enzyme CYP3A4.

Excretion.

In a study in 6 women administered a 14C-labelled dose of 2 mg cyproterone acetate in combination with 50 microgram oestrogen, approximately 30% of the label was found in the urine and 58% in the faeces. The renal and biliary 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).

Steady-state conditions.

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.

5.3 Preclinical Safety Data

Genotoxicity.

Cyproterone acetate was negative in a standard battery of genotoxicity studies. However, further tests showed that cyproterone acetate was capable of producing hepatocyte DNA adducts in rats, dogs and monkeys (and an increase in DNA repair activity in rats) in vivo and also in freshly isolated rat and human liver cells in vitro. This DNA adduct formation occurred at exposures that might be expected to occur in the recommended dose regimens for Cyprostat 50 mg. 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 presently remains uncertain.

Carcinogenicity.

Long-term animal carcinogenicity studies were performed in rats and mice. In one rat study, an increased incidence of hepatomas was reported at oral dose levels of 50 mg/kg cyproterone acetate and above. In mouse (and a second rat) carcinogenicity studies, increases in benign proliferative changes (nodular hyperplasia) in liver cells of female mice and male and female rats were reported at oral doses of 2 mg/kg. Because of shortcomings in these studies (inadequate pharmacokinetic data and the need to reassess the liver pathology), the carcinogenic potential of cyproterone acetate in animals could not be determined.
Clinical experience and limited epidemiological data available to date do not appear to have supported an increased incidence of hepatic tumours in humans. However, it must be borne in mind that steroidal sex hormones can promote the growth of certain hormone dependent tissues and tumours.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, maize starch, povidone, colloidal anhydrous silica, and magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Cyprostat 50 mg tablets are supplied in bottles* or (PVC/Al) blister pack of 20 and 50 tablets.
*Bottle packs are not marketed in Australia.
PBS availability (authority required):
Tablets 50 mg - max QTY 20; Rpts 5.
Tablets 50 mg - max QTY 50; Rpts 5.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Cyproterone acetate is a white to pale yellow crystalline powder. M.P. 206-213°C. Cyproterone acetate is very soluble in chloroform and dioxane, freely soluble in acetone and benzene, soluble in ethanol, methanol and ethyl acetate, sparingly soluble in solvent hexane, and almost insoluble in water.

Chemical structure.


Chemical name: 6-chloro-17α hydroxy-1α,2α-methylene-pregna-4,6-diene-3,20-dione acetate.
Molecular formula: C24H29ClO4. Molecular mass: 416.96.

CAS number.

427-51-0.

7 Medicine Schedule (Poisons Standard)

S4 Prescription Only Medicine.

Summary Table of Changes