Consumer medicine information

APO-Cyproterone 100 mg Tablets

Cyproterone acetate

BRAND INFORMATION

Brand name

APO-Cyproterone Acetate 100 mg

Active ingredient

Cyproterone acetate

Schedule

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 100 mg. It is an anti-androgen medication. It contains the active ingredient cyproterone (as cyproterone acetate).

It is used in men to treat cancer of the prostate gland. 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.

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

Some types of cancer of the prostate gland require androgenic hormones to grow. This medicine works in two ways. Firstly it stops the androgen hormones (testosterone) present in your body from being able to attach to the cancer cells. Secondly by an effect on the hormonal mechanisms that control androgen production by the body, it decreases the amount of androgen hormone present in your blood stream.

This medicine should only be taken by men. It should not be taken by women or children.

There is no evidence that this medicine is addictive.

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:

Liver disease or liver tumours
(except if you have cancer of the prostate and this is due to spread of the prostate cancer)
Dubin-Johnson or Rotor syndrome
(Your doctor would have told you this).
Previous or existing Meningioma, a type of benign brain tumour
A wasting disease or sickle cell disease
Severe and persistent depression
Problems with your blood clotting or blood clots
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:

You have allergies to:

any other medicines
any other substances, such as foods, preservatives or dyes.

You have or have had any medical conditions, especially the following:

problems with blood clotting or blood clots
heart attack or stroke
diabetes
anaemia 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)
a wasting disease
the Lapp-Lactase deficiency or lactose intolerance. These tablets contain lactose.

You are planning to have surgery or an anaesthetic.
You are currently receiving or are planning to receive dental treatment.
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
phenytoin, a medicine to control fits
medicines used to treat diabetes
medicines to treat fungal infections (ketoconazole, itraconazole, clotrimazole)
ritonavir, a medicine used to treat HIV infections
St John's wort, a herbal remedy for mood disorders.

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.

You 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. You 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 suffer from diabetes, tell your doctor as you will need to be kept under close observation, and your requirements for oral antidiabetics or insulin can change.

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.

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. The usual daily dose is 50-300 mg of APO-Cyproterone 100 mg. 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.

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 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 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.

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 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.

Alcohol may stop cyproterone 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:

tiredness, fatigue
loss of concentration which may affect your ability to drive or operate machinery
change in sex drive
nausea, stomach upset
inability to get or maintain an erection
breast pain, breast enlargement and /or tenderness; oozing of milky fluid from the nipples .This usually goes away after reducing the dose or stopping the tablets
changes in body weight
headache
sleep disturbances
hot flushes
restlessness

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.

depressive moods
blood clotting (which may lead to a clot on the lungs, stroke or heart attack)
fast heart rate
change in skin colour 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 you may need urgent medical attention or hospitalisation.

sudden severe headache, loss of vision, loss of coordination, slurred speech, shortness of breath, chest pain, numbness heat or swelling.
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.

If you were fertile before treatment, Androcur-100 will normally prevent sperm production. Fertility is usually regained within a few months of discontinuing therapy.

Androcur-100 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).

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

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 100 mg looks like

White to off-white, capsule-shaped tablet with '100' engraved on one face, and a break line on the other face.

APO-Cyproterone 100 mg tablets are presented in blister packs containing 50 tablets.

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

Ingredients

Each tablet contains 100 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 Number

APO-Cyproterone 100 mg tablets:
Blisters:
AUST R 101535.

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 100 mg

Active ingredient

Cyproterone acetate

Schedule

1 Name of Medicine

Cyproterone acetate.

2 Qualitative and Quantitative Composition

Each tablet contains 100 mg cyproterone acetate as the active ingredient.

3 Pharmaceutical Form

Tablets.

White to off-white, capsule-shaped tablet with '100' engraved on one face, and a break line on the other face.

4 Clinical Particulars

4.1 Therapeutic Indications

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 100 mg tablets are intended for oral administration.
The maximum daily dose is 300 mg.
The tablets should be taken with some liquid after a meal.

Inoperable prostatic carcinoma.

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

Initially 1 tablet APO-Cyproterone Acetate 100 mg twice daily (i.e. 200 mg a day) alone for 5-7 days, followed by 1 tablet APO-Cyproterone Acetate 100 mg twice daily (i.e. 200 mg a day) for 3-4 weeks together with an LHRH agonist in the dosage recommended by the manufacturer.

Long-term palliative treatment without orchidectomy.

100 mg (1 tablet APO-Cyproterone Acetate 100 mg) two or three times daily. Treatment should not be interrupted, nor the dosage reduced, after improvement or remissions have occurred.

Treatment of hot flushes (in patients treated with LHRH analogues or post-orchidectomy).

50 mg to 150 mg (half to one and a half tablets) per day with upward titration up to 1 tablet three times daily (300 mg) if necessary (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects); Section 4.9 Overdose).

Use in hepatic impairment.

The use of cyproterone acetate is contraindicated in patients with hepatic diseases.

Use in renal impairment.

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

Use in the elderly.

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

Paediatric use.

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.

4.3 Contraindications

Hepatic diseases.
Previous or existing hepatic tumours (only if these are not due to metastases from carcinoma of the prostate).
Dubin-Johnson syndrome, Rotor syndrome.
Presence or history of meningioma.
Wasting diseases (with the exception of inoperable carcinoma of the prostate).
Severe chronic depression.
Existing thromboembolic processes.
Severe diabetes with vascular changes.
Sickle-cell anaemia.
Hypersensitivity to any of the components of APO-Cyproterone Acetate 100 mg.

4.4 Special Warnings and Precautions for Use

APO-Cyproterone Acetate 100 mg is for use only in men.
During treatment, hepatic 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 APO-Cyproterone Acetate 100 mg 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.
In patients 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 hepatic impairment.

The use of cyproterone acetate is contraindicated in patients with hepatic diseases.
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 cases are in men with prostatic cancer. Toxicity is dose related and usually develops 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, 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.

Use in renal impairment.

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

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 100 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 100 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 men.

The sexual drive reducing effect of APO-Cyproterone Acetate 50 mg can be diminished under the influence of alcohol.

Use in the elderly.

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

Paediatric use.

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 antidiabetics or insulin can change.
At high therapeutic cyproterone acetate doses of three times 100 mg per day, cyproterone acetate may inhibit CYP2C8 (see below).
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 inhibition 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 CYP 450 studies, the recommended clinical doses are likely to inhibit CYP 2C8, and an inhibition of the CYP 2C9, 2C19, 3A4 and 2D6 is also possible at high therapeutic cyproterone acetate doses of 3 x 100 mg per day.
Thiazolidinediones (i.e. the antidiabetics pioglitazone and rosiglitazone) are substrates or CYP 2C8 (increased blood levels of these anti-diabetics may require dose adjustment).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Spermatogenesis is impaired during treatment and recovers gradually after discontinuation (see Section 4.4 Special Warnings and Precautions for Use; 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 to 20 months to return to normal after discontinuing therapy.
(Category D)
APO-Cyproterone Acetate 100 mg is for use only in men.
APO-Cyproterone Acetate 100 mg is for use only in men.

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 100 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.

Skin.

Rare: rash.
The most frequently observed adverse drug reactions (ADRs) in 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.
Cyproterone acetate may lead 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 acetate may lead to osteoporosis.
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 are: skin discolouration, and striae.

Postmarketing information.

The following adverse effects have been reported in users of cyproterone acetate (post marketing data) but for which the association to cyproterone acetate has neither been confirmed nor refuted. 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*, meningioma, intra-abdominal haemorrhage*, 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 (several years) 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 should be initiated as required.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Cyproterone acetate is an anti-androgenic 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 anti-androgenic 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.
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.

The ingestion of 100 mg of cyproterone acetate gives maximum serum levels of 239.2 ± 114.2 nanogram/mL at 2.8 ± 1.1 hours. Thereafter, drug serum levels declined during a time interval of typically 24 to 120 hours, with a terminal half-life of 42.8 ± 9.7 hours. The total clearance of cyproterone acetate from serum was determined to be 3.8 ± 2.2 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 I metabolism of cyproterone acetate is mainly catalysed by the CYP450 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 in the serum by a factor of about 3 can be expected during repeated daily administration.

5.3 Preclinical Safety Data

Genotoxicity.

Cyproterone acetate (CPA) was negative in a standard battery of genotoxicity studies. However, further tests showed that CPA 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 APO-Cyproterone Acetate. In vivo consequences of CPA 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 CPA 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 liver pathology), the carcinogenic potential of CPA 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

Blister Pack (aluminium silver foil/ clear PVC/PVDC).
50 tablets (AUST R 101535).

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.

Structural formula:

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

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APO-Cyproterone 100 mg Tablets

Cyproterone acetate

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APO-Cyproterone Acetate 100 mg Tablets