Consumer medicine information

CYROTONE

Cyproterone acetate

BRAND INFORMATION

Brand name

Cyrotone 50 mg

Active ingredient

Cyproterone acetate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using CYROTONE.

What is in this leaflet

This leaflet answers some of the common questions about CYROTONE tablets.

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 CYROTONE tablets against the benefits the medicine is expected to 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 CYROTONE is used for

CYROTONE is an anti-androgenic hormone medication which has several different uses.

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

MEN:

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

CYROTONE 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.

CYROTONE tablets are also used to reduce abnormal sex drive in men.

WOMEN:

In women, androgens may increase hair growth, loss of scalp hair and secretion of oil from the sweat glands. By blocking these hormones, CYROTONE 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. CYROTONE is only available on a doctor’s prescription.

There is no evidence that CYROTONE tablets are addictive.

Before you take CYROTONE

When you must not take it

Do not take CYROTONE if you have an allergy to:

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

Some of the symptoms of an allergic reaction may include:

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

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

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

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

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

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

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

Do not take this medicine after the expiry date printed on the pack and blister. The expiry date is printed on the carton and on each blister after “EXP”. If it has expired return it to your pharmacist for disposal.

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

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

Before you start to take CYROTONE

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

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

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

Tell your doctor if you are pregnant, planning to become pregnant or breastfeeding.

CYROTONE tablets should not be taken during pregnancy as it may lead to the development of female characteristics in male babies.

Therefore, your doctor will check that you are not pregnant before you start taking CYROTONE. Women should use a reliable form of contraception while taking CYROTONE.

Tell your doctor if fertility after treatment is important. For men it is recommended that a sperm count is taken to establish fertility before commencing CYROTONE. It can take 3-20 months for fertile sperm production to be re-established after stopping this medicine.

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

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

Taking other medicines

If you are taking other medicines you must tell your doctor or pharmacist. This includes medicines that you can buy without a prescription from a pharmacy, supermarket or a health food shop. Your doctor or pharmacist will be able to tell you what you should do when you have to take other medicines while you are on CYROTONE.

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

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

How to take CYROTONE tablets

Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet. If you do not understand the instructions on the pack, ask your doctor or pharmacist for help.

How much to take

The dosage of CYROTONE will be determined by your doctor.

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

MEN:

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

Reduction of abnormal sex drive
Generally treatment is started with 50 mg of CYROTONE 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 CYROTONE 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.

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

Shortness of breath may occur at high doses.

How to take it

Swallow the tablets whole with some liquid after a meal.

When to take it

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

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

How long to take it

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

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

If you forget to take it

If it is almost time to take your next dose, skip the dose that you have missed and take your next dose when you are meant to. Otherwise take it as soon as you remember, then go back to taking your tablets as usual.

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

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

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

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

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26 - Australia) for advice, or go to the casualty department at your nearest hospital, if you think that you or anyone else may have taken too many CYROTONE tablets. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention. Keep telephone numbers of these places/services handy.

While you are taking CYROTONE tablets

Things you must do

If you are about to start taking any new medicines, tell your doctor and pharmacist that you are taking CYROTONE tablets.

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

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

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 CYROTONE 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 re-orientation.

Things you must not do

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

Do not use CYROTONE tablets to treat any other medical complaints unless your doctor tells you to.

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 CYROTONE tablets affect you. This medicine may cause tiredness and can impair the ability to concentrate. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Be careful when drinking alcohol while you are taking this medicine. If you drink alcohol, tiredness and the ability to concentrate may be worse. The effectiveness of CYROTONE to reduce abnormal sex drive can also be diminished under the influence of alcohol.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking CYROTONE. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

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

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

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

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

If you were fertile before treatment, CYROTONE 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 CYROTONE will also normally result in the inability to get or maintain an erection (impotence). This ability is usually also regained within a few months of discontinuing therapy.

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

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

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

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

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

After using CYROTONE tablets

Storage

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

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

Do not store CYROTONE tablets or any other medicine in the bathroom or near a sink.

Do not leave CYROTONE tablets in the car or on window sills. Heat and dampness can destroy some medicines.

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

Disposal

Tell your doctor if you stop taking the tablets or the tablets have passed their expiry date. Ask your pharmacist what to do with any tablets left over.

Return any unused medicine to your pharmacist.

Product description

What it looks like

CYROTONE are white to off-white round, flat tablets engraved “50”, with a break line on one side and plain on the other side.

CYROTONE* is presented in bottles and blisters containing either 20 or 50 tablets.

*Some pack sizes and presentations may not be marketed.

Ingredients

Active ingredient:
cyproterone acetate

Inactive ingredients:

  • lactose;
  • microcrystalline cellulose;
  • croscarmellose sodium;
  • povidone; and
  • magnesium stearate.

Distributor

Eris Pharmaceuticals (Australia) Pty Ltd
6 Eastern Road
South Melbourne VIC 3205
www.eris-pharma.com.au

Cyrotone 50 mg tablet blister pack AUST R 184194
Cyrotone 50 mg tablet bottle AUST R 184196

This leaflet was prepared in January 2014.

Published by MIMS February 2015

BRAND INFORMATION

Brand name

Cyrotone 50 mg

Active ingredient

Cyproterone acetate

Schedule

S4

 

Name of the medicine

Cyproterone acetate.

Excipients.

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

Description

Chemical name: 6-chloro-17αhydroxy- 1α,2α-methylene- pregna-4,6-diene- 3,20-dione acetate. Molecular formula: C24H29ClO4. MW: 416.96. CAS: 427-51-0. Cyproterone acetate is a white to almost white crystalline powder. It is practically soluble in water, very soluble in methylene chloride, freely soluble in acetone, soluble in methanol, sparingly soluble in anhydrous ethanol.

Pharmacology

ATC code: G03HA01.
Pharmacotherapeutic group: antiandrogens plain.
Cyproterone acetate inhibits competitively the effect of androgens at androgen dependent target organs, e.g. it shields the prostate from the effect of androgens originating from the gonads and/or the adrenal cortex. Prostatic carcinoma and its metastases are in general androgen dependent, cyproterone acetate therefore exerts a direct antiandrogenic action on the tumour and its metastases.
Cyproterone acetate in addition has a progoestogenic action exerting a negative feedback effect centrally on the hypothalamic receptors, so leading to a reduction in gonadotropin release, and hence to diminished production of testicular androgens. Treatment with cyproterone acetate in men results in a reduction of sexual drive and potency and inhibition of gonadal function. These changes are reversible following discontinuation of the therapy.
The antigonadotropic effect of cyproterone acetate is also exerted when the substance is combined with LHRH agonists. The initial increase of testosterone provoked by this substance group is decreased by cyproterone acetate.
In women, hirsutism is diminished, but also androgen dependent loss of scalp hair and elevated sebaceous gland function are reduced. During the treatment ovarian function is inhibited.
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. There are no data for periods longer than 6 months.

Pharmacokinetics.

Absorption.

Following oral administration, cyproterone acetate is completely absorbed over a wide dose range.
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%-119%).
In a study to determine the bioequivalence of the Cyrotone 100 formulation in comparison to the reference formulation, Androcur-100, cyproterone acetate 100 mg tablets, the mean peak plasma concentration for cyproterone acetate from the Cyrotone 100 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 the Cyrotone 100 formulation versus 5953.3 nanogram.h/mL for Androcur-100 tablets 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.

Elimination.

Some drug is excreted unchanged with bile fluid. 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.

According to the long half-life of the terminal disposition phase from plasma (serum) and the daily intake, an accumulation of cyproterone acetate by a factor of about 3 can be expected in the serum during repeated daily administration.
Radioimmunoassays show that about 0.2% of the dose is eliminated with the breast milk.

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) and;
moderately severe/ severe forms of acne and/or seborrhea associated with other features of androgenisation.
Cyrotone 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 Cyrotone is taken during pregnancy, the properties of the preparation may lead to signs of feminisation in the male fetus. 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.

1. Reduction of drive in sexual deviations.

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

2. 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.

Contraindications

Women.

Pregnancy; lactation; liver diseases; a history of jaundice or persistent itching during a previous pregnancy; a history of herpes of pregnancy; Dubin-Johnson syndrome, Rotor syndrome; wasting diseases; severe chronic depression; previous or existing thromboembolic processes; severe diabetes with vascular changes; sickle cell anaemia; and hypersensitivity to any of the components listed in the Excipients section.

Men.

Reduction of drive in sexual deviations.

Liver disease; Dubin-Johnson syndrome, Rotor syndrome; previous or existing liver tumours; presence or history of meningioma; wasting diseases; severe chronic depression; previous or existing thromboembolic processes; severe diabetes with vascular changes; sickle cell anaemia; and hypersensitivity to any of the components listed in the Excipients section.

Inoperable carcinoma of the prostate.

Liver diseases; Dubin-Johnson syndrome, Rotor syndrome; previous or existing liver tumours (only if these are not due to metastases from carcinoma of the prostate); presence or history of meningioma; wasting diseases (with the exception of inoperable carcinoma of the prostate); severe chronic depression; and hypersensitivity to any of the components listed in the Excipients section.
In patients with prostatic carcinoma presenting 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 acetate is prescribed.
Cyproterone acetate 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 (see Dosage and Administration).

Precautions

During treatment liver function, adrenocortical function and red blood cell count should be checked regularly.

Liver.

Direct hepatic toxicity, including jaundice, hepatitis and hepatic failure, has been observed in patients treated with cyproterone acetate. At dosages of 100 mg and above, cases with fatal outcome have been reported. Most reported 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.
Benign and malignant hepatic tumours, leading very rarely to life threatening intra-abdominal haemorrhage, have been observed in isolated cases after the use of hormonal steroids. 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 and, if necessary, discontinuation of the preparation considered.

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 acetate is diagnosed with meningioma, treatment with cyproterone acetate must be stopped (see Contraindications).

Diabetes.

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

Shortness of breath.

A sensation of shortness of breath may occur in individual cases under high dose 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 temporal association with the use of cyproterone acetate. However, a causal relationship has not been established. Patients with previous arterial or venous thrombotic/ thromboembolic events (e.g. deep venous thrombosis, pulmonary embolism, myocardial infarction) or with a history of cerebrovascular accidents or with advanced malignancies are at increased risk of further thromboembolic events.

Adrenocortical function.

During treatment adrenocortical function should be checked regularly, as preclinical data suggest a possible suppression due to the corticoid-like effect of cyproterone acetate with higher 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 acetate tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
There is a risk of osteoporosis in long-term antiandrogen treatment.

Specifically to be observed in women.

Before the start of therapy a thorough general medical and gynaecological examination (including the breasts and a cytological smear of the cervix) should be carried out. Serious organic causes of androgenisation, e.g. Cushing's syndrome, ovarian tumours, adrenal carcinoma and adrenogenital syndrome should be excluded. Pregnancy must be excluded at the time of commencing treatment in women of childbearing potential.
If, during the combined treatment, spotting occurs during the 3 weeks in which the tablets are being taken, tablet taking should not be interrupted. However, if persistent or recurrent bleeding occurs at irregular intervals, a gynaecological examination must be carried out to exclude organic diseases.

Combined cyproterone acetate/ oestrogen therapy.

See also Dosage and Administration, Women of childbearing potential.

Specifically to be observed in men.

The sexual drive reducing effect of cyproterone acetate can be diminished under the influence of alcohol.

Additional information combined use of cyproterone acetate with oestrogen.

The following additional information is applicable to use of all cyclic combined oestrogen-progestogen therapies, including oral contraceptives.
Use of combined oestrogen-progestogen medication may be associated with an increased risk of thromboembolism, stroke and myocardial infarction, increasing over the age of 30 years and further increased by cigarette smoking, hypertension, obesity, diabetes, hypercholesterolaemia or a history of pre-eclamptic toxaemia. The risk of myocardial infarction is substantially increased in women aged 40 years and over. All users of combined oestrogen-progestogen medications should be encouraged not to smoke.
Therapy should be discontinued if feasible at least six weeks prior to elective surgery of a kind associated with increased risk of embolism and during any period of prolonged immobilisation. Optic neuritis and retinal thrombosis have been reported in association with combined oestrogen-progestogen treatment. Discontinue medication pending examination if there is unexplained sudden partial or complete loss of vision, sudden onset of proptosis, diplopia or migraine. If examination reveals papilloedema or retinal vascular lesions, medication should be withdrawn.
Susceptible women may experience a rise in blood pressure. The prevalence of hypertension increases with the duration of use and the age of the patient. Blood pressure should be measured and care should be exercised in prescribing these preparations for patients with hypertension. Regular monitoring of blood pressure is desirable.
The first spontaneous ovulation after stopping combined oestrogen-progestogen treatment is sometimes delayed; and there is evidence of temporary impairment of fertility in some women who discontinue combined oestrogen-progestogen treatment which appears to be independent of the duration of use. Impairment diminishes with time, but may be evident up to 30 months after cessation in nulliparous women. It should be suggested to patients who decide to become pregnant that alternative methods of contraception be used until they have their first spontaneous period, so that the estimated date of delivery may be made with more certainty.
Women with a strong family history of breast cancer, or who have breast nodules, fibrocystic disease or abnormal mammographs, should be monitored with particular care after they elect to use combined oestrogen-progestogen treatment.
Epidemiological studies report doubling of the risk of gall bladder disease in women who have used combined oestrogen-progestogen treatment for two or more years. The onset or exacerbation of migraine or other persistent severe headache requires discontinuation of combined oestrogen-progestogen treatment pending full investigation.
Contraceptive efficacy may be impaired by drug interactions, especially rifampicin, semisynthetic penicillins and anticonvulsant drugs, and also by severe diarrhoea, or by vomiting shortly after the ingestion of a tablet.
Before prescribing combined oestrogen-progestogen treatment, a complete history and physical examination should be undertaken, with particular reference to blood pressure, breasts, abdomen and pelvic organs. A Papanicolaou smear and urinalysis should be carried out.
Combined oestrogen-progestogen treatment may cause some degree of fluid retention. Care is therefore necessary in those diseases which may be aggravated, especially cardiac and renal insufficiency, migraine and asthma. Patients should be warned that vulvovaginal monilial infection may occur or recur, and of the need for appropriate treatment.
Pyridoxine and folate plasma levels may be depressed by combined oestrogen-progestogen treatment. Folate supplementation may be desirable if a patient becomes pregnant shortly after ceasing tablet taking.
Certain changes may be induced in laboratory data as follows.

Liver function tests.

Transaminases (AST, ALT) and bromsulfophthalein retention are increased.
Clotting factors VII, VIII, IX and X, prothrombin and platelet aggregation are increased, but antithrombin III decreased.

Thyroid function tests.

Thyroid binding globulin (TBG), total thyroxine (T4), and protein bound iodine (PBI) are increased. T3 resin uptake (reflecting TBG) is decreased, whilst free T4 and clinical thyroid state remain unaltered.

Adrenal function.

Plasma cortisol is increased (due to increase in steroid binding globulins) whilst adrenal function is essentially normal.

Agglutination reactions.

False positive rheumatoid factor and antinuclear factor are increased.
Blood glucose, phospholipids and triglycerides are increased. These tests usually return to pretherapy values shortly after discontinuation of oestrogen-progestogen treatment.

Carcinogenicity and mutagenicity.

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 acetate. 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.
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.

Impairment of fertility.

Men.

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.

Women.

The long term effects on female fertility are not known with certainty.

Use in pregnancy.

(Category D)
The use of cyproterone acetate is contraindicated during pregnancy (see Contraindications). Administration of cyproterone acetate during the hormone sensitive differentiation phase of the genital organs (after approx. day 45 of pregnancy) could lead to signs of feminisation in male fetuses.

Use in lactation.

The use of cyproterone acetate is contraindicated during lactation, as small amounts of cyproterone acetate are excreted in breast milk (see Contraindications).

Use in elderly.

There is reduced hepatic clearance in the elderly, and this should be considered when prescribing and monitoring treatment with cyproterone acetate.

Effect on ability to drive or operate machinery.

It should be pointed out to patients whose occupation demands great concentration (e.g. road users, machine operators) that cyproterone acetate can lead to tiredness and diminished vitality and can impair the ability to concentrate.

Interactions

The requirement for oral antidiabetics or insulin may change.
Contraceptive efficacy may be impaired by drug interactions especially anticonvulsant drugs, penicillins and rifampicin (antibiotics).

Adverse Effects

Adverse reactions reported in clinical trials.

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

General.

Very common: tiredness, weight increase. Common: headache, depressive moods. Uncommon: sleep disturbances, hot flushes, allergic reactions.

Cardiovascular.

Common: thrombotic phenomena. Uncommon: tachycardia.

Respiratory.

Rare: shortness of breath.

Gastrointestinal.

Common: nausea and other gastrointestinal complaints.

Hepatobiliary.

Rare: liver functions disturbance, hepatitis, jaundice, hepatic failure.

Musculoskeletal.

Uncommon: osteoporosis.

Reproductive.

Very common: diminished libido, impaired spermatogenesis, inhibition of ovulation. Common: gynaecomastia, breast tenderness, breast pain. Uncommon: galactorrhea, irregular menstrual cycles, dysmenorrhea, vaginal discharge, increased libido.

Skin.

Uncommon: skin discolouration, striae. Rare: rash. Unknown incidence: alteration in hair pattern.

Dosage and Administration

Cyproterone acetate is to be taken with some liquid after meals.

Women.

Women of childbearing potential.

Pregnant women must not take cyproterone acetate, therefore pregnancy must be excluded at the time therapy is commenced in women of childbearing potential.
In women of childbearing potential, the treatment is commenced on the 1st day of the cycle (= first day of bleeding). Only women with amenorrhoea or menstrual bleeding at very irregular intervals can start treatment immediately. In this case the first day of treatment is to be regarded as the 1st day of the cycle and the following recommendations then observed as normal.

Hirsutism secondary to female androgenisation.

The usual starting dose is 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.

Other severe signs of androgenisation.

Two 50 mg tablets daily for ten days (from the 1st to the 10th day of the cycle).
Following clinical improvement, the daily dose may be reduced to one or half a tablet during the ten days on which it is given in each treatment cycle. The dose regimen for ethinyloestradiol (see Combined cyproterone acetate/ oestrogen therapy, below) remains unchanged. If improvement is maintained over a further few months, cyproterone acetate 10 mg daily for 15 days per month (from the fifth to the 19th day of the cycle) may be sufficient.
Combined cyproterone acetate/ oestrogen therapy. In addition to cyproterone acetate, women of childbearing potential should receive a combined oral contraceptive, containing oestrogen, daily from the fifth to the 25th day of the cycle to provide the necessary contraceptive protection and to stabilise the cycle. See the full product information document for the chosen combined oral contraceptive preparation.
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 i.e. more than 36 hours have elapsed since the last tablets were taken), contraceptive protection in this cycle may be reduced. The use of cyproterone acetate and a combined oral contraceptive containing low dose oestrogen should nevertheless be continued according to the instructions, ignoring the missed tablet or tablets, in order to avoid premature bleeding in this cycle. However, an additional nonhormonal barrier method of contraception (not the rhythm or temperature methods) is to be employed for the rest of the cycle.
A seven day tablet free interval is observed after 21 days, during which time a withdrawal bleeding occurs. 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.
As the dose of cyproterone acetate is reduced, contraceptive efficacy may be impaired. Therefore, a reliable form of contraception (not the rhythm or temperature methods) must be employed during treatment. If a nonhormonal method is adopted, a combined oral contraceptive containing low dose oestrogen from day five to 25 will need to be continued to stabilise the cycle.
See also Precautions, Combined cyproterone acetate/ oestrogen therapy.
Postmenopausal and hysterectomised women. In postmenopausal or hysterectomised patients, cyproterone acetate may be administered alone. According to the severity of the complaints, the average dose should be half to one tablet (25 to 50 mg) once daily for 21 days, followed by a seven day tablet free interval.
Duration of treatment. The duration 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 half 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 half a tablet, at intervals of several weeks.
To stabilise the therapeutic effect it is necessary to take cyproterone acetate 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 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.

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

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.

Children and adolescents.

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 endrocine function cannot be ruled out.

Patients with hepatic impairment.

The use of cyproterone acetate is contraindicated in patients with liver diseases (see Contraindications).

Overdosage

There is no experience in overdose and individual clinical assessment and symptomatic treatment is required immediately as appropriate.
Use of cyproterone acetate at high doses has been associated with hepatic toxicity, particularly in the elderly: see Adverse Effects.
Contact the Poisons Information Centre (telephone no. in Australia 131 126) for advice on overdose management.

Presentation

Tablets (white to off white, round, flat, marked 50 over break line on one side, plain on reverse): 20's*, 50's (PVC/ PVDC/ Al blister pack: AUST R 184194, HDPE bottle: AUST R 184196)
*Not currently marketed in Australia.

Storage

Store below 30°C. Protect from light and moisture.

Poison Schedule

S4.