Consumer medicine information

APO-Cyproterone 50 mg Tablets

Cyproterone acetate

BRAND INFORMATION

Brand name

APO-Cyproterone Acetate 50 mg

Active ingredient

Cyproterone acetate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Cyproterone 50 mg Tablets.

What is in this leaflet

Read this leaflet carefully before taking your medicine.

This leaflet answers some common questions about cyproterone. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

You can also download the most up to date leaflet from www.apotex.com.au.

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

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

Keep this leaflet with your medicine. You may want to read it again.

What this medicine is used for

The name of your medicine is APO- Cyproterone 50 mg. It is an anti-androgen medicine. It contains the active ingredient cyproterone (as cyproterone acetate).

It is used to treat:

  • women who have a problem with facial or chest hair, are balding, have severe acne and/or secrete excess oil from the sweat glands.
  • men with cancer of the prostate. It can also be used in conjunction with other medications 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.
  • men with sexual deviations.

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

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

How it works

This medicine works by reducing the effects and the level of male sex hormones in the body (which are also produced in females to a lesser extent).

There is no evidence that this medicine is addictive.

Use in children

This medicine should not be used in children.

Before you take this medicine

When you must not take it

Do not take this medicine if you have or have had any of the following:

  • You are pregnant or suspect you may be pregnant
    Cyproterone may affect your developing baby if you take it during pregnancy.
  • You are breastfeeding
    Cyproterone may pass into human breast milk and there is a possibility that your baby may be affected.
  • You have or have had liver disease or liver tumours
    Except if they are caused by metastases from prostate cancer (your doctor would have told you if you have this).
  • You have previously had herpes or jaundice or persistent itching whilst pregnant
  • You have Dubin-Johnson or Rotor syndrome.
    (Your doctor would have told you if you have this).
  • You have or have had meningioma, a type of brain tumour.
  • You have a wasting disease or sickle cell disease
  • You have severe and persistent depression
  • You have or have had problems with your blood clotting or blood clots
  • You have severe diabetes which involves serious changes in blood flow through the veins
  • You have not yet completed puberty
  • You are hypersensitive to, or have had an allergic reaction to, cyproterone or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body, rash, itching or hives on the skin; fainting or hayfever-like symptoms
    If you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.
  • The expiry date (EXP) printed on the pack has passed.
  • The packaging is torn, shows signs of tampering or it does not look quite right.

Before you start to take it

Before you start taking this medicine, tell your doctor if:

  1. You have allergies to:
  • any other medicines
  • any other substances, such as foods, preservatives or dyes.
  1. You have or have had any medical conditions, especially the following:
  • problems with blood clotting or blood clots
  • heart attack or stroke
  • problems with your eyesight
  • diabetes
  • a close family history of breast cancer, or any physical changes (e.g. breast nodules)
  • 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)
  • anaemia or sickle cell anaemia
  • the Lapp-Lactase deficiency or lactose intolerance. These tablets contain lactose.
  1. You are planning to have surgery or an anaesthetic.
  2. You are currently receiving or are planning to receive dental treatment.
  3. You are pregnant, planning on becoming pregnant or are breastfeeding.
  4. You are taking or are planning to take any other medicines. This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

Some medicines may interact with cyproterone. These include:

  • statins, used for lowering cholesterol
  • antibiotics such as rifampicin or penicillins
  • medicine to control fits (phenytoin)
  • medicines to treat diabetes
  • medicine to treat fungal infections (ketoconazole, itraconazole, clotrimazole)
  • medicine to treat HIV infections (ritonavir)
  • St John's wort, a herbal remedy for depression.

If you are taking any of these you may need a different dose or you may need to take different medicines.

Other medicines not listed above may also interact with cyproterone.

Women must have a thorough medical and pelvic examination, including a Pap smear and breast examination, before taking cyproterone.

Your doctor will also make sure that your symptoms are not due to any other causes of androgenisation e.g. Cushing's syndrome, ovarian tumours, adrenal carcinoma and androgenital syndrome before starting treatment. You must not be pregnant or plan to become pregnant when taking cyproterone.

It is not known how cyproterone affects female fertility in the long term.

Men should be aware that cyproterone causes a decrease in sperm count. It may take 3 to 20 months for the sperm count to return to normal once therapy has been stopped. Men may need to have a sperm count.

Most reported cases of liver damage are in men with prostate cancer. Liver damage may be fatal in some cases. Such effects are more likely to happen when taking high doses of cyproterone and develop, usually, several months after treatment has begun. Your doctor will order liver function tests before you start taking cyproterone and whenever any symptoms or signs that suggest you have liver damage, for example jaundice (yellow skin and/or eyes), dark coloured urine. If you develop any of these signs you should contact your doctor immediately.

If you are required to concentrate (e.g. road users, machine operators) you should note that cyproterone acetate can make you feel tired or lethargic and can impair your ability to concentrate.

You may not be able to take this medicine if you drink alcohol. If you are taking this medicine to reduce your sex drive, alcohol may stop this medicine working as well as it should.

How to take this medicine

Follow carefully all directions given to you by your doctor or pharmacist. Their instructions may be different to the information in this leaflet.

How much to take

Your doctor or pharmacist will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.

Do not stop taking your medicine or change your dosage without first checking with your doctor.

MEN:

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

Reduction of abnormal sex drive
Generally treatment is started with 50 mg of APO-Cyproterone Acetate 50 mg 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 APO-Cyproterone Acetate 50 mg 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 APO-Cyproterone Acetate 50 mg should be avoided.

If you are postmenopausal or have had a hysterectomy, APO-Cyproterone Acetate 50 mg may be administered alone. The usual dose is 25-50 mg of APO-Cyproterone Acetate 50 mg 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

The tablets should be swallowed with some liquid (after food).

When to take it

Take this medicine at about the same time each day. Taking it at the same time each day will have the best effect and will also help you remember when to take it.

The tablets should be taken immediately after food.

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

Make sure you have enough to last over weekends and holidays.

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 to take your next dose, skip the missed dose and take your next dose at the usual time. 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 missed doses. This may increase the chance of you experiencing side effects.

If you are also taking an oral contraceptive and more than 12 hours has elapsed from the time APO-Cyproterone 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 to help you remember.

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively go to the Accident and Emergency Department at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

Tell your doctor that you are taking this medicine if:

  • you are about to be started on any new medicine
  • you are pregnant or are planning to become pregnant.
    Tell your doctor immediately if you become pregnant.
  • you are breastfeeding or are planning to breastfeed
  • you are about to have any blood tests
  • you are going to have surgery or an anaesthetic or are going into hospital.

Your doctor may do tests to make sure the medicine is working and to prevent side effects. Go to your doctor regularly for a check-up. Your doctor will check your liver function during treatment 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 cyproterone.

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

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

If you develop any signs of liver toxicity - yellow skin or eyes - tell your doctor immediately. Your doctor will make sure this is not due to any other cause, e.g. metastatic disease (spread of cancer) and will decide if you should keep taking cyproterone.

In very rare cases liver tumours may lead to life-threatening intra-abdominal haemorrhage. If you develop severe upper abdominal complaints or tenderness tell your doctor immediately.

A sensation of shortness of breath may occur in some people who are taking high doses of cyproterone acetate. If this occurs, tell your doctor.

Female patients who are taking APO-Cyproterone Acetate 50 mg in combination with ethinyloestradiol, that have a family history of breast cancer should have regular breast examinations.

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 APO-Cyproterone Acetate 50 mg to reduce abnormal sex drive, you should consider undertaking 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 reorientation.

Things you must not do

Do not:

  • Give this medicine to anyone else, even if their symptoms seem similar to yours
  • Take your medicine to treat any other condition unless your doctor or pharmacist tells you to
  • Stop taking your medicine, or change the dosage, without first checking with your doctor.

Things to be careful of

Be careful when driving or operating machinery until you know how this medicine affects you. This medicine may cause drowsiness and loss of concentration in some people.

Female patients should not smoke whilst taking APO-Cyproterone Acetate 50 mg in combination with ethinyloestradiol. Use of any oral contraceptives may be associated with an increased risk of heart attack and stroke.

Female patients should be aware that the contraceptive action of the combined treatment of APO-Cyproterone Acetate 50 mg and ethinyloestradiol may be reduced by diarrhoea or vomiting shortly after taking a tablet. In these cases, an additional form of contraception such as a condom or diaphragm should be used for the remainder of the cycle. In women taking APO- Cyproterone Acetate 50 mg in combination with ethinyloestradiol, if light bleeding or spotting occurs during the 3 weeks in which the tablets are being taken, do not stop taking your tablets. However, if unusual bleeding continues or if bleeding is heavy, consult your doctor immediately.

If you are a male patient and you are taking this medicine to reduce your sex drive, be careful when drinking alcohol. Alcohol may stop APO-Cyproterone Acetate 50 mg from working as well as it should.

Possible side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking cyproterone or if you have any questions or concerns.

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Infertility and impotence are expected effects of cyproterone acetate and cannot generally be avoided.

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

This list includes the more common side effects. Mostly, these are mild:

  • tiredness, fatigue
  • weight changes
  • headache
  • changes in sex drive
  • nausea and gut upset
  • unusual secretion of breast milk
  • sleep disturbances
  • hot flushes
  • restlessness

If you were fertile before treatment, APO- Cyproterone Acetate 50 mg 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 APO- Cyproterone Acetate 50 mg 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.

In men, long-term use of cyproterone may uncommonly lead to osteoporosis.

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 as soon as possible if you notice any of the following.

These may be serious side effects. You may need medical attention. Most of these side effects are rare.

  • depressive moods
  • blood clotting (which may lead to a clot on the lungs, stroke or heart attack)
  • menstrual cycle changes, vaginal discharge, period pain in women
  • gynaecomastia (swelling of the breast area which is sometimes also associated with tenderness or sensitivity). This usually goes away after reducing the dose or stopping the tablets
  • fast heart rate
  • change in skin colour (yellowing) or appearance of rashes
  • shortness of breath.
  • osteoporosis

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

These are very serious side effects and are usually very rare. You may need urgent medical attention or hospitalisation.

  • severe pain and/or swelling in the stomach and gut
  • pain in the groin, chest or leg
  • swelling of one leg with tenderness or pain
  • coughing up blood or sudden shortness of breath
  • upper abdominal pain, yellowing of the eyes or skin (jaundice), itching, dark urine, feeling generally unwell and having poor appetite. These may be due to problems with your liver.

Other side effects not listed above may occur in some patients.

Allergic reactions

If you think you are having an allergic reaction to cyproterone, do not take any more of this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • cough, shortness of breath, wheezing or difficulty breathing.
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hayfever-like symptoms

Some additional side effects may occur in women taking APO-Cyproterone Acetate 50 mg in combination with ethinyloestradiol. See your doctor immediately if you experience any of the following:

  • Severe migraine headache for the first time, or a change in the pattern of your migraine
  • Unusually bad headaches or headaches more often than before
  • Change or loss of eyesight
  • Rise in blood pressure.

In women, ovulation is inhibited under the combined treatment: APO-Cyproterone Acetate 50 mg in combination with ethinyloestradiol, so that it is not possible to become pregnant.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it.

If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 30°C. Protect it from light and moisture. Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine 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 or pharmacist tells you to stop taking this medicine or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What APO-Cyproterone 50 mg looks like

White to off white, flat, round tablet with '50' engraved over a break line on one face, the other a plain face.

APO-Cyproterone 50 mg tablets are presented in bottles containing either 20 or 50 tablets.

* Not all strengths, pack types and/or pack sizes may be available.

Ingredients

Each tablet contains 50 mg of cyproterone (as cyproterone acetate) as the active ingredient.

It also contains the following inactive ingredients:

  • lactose monohydrate
  • microcrystalline cellulose
  • croscarmellose sodium
  • povidone
  • magnesium stearate.

This medicine is gluten-free, sucrose-free, tartrazine-free and free of other azo dyes.

Australian Registration Numbers

APO-Cyproterone 50 mg tablets:
Bottles:
AUST R 101534.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

This leaflet was last updated in: April 2021.

Published by MIMS May 2021

BRAND INFORMATION

Brand name

APO-Cyproterone Acetate 50 mg

Active ingredient

Cyproterone acetate

Schedule

S4

 

1 Name of Medicine

Cyproterone acetate.

2 Qualitative and Quantitative Composition

Each tablet contains 50 mg cyproterone acetate as the active ingredient.

Excipients with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablets.

White to off white, round, flat tablet with 50 engraved over a break line on one face, plain on the other.

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.
APO-Cyproterone Acetate 50 mg inhibits the influence of male sex hormones which are also produced by the female. It is thus possible to treat diseases in women caused by either 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 APO-Cyproterone Acetate 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.

APO-Cyproterone Acetate 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 pre-requisite for therapy is the desire by the patient for treatment.
APO-Cyproterone Acetate 50 mg 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 luteinising hormone releasing hormone (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

APO-Cyproterone Acetate 50 mg Tablets are intended for oral administration.
The tablets are to be taken with some liquid after a meal.

Women.

Pregnant women must not take APO-Cyproterone Acetate 50 mg, therefore pregnancy must be excluded before the start of therapy.
In women of childbearing potential, the treatment is commenced on the first 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 first day of the cycle and the following recommendations then observed as normal.
For hirsutism secondary to female androgenisation; the usual starting dose should be one 50 mg tablet taken daily for ten 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/day for ten days per month have been shown to be adequate for maintenance therapy in this condition.
For other severe signs of androgenisation; two 50 mg tablets 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 take their tablets at the same time each day. If a tablet is missed and 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 APO-Cyproterone Acetate 50 mg. If bleeding fails to occur after this cycle, pregnancy must be excluded before tablet-taking is resumed.
Missed APO-Cyproterone Acetate 50 mg tablets may diminish the therapeutic efficacy and may lead to intermenstrual bleeding. The missed APO-Cyproterone Acetate 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 four 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 interval, the possibility of pregnancy must be excluded before restarting tablet taking.
Following clinical improvement, the daily dose of APO-Cyproterone Acetate 50 mg may be reduced to 1 or ½ a 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 cyproterone 50 mg at the start of the menopause. Long-term use (years) of cyproterone 50 mg should be avoided (see Section 4.4 Special Warnings and Precautions for Use, Meningioma).
In postmenopausal or hysterectomised patients APO-Cyproterone Acetate 50 mg may be administered alone. According to the severity of the complaints, the average dose should be 1/2 to 1 tablet APO-Cyproterone Acetate 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 deviation.

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. If a satisfactory result is achieved, the therapeutic effect should be maintained with the lowest possible dose. Quite often 1/2 a tablet twice daily is sufficient. When establishing the maintenance dose or when discontinuing the preparation, the dosage should not be reduced abruptly, but gradually. To this end, the daily dose should be reduced by one tablet, or better, by 1/2 a tablet, at intervals of several weeks.
To stabilise the therapeutic effect it is necessary to take APO-Cyproterone Acetate 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 of cyproterone acetate 50 mg) twice daily alone for 5-7 days, then 100 mg (2 tablets of cyproterone acetate 50 mg) twice daily for 3-4 weeks together with an LHRH agonist at 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 of cyproterone acetate 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.

Cyproterone acetate 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.
Cyproterone acetate 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.
Cyproterone acetate 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 cyproterone acetate 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; hepatic diseases; Dubin-Johnson syndrome, Rotor syndrome; history of jaundice or persistent itching during a previous pregnancy; history of herpes of pregnancy; previous or existing hepatic 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 APO-Cyproterone Acetate 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 cyproterone acetate 50 mg.

Contraindications in men.

Reduction of drive in sexual deviations.

Hepatic diseases; Dubin-Johnson syndrome, Rotor syndrome; previous or existing hepatic 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 APO-Cyproterone Acetate 50 mg.

Inoperable carcinoma of the prostate.

Hepatic 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 APO-Cyproterone Acetate 50 mg.
APO-Cyproterone Acetate 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

Identified precautions.

During treatment liver function, adrenocortical function and red blood cell count should be checked regularly.
As with other anti-androgenic treatments, in male patients long-term androgen deprivation with cyproterone acetate may lead to osteoporosis.

Thromboembolic events.

The occurrence of thromboembolic events has been reported in patients using cyproterone acetate, 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.

Liver.

Liver function tests should be performed pre-treatment, at regular intervals during treatment and whenever any symptoms or signs suggestive of hepatotoxicity occur.
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 prostatic cancer. Toxicity is dose related and usually develops several months after treatment has begun. If hepatotoxicity is confirmed, cyproterone acetate should be withdrawn, unless hepatotoxicity can be explained by another cause, e.g. metastatic disease, in which case cyproterone acetate should be continued only if the perceived benefit outweighs the risk.
Cases of benign and malignant hepatic tumours, which may lead to life-threatening intra-abdominal haemorrhage, have been observed after the use of cyproterone acetate. If severe upper abdominal complaints, hepatic enlargement or signs of intra-abdominal haemorrhage occur, a hepatic 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 cyproterone acetate is diagnosed with meningioma, treatment with cyproterone acetate must be 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 cyproterone acetate treatment (see Section 4.3 Contraindications).

Shortness of breath.

A sensation of shortness of breath may occur in individual cases under high dose treatment with APO-Cyproterone Acetate 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.

Adrenocortical function.

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

Anaemia.

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

Other conditions.

APO-Cyproterone Acetate 50 mg tablets contain lactose. 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 combined treatment, spotting occurs during the three 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 reduction effect of APO-Cyproterone Acetate 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 cyproterone acetate is prescribed.

Use in the elderly.

There is reduced hepatic clearance in the elderly, and this should be considered when prescribing and monitoring treatment with APO-Cyproterone Acetate 50 mg.

Paediatric use.

Cyproterone acetate 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.
Cyproterone acetate is not recommended for use in female patients before the conclusion of puberty.
Cyproterone acetate 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.

Effects on laboratory tests.

Currently, there are no available data regarding the effects on laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The requirement for oral anti-diabetics or insulin can change.
Although clinical interaction studies have not been performed, since this drug is metabolized 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, e.g. rifampicin, phenytoin and products containing St John's wort (Hypericum perforatum) may reduce the levels of cyproterone acetate.
The risk of statin associated myopathy or rhabdomyolysis may be increased when those HMG-CoA 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 CYP2C9, 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.

The long term effects on female fertility are not known with certainty.
Spermatogenesis is impaired during treatment and recovers gradually after discontinuation of therapy (see Section 4.8 Adverse Effects (Undesirable Effects)). 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.
(Category D)
The use of APO-Cyproterone Acetate 50 mg is contraindicated during pregnancy (also 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 the male foetus.
 The use of APO-Cyproterone Acetate 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 APO-Cyproterone Acetate 50 mg can lead to tiredness and diminished vitality and can impair the ability to concentrate.

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 ≥ 1/1000 and < 1/100; rare ≥ 1/10,000 and < 1/1000; 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 cyproterone acetate are spotting, weight increase and depressed mood.
The most frequently observed ADRs in male patients receiving cyproterone acetate are decreased libido, erectile dysfunction and reversible inhibition of spermatogenesis.
The most serious ADRs in patients receiving cyproterone acetate are hepatic toxicity, benign and malignant liver tumours which may lead to intra-abdominal haemorrhage, and thromboembolic events.
Over the course of several weeks cyproterone acetate gradually impairs spermatogenesis as a result of the antiandrogenic and antigonadotropic actions. Spermatogenesis recovers gradually within several months of discontinuing therapy.
In male patients cyproterone acetate 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 cyproterone 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 dosed cyproterone acetate treatment.
Changes in body weight 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 post marketing data and cumulative experience with cyproterone acetate. 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 post-marketing surveillance and for which a frequency could not be estimated are: anaemia*, meningioma, intra-abdominal haemorrhage*, rash, menstrual spotting*, thromboembolic events*+.
In male patients under treatment with cyproterone acetate, 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 of cyproterone acetate doses of 25 mg and above (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
* For further information see Section 4.4 Special Warnings and Precautions for Use.
+ A causal relationship with cyproterone acetate has not been established.

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/reporting-problems and contact Apotex medical information enquiries/adverse drug reaction reporting on 1800 195 055.

4.9 Overdose

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

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Cyproterone acetate is an anti-androgenic hormone.
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 exerts a direct anti-androgenic action on the tumour and its metastases.
Cyproterone acetate in addition has a progestogenic action exerting a negative feedback effect 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 luteinising hormone releasing hormone (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 may increase with 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/min/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 3.5-4.0%. 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.

Due 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 cyproterone acetate. In vivo consequences of cyproterone acetate treatment were the increased incidence of focal, possibly pre-neoplastic, 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, microcrystalline cellulose, croscarmellose sodium, povidone, magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine. See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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. Protect from light and moisture.

6.5 Nature and Contents of Container

Bottles (white HDPE with PP cap):
20 tablets (AUST R 101534).
50 tablets (AUST R 101534).

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. It 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-17αhydroxy-1α,2α-methylene- pregna-4,6-diene-3,20-dione acetate.
Molecular Formula: C24H29ClO4.
Molecular Weight: 416.94.

CAS number.

427-51-0.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes