Consumer medicine information

Cyproterone Sandoz

Cyproterone acetate

BRAND INFORMATION

Brand name

Cyproterone Sandoz

Active ingredient

Cyproterone acetate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Cyproterone Sandoz.

What is in this leaflet

This leaflet answers some common questions about Cyproterone Sandoz.

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 this medicine 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 Cyproterone Sandoz is used for

MEN:
This medicine is used to treat cancer of the prostate gland. It can also be used in conjunction 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.

It is also used for the reduction of sex drive in men with sexual deviations.

WOMEN:
This medicine is used to treat:

  • excessive hairiness (hirsutism)
  • androgen-dependent loss of scalp hair (androgenic alopecia)
  • dandruff
  • acne
  • oily skin.

It contains the active ingredient cyproterone acetate.

Cyproterone acetate belongs to a group of medicines called anti-androgen hormones.

It works by blocking androgens (e.g. testosterone), which are natural male sex hormones. Androgens are also produced, to a slight extent, in females.

In men, androgens may help cancer cells to grow in some types of prostate cancer. By blocking these hormones, Cyproterone Sandoz may slow or stop the growth of cancer.

In women, androgens may increase hair growth, loss of scalp hair and secretion of oil from the sweat glands. By blocking these hormones, Cyproterone Sandoz 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 not addictive.

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

Before you take Cyproterone Sandoz

When you must not take it

Do not take this medicine if you have an allergy to:

  • cyproterone acetate, the active ingredient, or to any of the other ingredients listed at the end of this leaflet under Product Description.

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.

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

  • liver disease or liver tumours unless they are caused by metastases from prostate cancer
  • severe chronic depression
  • Dubin-Johnson or Rotor syndrome
  • wasting disease (a disease causing muscle loss or loss of strength, with the exception of prostate cancer)
  • severe diabetes that has damaged your blood vessels
  • sickle-cell anaemia
  • existing blood clots
  • benign brain tumour (meningioma).

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

  • liver tumours
  • jaundice (yellowing of the skin and/or eyes), herpes or persistent itching during a previous pregnancy
  • history of blood clotting problems (e.g. blood clots in the leg, lungs, stroke or heart attack)
  • benign brain tumour (meningioma).

In men with cancer of the prostate with some of the above medical conditions, the benefits of taking this medicine may outweigh the risks. Your doctor will consider the risks and benefits of taking this medicine.

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 Cyproterone Sandoz passes into breast milk and there is a possibility that your baby may be affected.

Do not give this medicine to children. This medicine 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 after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or 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 of the following medical conditions:

  • 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)
  • amenorrhea (no menstrual periods)
  • a hysterectomy (surgical removal of the uterus).

Tell your doctor if you are pregnant or plan to become pregnant. It may affect your developing baby if you take it during pregnancy. Therefore, your doctor will check that you are not pregnant before you start taking Cyproterone Sandoz.

Women should use a reliable form of contraception while taking Cyproterone Sandoz.

Tell your doctor if fertility after treatment is important. It is advisable for men to have a spermatogram before taking Cyproterone Sandoz to establish your fertility. It can take 3-20 months for fertile sperm production to be re-established after stopping this medicine.

The long-term effects of Cyproterone Sandoz on female fertility are not known.

Cyproterone Sandoz contains lactose. If you have been told by your doctor that you have intolerance to some sugars, tell your doctor before taking it.

If you have not told your doctor about any of the above, tell him/her before you start taking Cyproterone Sandoz.

Taking other medicines

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

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

  • medicines used to treat fungal infections, such as ketoconazole, itraconazole, clotrimazole
  • rifampicin, an antibiotic used to treat infections such as tuberculosis and leprosy
  • ritonavir, a medicine used in the treatment of HIV
  • St John's Wort, a herbal remedy used to treat mood disorders
  • phenytoin, a medicine used to treat epilepsy
  • statins (HMGCoA inhibitors), medicines used to lower cholesterol levels
  • medicines used to treat diabetes, such as oral anti-diabetic medicines or insulin.

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

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

How to take Cyproterone Sandoz

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, ask your doctor or pharmacist for help.

How much to take

MEN:
Your doctor will tell you the dose that you should take.

Do not alter the dose yourself.

Prostate cancer:
The usual daily dose is 50-300 mg (half to three tablets) of Cyproterone Sandoz 100 mg.

Your doctor may request that you take Cyproterone Sandoz with other medicines and/or change your dose during treatment.

Reduction of drive in sexual deviations:
The usual starting dose is one tablet of Cyproterone Sandoz 50 mg twice daily.

Your doctor may change your dose during treatment.

WOMEN:
Your doctor will tell you the dose that you should take and when to start taking Cyproterone Sandoz.

When you start taking Cyproterone Sandoz depends on whether you:

  • are of childbearing age
  • have amenorrhea (no menstrual periods)
  • have had a hysterectomy (surgical removal of the uterus)
  • are post menopausal.

Additionally, your doctor will advise the most appropriate "Pill" for you to take to provide the necessary contraceptive protection and to stabilise your menstrual cycle.

Ask your doctor or pharmacist if you are unsure of the correct dose for you. They will tell you exactly how much to take.

Follow the instructions they give you.

If you take the wrong dose, Cyproterone Sandoz may not work as well and your problem may not improve.

How to take it

Swallow the tablets whole with a full glass of water after meals.

When to take it

Take your medicine 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.

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

Take your dose as soon as you remember, and continue to take it as you would normally.

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

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.

Missed Cyproterone Sandoz tablets in women may reduce the effectiveness of treatment and may lead to intermenstrual bleeding.

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

If bleeding fails to occur after a cycle where the "Pill" was missed, you must see your doctor. Your doctor may need to check whether or not you are pregnant before you can continue treatment.

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

While you are taking Cyproterone Sandoz

Things you must do

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

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

If you become pregnant while taking this medicine, tell your doctor immediately.

For females taking the "Pill" during treatment:
If light bleeding or spotting occurs during the three weeks in which the tablets are being taken, do not stop taking your tablets.

However, if unusual bleeding patterns continue, tell your doctor.

If no bleeding occurs during the tablet-free/placebo interval, tell your doctor. Your doctor may need to check whether you are pregnant before you can continue treatment.

For males taking Cyproterone Sandoz 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.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some tests (such as liver or blood 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 Cyproterone Sandoz and whenever any sypmtoms 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 Sandoz.

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

Things you must not do

Do not take Cyproterone Sandoz 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 Cyproterone Sandoz affects you. This medicine may cause tiredness and can impair the ability to concentrate in some people. 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.

If you are taking Cyproterone Sandoz to reduce your sex drive, alcohol may stop Cyproterone Sandoz from working as well as it should.

Side effects

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

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention 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 changes (increase or decrease)
  • decreased sexual drive
  • headache
  • depressed mood
  • nausea and other stomach complaints
  • breast pain, changes in breast size, breast swelling and/or tenderness
  • breast enlargement in men
  • irregular menstrual cycle, spotting
  • hot flushes, sweating
  • shortness of breath
  • osteoporosis.

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

If you were fertile before treatment, Cyproterone Sandoz may also result in the inability to produce sperm (males) or ovulate (females). In males, fertility is usually regained within a few months of discontinuing therapy. The long-term effects on female fertility are not known.

In males, Cyproterone Sandoz may result in the inability to get or maintain an erection (impotence). This is usually regained within a few months of discontinuing therapy.

Tell your doctor as soon as possible if you notice any of the following:

  • yellowing of the skin and/or eyes, light coloured bowel motions, dark coloured urine (jaundice)
  • 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.

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

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing
  • signs of a stroke, such as sudden severe headache, loss of vision, loss of co-ordination, slurred speech, numbness, heat or swelling in the arms and legs
  • signs of a heart attack, such as chest pain or shortness of breath.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

After taking Cyproterone Sandoz

Storage

Keep your medicine in the original container.

If you take it out of its original container it may not keep well.

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

Do not store Cyproterone Sandoz 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 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

Cyproterone Sandoz comes in two types of tablets:

Cyproterone Sandoz 50 mg – white to off white, round tablets engraved with ‘50’ over a break line on one face, plain on the other face.

Available in bottles of 20 or 50 tablets.

Cyproterone Sandoz 100 mg – white to off white, capsule shaped tablets with ‘100’ engraved on one face and a break line on the other face.

Available in blisters of 50 tablets.

Ingredients

Active ingredients:

  • Cyproterone Sandoz 50 mg - 50 mg cyproterone acetate
  • Cyproterone Sandoz 100 mg - 100 mg cyproterone acetate

Inactive ingredients:

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

This medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

Supplier

Cyproterone Sandoz is supplied in Australia by:

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park, NSW 2113
Australia
Tel: 1800 726 369

This leaflet was revised in June 2019.

Australian Register Number(s)

50 mg tablets: AUST R 107330 (bottles)

100 mg tablets: AUST R 107331 (blisters)

Published by MIMS August 2019

BRAND INFORMATION

Brand name

Cyproterone Sandoz

Active ingredient

Cyproterone acetate

Schedule

S4

 

1 Name of Medicine

Cyproterone acetate.

6.7 Physicochemical Properties

Cyproterone acetate is a white to pale yellow crystalline powder. Melting point: 206 to 213°C. 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 name: 6-chloro-17αhydroxy-1α,2α-methylene-pregna- 4,6-diene-3,20-dione acetate. Empirical formula: C24H29ClO4. Molecular Weight: 416.94.

Chemical structure.


CAS number.

427-51-0.

2 Qualitative and Quantitative Composition

Each Cyproterone Sandoz 100 mg tablet contains 100 mg cyproterone acetate.

Excipient with known effect.

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

3 Pharmaceutical Form

Cyproterone Sandoz 100 mg tablets are white to off white, capsule shaped tablet with '100' engraved on one face, and a break line on the other face.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Cyproterone acetate is an antiandrogenic hormone preparation.
Cyproterone acetate is believed to prevent the effect of endogenously produced and exogenously administered androgens at the target organs by means of competitive inhibition. The stimulating effect of male sex hormones on androgen dependent structures and functions is weakened or counteracted by cyproterone acetate.
Cyproterone acetate also exerts a progestational and antigonadotrophic effect.
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 function of androgen dependent target organs, such as the prostate, is restricted.
Prostatic carcinoma and its metastases are in general androgen dependent. Cyproterone acetate exerts a direct antiandrogenic action on the tumour and its metastases, and in addition it exerts a negative feedback effect on the hypothalamic receptors, so leading to a reduction in gonadotropin release, and hence to diminished production of testicular androgens.
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.
Serum prolactin levels may increase with higher doses of CPA. Prolactin levels increased up to 20 nanogram/mL (normal range 5-15 nanogram/mL) in studies of up to six months duration.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration, cyproterone acetate is absorbed slowly. Relative bioavailability was calculated from a dose corrected comparison of area under the curves of serum levels after 100 mg oral and 300 mg intramuscular depot administration in 8 young women, and was found to be 80 ± 30% (range 23%-199%). In a study to determine the bioequivalence of Cyproterone Sandoz 100 mg in comparison to cyproterone acetate 100 mg tablets distributed by Schering Proprietary Ltd, the mean peak plasma concentration for cyproterone acetate from the Cyproterone Sandoz 100 mg formulation after administration of a single 100 mg dose, was 176.2 nanogram/mL at about 4 hours in comparison to 161.7 nanogram/mL after about 3 hours for the reference product. The 90% confidence interval (CI) for comparison of the log transformed peak concentrations was 0.97-1.22. The area under the plasma concentration time curve (AUC0-∞) was 5756.0 nanogram.h/mL for Cyproterone Sandoz 100 mg versus 5953.3 nanogram.h/mL for 100 mg cyproterone acetate tablets distributed by Schering Proprietary Ltd with the 90% confidence interval (CI) for comparison of the log transformed data being 0.91-1.03.

Distribution.

Cyproterone acetate within the cardiovascular system is almost exclusively bound to plasma albumin. About 3.5-4% of total drug levels are present unbound. Because protein binding is nonspecific, changes in SHBG (sex hormone binding globulin) levels do not affect the pharmacokinetics of cyproterone acetate. In animals, cyproterone acetate has been shown to distribute into the liver, kidney, brain and heart. Levels in these organs may be higher than in plasma.

Metabolism.

Cyproterone acetate is metabolised by various pathways, including hydroxylations and glucuronide conjugations. The main metabolite in human plasma is 15β-hydroxycyproterone acetate. Some drug is excreted unchanged with bile fluid. Phase I metabolism of cyproterone acetate is mainly catalysed by the CYP450 enzyme CYP3A4.

Excretion.

Most of the dose is excreted in the form of metabolites at a urinary to biliary ratio of 3:7. Unconjugated metabolites appear in the urine whereas glucuronide metabolites appear in the bile. In the study discussed above, cyproterone acetate was eliminated with a mean half-life of approximately 70 hours for both preparations.

Steady-state conditions.

An accumulation of cyproterone acetate in the serum by a factor of about 3 can be expected during repeated daily administration.
Radioimmunoassays show that about 0.2% of the dose is eliminated with the breast milk.

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 Cyproterone Sandoz 100 mg. In vivo consequences of CPA 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 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.

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.

4.3 Contraindications

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 carcinoma of the prostate);
severe chronic depression;
existing thromboembolic processes;
hypersensitivity to any of the components of Cyproterone Sandoz 100 mg.
In patients with a history of thromboembolic processes or suffering from sickle-cell anaemia, or from severe diabetes with vascular changes, the risk/benefit ratio must be considered carefully in each individual case before Cyproterone Sandoz 100 mg is prescribed.

4.4 Special Warnings and Precautions for Use

Cyproterone Sandoz 100 mg is for use only in men.
During treatment, liver function, adrenocortical function and red blood cell count should be checked regularly.
As with other antiandrogenic treatments, in male patients long-term androgen deprivation with cyproterone acetate may lead to osteoporosis.
In patients with diabetes, strict medical supervision is necessary. Carbohydrate metabolism should be monitored carefully.
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.

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.
If a patient treated with cyproterone is diagnosed with meningioma, treatment with cyproterone 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-dosed treatment with cyproterone acetate. 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 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.

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.

Cyproterone Sandoz tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose mal-absorption should not take this medicine.
The sexual drive-reducing effect of cyproterone acetate can be diminished under the influence of alcohol.

Use in hepatic impairment.

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 pre-treatment 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 liver tumors, which may lead to life-threatening intra-abdominal haemorrhage, have been observed after the cyproterone acetate use. 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 and, if necessary, discontinuation of the preparation considered.

Use in the elderly.

There is reduced hepatic clearance in the elderly, and this should be considered when prescribing and monitoring treatment with Cyproterone Sandoz 100 mg.

Paediatric use.

See Section 4.2 Dose and Method of Administration, Children and adolescents.

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 may 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 levels of cyproterone acetate.
The risk of statin associated myopathy or rhabdomyolysis may be increased when those HMG-CoA inhibitors (statins), which are primarily metabolized 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.

Spermatogenesis is impaired during treatment and recovers gradually after discontinuation. 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 to 20 months to return to normal after discontinuing therapy.
The long-term effects on female fertility are not known with certainty.
(Category D)
Cyproterone Sandoz 100 mg is for use only in men.
No data available.

4.8 Adverse Effects (Undesirable Effects)

Adverse effects reported in clinical trials.

The following adverse effects 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.

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 100 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 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 bodyweight are possible.
Other adverse events reported at a low incidence are skin discolouration and striae.

Post-marketing 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 confirm 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.
Very common ≥ 1/10; common ≥ 1/100 and < 1/10; uncommon ≥o 1/1,000 and < 1/100; rare ≥ 1/10,000 and < 1/1,000; very rare < 1/10,000.

General.

Common: fatigue, hot flushes, sweating. Very rare: tiredness, sleep disturbances.

Cardiovascular.

Very rare: thrombotic phenomena, tachycardia.

Respiratory.

Very rare: shortness of breath.

Gastrointestinal.

Very rare: nausea and other gastrointestinal complaints.

Hepatobiliary.

Common: hepatic toxicity, including jaundice, hepatitis, hepatic failure. Rare: jaundice, increased liver enzymes. Very rare: hepatitis, liver function disturbance, hepatic failure.

Reproductive system.

Very common: reversible inhibition of spermatogenesis. Common: gynaecomastia. Very rare: impaired spermatogenesis, breast tenderness, breast pain.

Skin.

Uncommon: rash.

Musculoskeletal and connective tissue disorders.

Very rare: osteoporosis.

Immune system disorders.

Rare: hypersensitivity reaction.

Metabolic and nutrition disorders.

Common: weight increased or weight decreased.

Psychiatric disorders.

Very common: libido decreased, erectile dysfunction. Common: depressed mood, restlessness (temporary).

Neoplasms benign and malignant.

Very rare: benign and malignant liver tumours.

Respiratory, thoracic and mediastinal disorders.

Common: shortness of breath.
The ADRs identified only during postmarketing surveillance and for which a frequency could not be estimated are anaemia, meningioma, intra-abdominal haemorrhage, thromboembolic events.
Under treatment with Cyproterone Sandoz, 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 Sandoz 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/reporting-problems.

4.2 Dose and Method of Administration

Dosage.

Cyproterone Sandoz 100 mg tablets are to be taken with some liquid after meals.

Inoperable prostatic carcinoma.

Suppression of flare with initial LHRH analogue therapy.

Initially 100 mg twice daily alone for 5-7 days, then 100 mg twice daily for 3-4 weeks together with an LHRH agonist at the dosage recommended by the manufacturer.

Long-term palliative treatment without orchidectomy.

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 postorchidectomy).

Low initial dose of 50 mg once to three times daily, with upward titration to 100 mg three times daily if necessary.
See Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects); Section 4.9 Overdose.

Dosage adjustment.

Renal impairment.

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

Hepatic impairment.

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

Children and adolescents.

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.

Elderly.

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

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 Cyproterone Sandoz 100 mg can lead to tiredness and diminished vitality and can impair the ability to concentrate.

4.9 Overdose

There is no experience in overdose and individual clinical assessment and symptomatic treatment is required immediately as appropriate.
Use of Cyproterone Sandoz 100 mg at high doses has been associated with hepatic toxicity, particularly in the elderly (see Section 4.8 Adverse Effects (Undesirable Effects)).
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone and magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, 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

Cyproterone Sandoz 100 mg tablets is available in (PVC/PVDC/Al) blister packs of 50 tablets.

6.6 Special Precautions for Disposal

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

Summary Table of Changes