Consumer medicine information

Estelle-35 ED

Cyproterone acetate; Ethinylestradiol

BRAND INFORMATION

Brand name

Estelle-35 ED

Active ingredient

Cyproterone acetate; Ethinylestradiol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Estelle-35 ED.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Estelle-35 ED. 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 Estelle-35 ED against the benefits they expect it will have for you.

If you have any concerns or are unsure about taking this medicine, ask your doctor or pharmacist for more advice.

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

WHAT ESTELLE-35 ED IS USED FOR

Estelle-35 ED is used for the treatment of signs of physical male characteristics caused by the male sex hormone, androgen, produced by in women in small amounts (androgenisation), such as:

  • severe acne where other treatments have not been successful
  • for excessive growth of facial or body hair (known as hirsutism) of a mild to moderate degree, where no underlying cause has been found.

Estelle-35 ED can also be used as a contraceptive to prevent pregnancy in women who are taking it for the treatment of signs of physical male characteristics as described above. Estelle-35 ED contains a progestogen and an estrogen hormone, and therefore works similarly to the combined oral contraceptive birth control pill, also known as ‘the Pill’. It should not be used in combination with another hormonal contraceptive.

While taking Estelle-35 ED you may also experience the following benefits:

  • more regular and lighter periods - potentially resulting in a decreased risk in anaemia (iron deficiency)
  • a decrease in period pain
  • reduction of greasiness in skin and hair.

Some conditions such as pelvic inflammatory disease, ovarian cysts, ectopic pregnancy (where the foetus is carried outside of your womb), lumpy breasts and cancer of the uterus (womb) and ovaries may be less common in women taking Estelle-35 ED.

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.

BEFORE YOU TAKE ESTELLE-35 ED

When you must not take it

Do not take Estelle-35 ED if you have an allergy to:

  • cyproterone acetate and/or ethinylestradiol (the active ingredients in Estelle-35 ED)
  • 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 in breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Estelle-35 ED is not for use in men.

Do not take Estelle-35 ED if you are taking antiviral medicines which contain ombitasvir, paritaprevir, or dasabuvir, and combinations of these. These antiviral medicines are used to treat chronic (long-term) hepatitis C (an infectious disease that affects the liver, caused by the hepatitis C virus).

Do not take Estelle-35 ED if you have, or have had, a blood clot in:

  • the blood vessels of the legs (deep vein thrombosis - DVT)
  • the lungs (pulmonary embolism - PE)
  • the heart (heart attack)
  • the brain (stroke)
  • other parts of the body.

Do not take Estelle-35 ED if you are concerned about or have an increased risk of blood clots. Blood clots are rare. Very occasionally blood clots may cause serious permanent disability and may even be fatal.

All combined oral contraceptive pills, including Estelle-35 ED, increase the risk of having a blood clot. However, the risk of having a blood clot when taking Estelle-35 ED is less than the risk of having a blood clot during pregnancy.

Do not take Estelle-35 ED if you are concerned about an increased risk of blood clots because of age or smoking. The risk of having a heart attack or stroke increases as you get older. It also increases if you smoke. You should stop smoking when taking Estelle-35 ED, especially if you are older than 35 years of age.

Do not take Estelle-35 ED if you have, or have had:

  • blood clots in your legs
  • any blood clotting disorders such as Protein C deficiency, Protein S deficiency, Leiden Factor V mutation, Antithrombin III deficiency or other inherited blood clotting conditions
  • a confirmed blood test showing:
    - increased levels of homocysteine
    - antiphospholipid antibodies (APLAs) e.g. anticardiolipin-antibodies and lupus anticoagulant. These may increase your risk of blood clots or pregnancy losses (miscarriage).
  • major surgery after which you have not been able to move around for a period of time
  • angina (chest pain)
  • a mini-stroke (also known as TIA or transient ischaemic attack)
  • migraine, where you have also had problems with seeing, speaking or had weakness or numbness in any part of your body
  • high risk of blood clots due to conditions such as diabetes with blood vessel damage, severe high blood pressure or severe high or low level of fats in your blood
  • pancreatitis (an inflammation of the pancreas) associated with high levels of fatty substances in your blood
  • severe liver disease and your liver function has not returned to normal
  • a benign or malignant liver tumour
  • cancer that may grow under the influence of sex hormones (e.g. of the breast or the genital organs)
  • meningioma or history of meningioma (a generally benign tumour of the tissue layer between the brain and the skull)
  • unexplained vaginal bleeding.

If any of these conditions appear for the first time while using Estelle-35 ED, stop taking it at once and tell your doctor. In the meantime use non-hormonal (barrier) methods of contraception (such as condoms or a diaphragm).

Do not take Estelle-35 ED if you are using another hormonal contraceptive.

Do not take this medicine if you are pregnant or think you might be pregnant.

Do not breast-feed if you are taking this medicine.

Do not give this medicine to a child.

Do not take this medicine after the expiry date printed on the pack and blister. If it has expired return it to your pharmacist for disposal.

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

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

Before you start to take it

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

Tell your doctor if:

  • you smoke
  • you, or anyone in your immediate family has had blood clots in the legs (DVT), or lungs (PE), a heart attack, a stroke, breast cancer or high cholesterol.

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

  • diabetes
  • high blood pressure
  • heart valve disorders or certain heart rhythm disorders
  • migraine
  • cancer
  • polycystic ovary syndrome, a hormonal condition which can cause menstrual irregularity and excess hair growth
  • hyperhomocysteinaemia, a condition characterised by high levels of the amino acid homocysteine in the blood
  • severe high or low levels of fats in the blood.

Ask your doctor to check if you:

  • are overweight
  • have any hereditary or acquired conditions that may make it more likely for you to get blood clots
  • have high cholesterol or triglycerides
  • have liver disease
  • have jaundice (yellowing of the skin) and/or pruritus (itching of the skin) related to cholestasis (condition in which the flow of bile from the liver stops or slows)
  • have gall bladder disease
  • have Crohn’s disease or ulcerative colitis (chronic inflammatory bowel disease)
  • have systemic lupus erythematosus (SLE - a disease affecting the skin all over the body)
  • have haemolytic uraemic syndrome (HUS - a disorder of blood coagulation causing failure of the kidneys)
  • have sickle cell disease
  • have a condition that occurred for the first time, or worsened during pregnancy or previous use of sex hormones (e.g. hearing loss, a metabolic disease called porphyria, a skin disease called herpes gestationis, a neurological disease called Sydenham’s chorea)
  • have chloasma (yellowish-brown pigmentation patches on the skin, particularly of the face) - if so, avoid exposure to the sun or ultraviolet radiation
  • have hereditary angioedema, you should see your doctor immediately if you experience symptoms of angioedema, such as swollen face, tongue and/or pharynx and/or difficulty swallowing, or hives together with difficulty in breathing.

If any of the above conditions appear for the first time, recur or worsen while taking Estelle-35 ED, you should tell your doctor.

Estelle-35 ED contains lactose monohydrate. If you have an intolerance to some sugars, tell your doctor before you start taking Estelle-35 ED.

If you have not told your doctor about any of the above, tell him/her before you start taking Estelle-35 ED.

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 Estelle-35 ED may interfere with each other. These include:

  • medicines used to treat tuberculosis such as rifampicin, rifabutin
  • medicines used to treat epilepsy such as phenytoin, primidone, barbiturates (e.g. phenobarbital (phenobarbitone)), carbamazepine, oxcarbazepine, topiramate, felbamate, lamotrigine
  • medicines used to treat HIV, such as ritonavir or nevirapine
  • some medicines used to treat Hepatitis C Virus (HCV) such as boceprevir, telaprevir
  • macrolide antibiotics (e.g. clarithromycin, erythromycin)
  • medicines used to treat fungal infections, such as ketoconazole and griseofulvin
  • ciclosporin, an immunosuppressant medicine
  • medicines used to treat high blood pressure, chest pain and/or irregular heartbeats such as diltiazem, verapamil
  • etoricoxib, an anti-inflammatory medicine used to treat pain
  • tizanidine, melatonin or midazolam which are medicines used to relax the body
  • theophylline, a medicine that helps with breathing
  • herbal medicines containing St John’s Wort
  • grapefruit juice.

These medicines may be affected by Estelle-35 ED or may affect how well it works. Your doctor may need to alter the dose of your medicine or prescribe a different medicine.

Some medicines:

  • can have an influence on the blood levels of Estelle-35 ED
  • can make it less effective in preventing pregnancy or
  • can cause unexpected bleeding.

You may need to use additional barrier methods of contraception (such as condoms or a diaphragm) while you are taking any of these medicines with Estelle-35 ED and for some time after stopping them.

Your doctor will be able to tell you how long you will need to use additional contraceptive methods.

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

HOW TO TAKE ESTELLE-35 ED

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 on the label or in this leaflet, ask your doctor or pharmacist for help.

How to take it

Take one tablet daily at about the same time every day. You must take Estelle-35 ED every day regardless of how often you have sex. It will also help you remember when to take it.

Swallow the tablet whole with a full glass of water. It does not matter if you take it before or after food.

Each blister pack is marked with the day of the week.

Take your first tablet from the red area on the blister pack corresponding to the day of the week.

Follow the direction of the arrows on the blister pack until all the tablets have been taken.

A period should begin 2-3 days after starting to take the white inactive tablets (last row) and may not have finished before the next pack is started.

Always start a new blister pack on the same day of the week as your previous pack.

Taking Estelle-35 ED for the first time

If you are starting Estelle-35 ED after a natural cycle, and you have not used a hormonal contraceptive in the past month, start on the first day of your period, i.e. on the first day of your menstrual bleeding.

You must also use additional barrier contraceptive precautions (e.g. condoms or a cap or a diaphragm plus spermicide) for the first 14 days of tablet-taking when having intercourse.

Your doctor will advise you when to start if you:

  • are taking Estelle-35 ED after having a baby
  • have had a miscarriage or an abortion.

Changing from another contraceptive

Changing from a combined oral contraceptive:
Start taking Estelle-35 ED on the day after taking the last active tablet in your previous pill pack. Bleeding may not occur until the end of the first pack of Estelle-35 ED.

If you are not sure which were the active/inactive tablets were in your previous pill pack, ask your doctor or pharmacist. Your previous pill pack may have different colour tablets to those of Estelle-35 ED.

Changing from a vaginal ring:
Start taking Estelle-35 ED on the day of removal of the last vaginal ring.

Changing from a progestogen-only pill (‘minipill’):
Stop taking the minipill on any day and start taking Estelle-35 ED at the same time the next day.

You must also use additional barrier contraceptive precautions (e.g. condoms or a diaphragm) for the first 14 days of tablet-taking when having intercourse.

Changing from a progestogen only injection, implant or intrauterine system (IUS):
Start taking Estelle-35 ED when your next injection is due, or on the day that your implant or IUS is removed.

You must also use additional barrier contraceptive precautions (e.g. condoms or a diaphragm) for the first 14 days of tablet-taking when having intercourse.

How long to take Estelle-35 ED

You may have to take Estelle-35 ED for at least 6 months before you see an improvement in your condition. The length of treatment depends on the severity of the condition and how well it responds to treatment.

You may be advised by your doctor to stop Estelle-35 ED 3 to 4 months after your symptoms have completely resolved.

You should have regular check- ups with your doctor to determine how long to keep taking Estelle-35 ED.

Stopping Estelle-35 ED

You can stop taking Estelle-35 ED at any time.

It is possible that the original condition may recur once Estelle-35 ED is stopped. Do not start taking Estelle-35 ED again without seeing your doctor first.

If you do not wish to fall pregnant, you should use additional barrier contraceptive precautions (e.g. condoms or a diaphragm) when you stop taking Estelle-35 ED.

If you are considering becoming pregnant, it is recommended that you begin taking a vitamin supplement containing folic acid. It is best that you start taking folic acid tablets before you stop taking Estelle-35 ED and not stop until your doctor advises this. Ask your doctor or pharmacist about suitable supplements. It is both safe and recommended that you take folic acid during pregnancy.

If you forget to take Estelle-35 ED

If you miss a tablet and take the missing tablet within 12 hours of missing it, you will be protected against pregnancy. If you are more than 12 hours late follow these detailed instructions:

For Estelle-35 ED to be most effective, yellow active tablets need to be taken uninterrupted for 7 days.

If you have been taking the yellow active tablets for 7 uninterrupted days and miss a yellow active tablet, take the missed tablet as soon as you remember, then go back to taking your medicine as you would normally, even if this means taking two tablets in one day. You will not need to use additional barrier contraceptive precautions.

The chance of pregnancy after missing a yellow active tablet depends on when you missed the tablet. There is a higher risk of becoming pregnant if you miss a tablet at the beginning or end of a pack.

If after taking your missed tablet you have less than 7 days of yellow active tablets left in a row, you should finish the active tablets in your pack but skip the white inactive tablets and start a new pack. This is the best way to maintain contraceptive protection. However, you may not have a period until the end of the yellow active tablets of the second pack. You may have spotting or breakthrough bleeding on tablet-taking days.

If you have been taking the yellow active tablets for less than 7 days and miss a yellow active tablet, take the missed tablet as soon as you remember, then go back to taking your medicine as you would normally, even if this means taking two tablets in one day. In addition, you must also use additional barrier contraceptive precautions (e.g. condoms or a diaphragm) for the next 7 days. If you have had sexual intercourse during that time, there is a possibility of pregnancy and you may need emergency contraception. You should discuss this with your doctor or pharmacist.

If you forget to take more than one yellow active tablet, seek advice from your doctor or pharmacist about what to do. If you have had sexual intercourse in the week before missing your tablets, there is a possibility of becoming pregnant. You should discuss this with your doctor or pharmacist.

If you forget to take a white inactive tablet, take it as soon as you remember and take the next tablet at the usual time. You are still protected against pregnancy because the white tablets do not contain any active ingredients.

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

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (13 11 26) for advice, or go to the Accident and Emergency Department at your nearest hospital, if you think that you or anyone else may have taken too much Estelle-35 ED. Do this even if there are no signs of discomfort or poisoning. You may need medical attention.

If you take several yellow active tablets at once, you may feel sick or vomit or may bleed from the vagina. Even girls who have not yet started to menstruate but have accidentally taken this medicine may experience such bleeding.

WHILE YOU ARE TAKING ESTELLE-35 ED

Things you must do

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

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Have regular check-ups with your doctor. When you are taking Estelle-35 ED, your doctor will tell you to return for regular check-ups, including getting a Cervical Screening Test. Your doctor will advise how often you need a Cervical Screening Test. A Cervical Screening Test can detect abnormal cells lining the cervix. Sometimes abnormal cells can progress to cancer.

If you are about to start on any new medicine, remind your doctor and pharmacist that you are taking Estelle-35 ED.

Stop taking Estelle-35 ED and see your doctor immediately or go to the Emergency Department at your nearest hospital if you notice the following signs:

  • one-sided swelling of the leg and/or foot or along a vein in the leg
  • pain or tenderness in the leg which may be felt only when standing or walking
  • increased warmth in the affected leg; red or discoloured skin on the leg
  • sudden onset of unexplained shortness of breath or rapid breathing
  • sudden coughing or coughing up of blood
  • sharp chest pain or sudden severe pain in the chest which may increase with deep breathing
  • severe light headedness or dizziness
  • rapid or irregular heartbeat
  • sudden pain, swelling and slight blue discoloration of an extremity
  • sudden numbness or weakness of the face, arm or leg, especially on one side of the body
  • sudden trouble walking, dizziness, loss of balance or coordination
  • sudden confusion, slurred speech or aphasia; sudden partial or complete loss of vision, double vision, painless blurring of vision which can progress to loss of vision
  • sudden, severe or prolonged headache with no known cause
  • loss of consciousness or fainting with or without seizure.
  • pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone
  • discomfort radiating to the back, jaw, throat, arm, stomach
  • feeling of being full, having indigestion or choking
  • sweating, nausea, vomiting
  • extreme weakness and anxiety

If you are going to have surgery, tell the surgeon or anaesthetist beforehand that you are taking Estelle-35 ED. The risk of having blood clots is temporarily increased as a result of major surgery, any surgery to the legs or pelvis, neurosurgery or major trauma. In women who take Estelle-35 ED, the risk may be higher.

In women at risk of prolonged immobilisation (including major surgery, any surgery to the legs or pelvis, neurosurgery, or major trauma), your doctor may tell you to stop taking (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation. Another method of contraception should be used to avoid unintentional pregnancy. Your doctor may prescribe other treatment (e.g. treatment for blood clots) if Estelle-35 ED has not been discontinued in advance.

Other risk factors for blood clotting include temporary immobilisation including air travel of greater than 4 hours, particularly in women with other risk factors. Consult your doctor if you plan to air travel for greater than 4 hours.

Consult your doctor if you develop high blood pressure while taking Estelle-35 ED, you may be told to stop taking it.

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

If you vomit within 3-4 hours or have severe diarrhoea after taking a yellow active tablet, the active ingredients may not have been completely absorbed. This is like missing a tablet. Follow the advice for missed tablets.

If you have unexpected bleeding and it continues, becomes heavy, or occurs again, tell your doctor. When taking these tablets for the first few months, you can have irregular vaginal bleeding (spotting or breakthrough bleeding) between your periods. You may need to use sanitary products, but continue to take your tablets as normal. Irregular vaginal bleeding usually stops once your body has adjusted to Estelle-35 ED, usually after about 3 months.

If you have missed a period, but you have taken all your tablets, it is unlikely that you are pregnant, as long as:

  • you have taken the yellow active tablets at the right time
  • you have not been taking medicine(s) that may interfere with Estelle-35 ED.
  • you have not vomited or had severe diarrhoea during this cycle.

If this is so, continue to take Estelle-35 ED as usual. If you have any concerns consult your doctor or pharmacist.

If you miss your period twice in a row, you may be pregnant even if you have taken Estelle-35 ED correctly. Stop taking Estelle-35 ED and seek advice from your doctor. You must use a non-hormonal method of contraception, (such as condoms or a diaphragm) until your doctor rules out pregnancy.

Estelle-35 ED will not protect you from HIV-AIDS or any other sexually transmitted infections (STIs), such as chlamydia, genital herpes, genital warts, gonorrhoea, hepatitis B, human papilloma virus and syphilis.

To protect yourself from STIs, you will need to use additional barrier contraceptives (e.g. condoms).

Things you must not do

Do not take Estelle-35 ED to treat any other conditions, unless your doctor tells you to.

Do not give your medicine to anyone else.

Do not stop taking your medicine or change the dosage without checking with your doctor. You may become pregnant if you are not using any other contraceptive and you stop taking Estelle-35 ED, or do not take a tablet every day.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Estelle-35 ED.

This medicine helps most women, but it may have unwanted side effects in some women.

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.

The following list includes the more common side effects of Estelle-35 ED. These are usually mild and lessen with time.

If you notice any of the following side effects and they worry you, tell your doctor or pharmacist:

  • nausea
  • stomach pain or discomfort
  • changes in weight
  • headache, including migraines
  • mood changes, including depression
  • breast tenderness or pain.

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

If you experience any of the following, tell your doctor immediately, or go to the Emergency Department at your nearest hospital:

  • pain in the chest, arm, or below the breastbone
  • pain or discomfort that goes to your back
  • breathlessness and/or difficulty breathing
  • swelling, pain or tenderness of one leg or along a vein in the leg
  • sudden weakness, numbness or bad ‘pins and needles’ of the face, arm or leg, especially on one side of the body
  • sudden trouble walking, dizziness, loss of balance or coordination
  • severe, sudden stomach pains
  • a fainting attack or you collapse
  • unusual headaches or migraines that are worse than usual
  • sudden problems with speaking, seeing or understanding what people are saying to you.

The side effects listed above are possible signs of a blood clot (thrombosis).

  • jaundice (yellowing skin or yellowing eyes)
  • you cough up blood
  • breast lumps
  • unexplained vaginal bleeding.

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

Other side effects not listed above may also occur in some people.

Blood clots and Estelle-35 ED

Blood clots may block blood vessels in your body. This type of blood clot is also called thrombosis.

Blood clots sometimes occur in the deep veins of the legs. If a blood clot breaks away from the veins where it has formed, it may reach and block the blood vessels of the lungs, causing pulmonary embolism.

Blood clots can also occur in the blood vessels of the heart (causing a heart attack) or the brain (causing a stroke).

Blood clots are a rare occurrence and can develop whether or not you are taking Estelle-35 ED. They can also happen during pregnancy.

The risk of having blood clots is higher in Estelle-35 ED users than in non-users, but not as high as during pregnancy. The risk of a blood clot is highest during the first year of taking Estelle-35 ED for the first time, or after having a break from Estelle-35 ED for 4 weeks or more.

If you notice possible signs of a blood clot, stop taking Estelle-35 ED and consult your doctor immediately. To prevent pregnancy, you must also use additional barrier contraceptive precautions (e.g. condoms or a diaphragm).

If you are concerned about an increased risk of blood clots, while on Estelle-35 ED, speak to your doctor.

Cancer and Estelle-35 ED

Estelle-35 ED contains progestogen and estrogen hormone, and therefore works similarly to the combined oral contraceptive birth control pill, the Pill.

Breast cancer has been diagnosed slightly more often in women who take the Pill than in women of the same age who do not take the Pill.

This slight increase in the numbers of breast cancer diagnoses gradually disappears during the course of the 10 years after women stop taking the Pill.

It is not known whether the difference is caused by the Pill. It may be that these women were examined more often, so that the breast cancer was noticed earlier.

It is important that you check your breasts regularly and contact your doctor if you feel any lumps. In rare cases benign liver tumours and, even more rarely, malignant liver tumours have been reported in users of the Pill. These tumours may lead to internal bleeding.

Contact your doctor immediately if you have severe pain in your abdomen.

Cervical cancer has been reported to occur more often in women who have been taking the Pill for a long time. This finding may not be caused by the Pill, but may be related to sexual behaviour and other factors.

For high doses (25 mg and above) of cyproterone acetate an increased risk of a benign brain tumour (meningioma) has been reported. If you are diagnosed with meningioma, your doctor will stop all cyproterone containing products, including Estelle-35 ED as a precautionary measure (see section ‘Do not take Estelle-35 ED’).

AFTER TAKING ESTELLE-35 ED

Storage

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

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

Do not store your tablets or any other medicine in the bathroom, near a sink, or on a window-sill. Do not leave medication in the car. Heat and damp can destroy some medicines.

Keep Estelle-35 ED 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

Estelle-35 ED is a calendar pack containing 21 small yellow active tablets and 7 larger white non- active tablets per blister strip.

Available as packs of 28 tablets and 84 tablets.

Ingredients

The ingredients in Estelle-35 ED yellow active tablets are:

  • cyproterone acetate
  • ethinylestradiol
  • lactose monohydrate
  • microcrystalline cellulose
  • povidone
  • croscarmellose sodium
  • magnesium stearate
  • sucrose
  • Opadry white
  • Opadry buff
  • Opaglos white
  • Quinoline yellow.

The ingredients in Estelle-35 ED white non-active tablets are:

  • lactose monohydrate
  • microcrystalline cellulose
  • magnesium stearate.

This medicine contains lactose.

Supplier

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel St
Cremorne VIC 3121
Australia

Australian Registration Number

AUST R 93607

Date of preparation:

July 2022

Published by MIMS September 2022

BRAND INFORMATION

Brand name

Estelle-35 ED

Active ingredient

Cyproterone acetate; Ethinylestradiol

Schedule

S4

 

1 Name of Medicine

Cyproterone acetate and ethinylestradiol.

2 Qualitative and Quantitative Composition

Estelle-35 ED contains the synthetic progestogen, cyproterone acetate and the synthetic estrogen, ethinylestradiol.
Each yellow active tablet contains cyproterone acetate 2.0 mg and ethinylestradiol 35 microgram.

List of excipients with known effect.

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

3 Pharmaceutical Form

Estelle-35 ED consists of 21 yellow active tablets and 7 white inactive tablets (placebos).
Yellow active film-coated tablet is a yellowish buff, round, biconvex tablet, plain on both faces.
White inactive film-coated tablet (placebo) is a white, round, biconvex tablet, plain on both surfaces.
The calendar-pack consists of a foil backed blister platform containing twenty-eight tablets. On the foil reverse side of the platform, the tablets are allocated to days of the week in calendar format. The starting sector is coloured red.

4 Clinical Particulars

4.1 Therapeutic Indications

For the treatment of signs of androgenisation in women such as severe acne (involving inflammation or nodularity or risk of scarring) where prolonged oral antibiotics or local treatment alone has not been successful or idiopathic hirsutism of mild to moderate degree.
Estelle-35 ED will also provide effective oral contraception in this patient group. It should not be used in combination with other hormonal contraceptives (see Section 4.3 Contraindications).
If the hirsutism has only recently appeared or has lately intensified to a considerable extent the cause (androgen producing tumour or an adrenal enzyme defect) must be clarified by differential diagnosis.

4.2 Dose and Method of Administration

Combined oral contraceptives (COCs), when taken correctly have a failure rate of approximately 1% per year.
Estelle-35 ED is to be taken regularly in order to achieve therapeutic efficacy and the required contraceptive protection. Previously used hormonal contraception should be discontinued. The dose regimen of Estelle-35 ED is similar to the usual regimen of most of the COCs. Thus, the same administration rules must be considered. The irregular intake of Estelle-35 ED can lead to intermenstrual bleeding and could deteriorate the therapeutic and contraceptive reliability. Therapy should not be initiated unless pregnancy has been excluded.

Duration of treatment.

Treatment will probably need to be continued for about 6 months and probably much longer to gain an acceptable therapeutic effect, especially if Estelle-35 ED is being used for the treatment of excessive hair. The length of use depends on the severity of the symptoms of androgenisation and their response to treatment. Acne and seborrhoea usually respond sooner than hirsutism. The need to continue treatment should be evaluated periodically by the treating doctor. It is possible that the original condition will recur once treatment with Estelle-35 ED is stopped.
Estelle-35 ED should be withdrawn 3 to 4 cycles after the treated condition has completely resolved. Repeat course of Estelle-35 ED may be given if the androgen dependent condition(s) recur. In case of a restart with Estelle-35 ED (following a 4 week or greater tablet free interval), the increased risk of venous thromboembolism (VTE) should be considered (see Section 4.4 Special Warnings and Precautions for Use).

How to take Estelle-35 ED.

The first tablet is taken on the first day of a menstrual period, from the red section of the calendar pack marked with the appropriate day of the week. A tablet is then taken daily until the pack is empty. A new pack is commenced on the very next day, again selecting the appropriate tablet from the red section.
A bleeding usually occurs whilst the white inactive tablets are being taken.
The tablet should be swallowed whole, with a little water. The time of day at which the tablet is taken is immaterial, but once a time has been chosen, the patient should keep to it every day; for example, after breakfast or at bedtime.

Instructions for the patient.

Estelle-35 ED has been prescribed for you to treat acne, excessive hair or other skin conditions responding to antiandrogen therapy. It is also an effective oral contraceptive if the following advice is followed.
Estelle-35 ED is not for use in men.
How to start Estelle-35 ED.

No preceding hormonal contraceptive use (in the past month).

Tablet taking has to start on day 1 of the woman's natural cycle (i.e. the first day of her menstrual bleeding). Additional nonhormonal contraceptive methods must be used for the next 14 days.

Changing from a combined hormonal contraceptive (CHC), (COC), vaginal ring.

The woman should start with Estelle-35 ED on the day after the last active tablet (the last tablet containing the active substances) of her previous COC.
In case of a vaginal ring has been used the woman should start taking Estelle-35 ED on the day of removal.

Changing from a progestogen only method (minipill, injection, implant) or from a progestogen releasing intrauterine system (IUS).

The woman may switch any day from the minipill (from an implant, or the IUS on the day of its removal, from an injectable when the next injection would be due) but in all of these cases should be advised to additionally use an additional nonhormonal method of contraception for the first 14 days of tablet taking.

Following first trimester abortion.

The woman may start immediately. Additional nonhormonal contraceptive methods are necessary for the next 14 days.

After childbirth or a second trimester abortion.

Women should be advised to start 21 to 28 days after delivery or second trimester abortion.
Additional nonhormonal contraceptive methods are necessary for the next 14 days. If intercourse has already occurred, pregnancy should be excluded before the actual start of COC use or the woman has to wait for her first menstrual period.
Estelle-35 ED should not be used in breastfeeding women (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation).

Additional contraceptive precautions.

When additional contraceptive precautions are required the woman should be advised either to abstain from sex, or to use a barrier method of contraception, such as a cap (or diaphragm) plus spermicide, or for her partner to use a condom. Rhythm methods should not be advised as the pill disrupts the cyclical changes associated with the natural menstrual cycle e.g. changes in temperature and cervical mucus.
If a tablet of Estelle-35 ED is forgotten, it must, without fail, be taken within 12 hours of the usual time of day for taking it. Contraceptive reliability depends on no more than 36 hours interval between tablets.
If this interval is exceeded the forgotten tablet(s) should be taken and regular tablet taking resumed, but an additional nonhormonal method of contraception should be employed for the rest of the cycle.
If a withdrawal bleeding ('period') fails to occur whilst taking the 7 inactive tablets, tablet taking should be provisionally stopped and medical advice should be sought. A supplementary method of contraception should be used in the meantime.
Bleeding between periods: slight spotting or staining is normally of no significance. However, if bleeding persists or is heavy, medical advice should be sought.
Absorption of the Estelle-35 ED may be impaired, with consequent increased risk of pregnancy, by gastrointestinal disease causing diarrhoea and vomiting. If there is doubt that a tablet has been absorbed it should be treated as a missed tablet (2 above).
Women who use Estelle-35 ED are advised not to smoke cigarettes.
Treatment will probably need to be continued for about 6 months and probably much longer to gain an acceptable therapeutic effect, especially if Estelle-35 ED is being used for the treatment of excessive hair. It is possible that the original condition will recur once treatment with Estelle-35 ED is stopped.
Estelle-35 ED should be withdrawn 3 to 4 cycles after the treated condition has completely resolved.

Advice in case of gastrointestinal disturbances.

In case of severe gastrointestinal disturbances, absorption may not be complete and additional contraceptive measures should be taken.
If vomiting occurs within 3-4 hours after taking an active tablet, the advice concerning management of missed tablets is applicable. If the woman does not want to change her normal tablet taking schedule, she should take the extra tablet(s) needed from another pack.

4.3 Contraindications

Preparations containing estrogen/ progestogen combinations should not be used in the presence of any of the conditions listed below. Should any of the conditions appear for the first time during their use, the product should be stopped immediately.
Presence or risk of VTE (see Section 4.4 Special Warnings and Precautions for Use):
current VTE (on anticoagulants) or history of deep venous thrombosis [DVT] or pulmonary embolism [PE];
known hereditary or acquired predisposition for VTE, such as APC-resistance (including Factor V Leiden), antithrombin-III-deficiency, protein C deficiency, protein S deficiency;
major surgery with prolonged immobilisation;
a high risk of VTE due to the presence of multiple risk factors.
Presence or risk of arterial thromboembolism (ATE) (see Section 4.4 Special Warnings and Precautions for Use):
current ATE or history of ATE (e.g. myocardial infarction (MI) or stroke) or prodromal condition (e.g. angina pectoris or transient ischaemic attack [TIA]);
known hereditary or acquired predisposition for ATE, such as hyperhomocysteinaemia and antiphospholipid-antibodies (e.g. anticardiolipin-antibodies and lupus anticoagulant).
History of migraine with focal neurological symptoms.
A high risk of ATE due to multiple risk factors or to the presence of one serious risk factor such as: diabetes mellitus with vascular symptoms; severe hypertension; severe dyslipoproteinaemia.
Pancreatitis or a history thereof if associated with severe hypertriglyceridemia.
Presence or history of severe hepatic disease as long as liver function values have not returned to normal.
Estelle-35 ED is contraindicated for concomitant use with the medicinal products glecaprevir, pibrentasvir, sofosbuvir, velpatasvir, voxilaprevir, ombitasvir, paritaprevir or dasabuvir and combinations of these (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Presence or history of liver tumours (benign or malignant).
Known or suspected sex steroid influenced malignancies (e.g. of the genital organs or the breasts).
Meningioma or history of meningioma.
Concomitant use with another hormonal contraceptive.
Undiagnosed vaginal bleeding.
Known or suspected pregnancy.
Lactation.
Hypersensitivity to any of the ingredients in Estelle-35 ED.
A history of otosclerosis with deterioration during pregnancy.
A history of herpes gestationis.
Sickle-cell anaemia.
Abnormal lipid metabolism.
Estelle-35 ED is not for use in men.
Estelle-35 ED is composed of the progestogen cyproterone acetate and the estrogen ethinylestradiol and is administered for 21 days of a monthly cycle. It has a similar composition to that of a COC. The clinical and epidemiological experience with estrogen/ progestogen combinations like Estelle-35 ED is predominantly based on COCs. Therefore, the following warnings related to the use of COCs apply also for Estelle-35 ED.

4.4 Special Warnings and Precautions for Use

If any of the conditions/ risk factors mentioned below are present, the benefits of the use of Estelle-35 ED should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start taking it. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the woman should contact her doctor. The doctor should then decide on whether use of Estelle-35 ED should be discontinued.

Circulatory disorders.

Epidemiological studies have suggested an association between the use of COCs containing ethinylestradiol and an increased risk of arterial and venous thrombotic and thromboembolic diseases such as MI, stroke, DVT, and PE. These events occur rarely in average-risk women.
Risk of venous thromboembolism (VTE). The use of any combined hormonal contraceptive (CHC) increases the risk of VTE compared with no use. The woman should be advised that her VTE risk is highest in the first ever year of use and that there is some evidence that the risk is increased when a CHC is re-started after a break in use of 4 weeks or more.
It is important that women understand that VTE associated with CHC use is rare in average-risk women (see Table 1). The risk in pregnancy (5-20 per 10,000 women over 9 months) and the risk in the post-partum period (45-65 per 10,000 women over 12 weeks) is higher than that as associated with CHC use.
Combined hormonal contraceptive (CHC) in Table 1 refers to oral contraceptives with a low estrogen dose (< 50 microgram ethinylestradiol). An additional increase in VTE risk for CHCs containing ≥ 50 microgram ethinylestradiol cannot be excluded.
The decision to use any product other than one with the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with CHCs, and how her current risk factors influence this risk.
Products that contain the progestogens levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. Products containing cyproterone such as Estelle-35 ED may have up to twice this level of risk.
The increased risk of VTE during the postpartum period must be considered. See Section 4.2 Dose and Method of Administration; Section 4.6 Fertility, Pregnancy and Lactation.
VTE may be life-threatening or may have a fatal outcome (in 1%-2% of cases). Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral or retinal veins and arteries.
The risk for venous thromboembolic complications in CHC users may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see list below).
Estelle-35 ED is contraindicated if a woman has multiple risk factors that put her at high risk of venous thrombosis. If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors - in this case her total risk of VTE should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed.
When considering risk/benefit, the doctor should take into account that the adequate treatment of a condition may reduce the associated risk of thrombosis.

Risk factors for VTE.

Obesity (body mass index over 30 kg/m2). Risk increases substantially as BMI rises.
Prolonged immobilisation, major surgery, any surgery to the legs or pelvis, neurosurgery, or major trauma.
Temporary immobilisation including air travel > 4 hours can also be a risk factor for VTE, particularly in women with other risk factors.
Positive family history (VTE ever in a sibling or parent especially at a relatively early age e.g. before 50).
Biochemical factors that may be indicative of hereditary or acquired predisposition for VTE include Activated Protein C (APC) resistance (including Factor V Leiden), antithrombin-III deficiency, protein C deficiency, protein S deficiency.
Other medical conditions associated with VTE include: cancer, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis), sickle cell disease.
Increasing age, particularly above 35 years.
Smoking.
In women at risk of prolonged immobilisation (including major surgery, any surgery to the legs or pelvis, neurosurgery, or major trauma), it is advisable to discontinue use of Estelle-35 ED (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation. Another method of contraception should be used to avoid unintentional pregnancy. Antithrombotic treatment should be considered if Estelle-35 ED has not been discontinued in advance.
If a hereditary predisposition to VTE is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use.
There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in VTE.

Symptoms of VTE (DVT and PE).

Women should be informed of the symptoms of VTE and be advised to seek urgent medical attention if VTE symptoms develop and to inform the healthcare professional that she is taking a CHC.
Symptoms of DVT can include:
unilateral swelling of the leg and/or foot or along a vein in the leg;
pain or tenderness in the leg which may be felt only when standing or walking;
increased warmth in the affected leg; red or discoloured skin on the leg.
Symptoms of PE can include:
sudden onset of unexplained shortness of breath or rapid breathing;
sudden coughing which may be associated with haemoptysis;
sharp chest pain or sudden severe pain in the chest which may increase with deep breathing;
severe light headedness or dizziness;
rapid or irregular heartbeat.
Some of these symptoms (e.g. "shortness of breath", "coughing") are non-specific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections).
Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of an extremity.
If the occlusion occurs in the eye, symptoms can range from painless blurring of vision which can progress to loss of vision. Sometimes loss of vision can occur almost immediately.
Risk of ATE. Epidemiological studies have associated the use of CHCs with an increased risk for ATE (e.g. MI, angina pectoris, stroke or TIA). Arterial thromboembolic events may be fatal.
The risk of arterial thromboembolic complications in CHC users increases in women with risk factors. Estelle-35 ED is contraindicated if a woman has one serious or multiple risk factors for ATE that puts her at high risk of arterial thrombosis. If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors - in this case her total risk should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed.

Risk factors for ATE.

Increasing age, particularly above 35 years.
Smoking.
Hypertension.
Obesity.
Positive family history (ATE ever in a sibling or parent especially at relatively early age e.g. below 50).
Biochemical factors that may be indicative of hereditary or acquired predisposition for ATE include: hyperhomocysteinaemia and antiphospholipid antibodies (e.g. anticardiolipin antibodies, and lupus anticoagulant).
Migraine.
Other medical conditions associated with adverse vascular events: diabetes mellitus, polycystic ovary syndrome, hyperhomocysteinaemia, valvular heart disease, atrial fibrillation, dyslipoproteinaemia, systemic lupus erythematosus.
Women should be advised not to smoke if they wish to use a CHC. Women over 35 years who continue to smoke should be strongly advised to use a different method of contraception.
If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use.
An increase in frequency or severity of migraine during CHC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation.
The user group of Estelle-35 ED is likely to include patients that may have an inherently increased cardiovascular risk.

Symptoms of ATE.

Women should be informed of the symptoms of ATE and be advised to seek urgent medical attention if ATE symptoms develop and to inform the healthcare professional that she is taking a CHC.
Symptoms of a stroke can include:
sudden numbness or weakness of the face, arm or leg, especially on one side of the body;
sudden trouble walking, dizziness, loss of balance or coordination;
sudden confusion, slurred speech or aphasia; sudden partial or complete loss of vision; diplopia;
sudden, severe or prolonged headache with no known cause;
loss of consciousness or fainting with or without seizure.
Temporary symptoms suggest the event is a TIA.
Symptoms of MI can include:
pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone;
discomfort radiating to the back, jaw, throat, arm, stomach;
feeling of being full, having indigestion or choking;
sweating, nausea, vomiting or dizziness;
extreme weakness, anxiety, or shortness of breath;
rapid or irregular heartbeats.

Tumours.

The most important risk factor for cervical cancer is persistent human papillomavirus (HPV) infection. Some epidemiological studies have indicated that long-term use of COCs may further contribute to this increased risk but there continues to be controversy about the extent to which this finding is attributable to confounding effects, e.g. cervical screening and sexual behaviour including use of barrier contraceptives.
A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently taking COCs. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. These studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both. The breast cancers diagnosed in ever users tend to be less advanced clinically than the cancers diagnosed in never users.
In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been reported in users of COCs. In isolated cases, these tumours have led to life threatening intra-abdominal haemorrhages. A liver tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage occur in women taking COCs.
Malignancies may be life-threatening or have a fatal outcome.

Meningioma.

The occurrence of meningiomas (single and multiple) has been reported in association with use of cyproterone acetate, especially at high doses of 25 mg and above and for prolonged time. If a patient is diagnosed with meningioma, any cyproterone containing treatment, including Estelle-35 ED, must be stopped, as a precautionary measure.

Other conditions.

Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when taking COCs.
Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. A relationship between COC use and clinical hypertension has not been established. However, if a sustained clinically significant hypertension develops during the use of a COC then it is prudent for the doctor to withdraw the COC and treat the hypertension. Where considered appropriate, COC use may be resumed if normotensive values can be achieved with antihypertensive therapy.
The following conditions have been reported to occur or deteriorate with both pregnancy and COC use, but the evidence of an association with COC use is inconclusive: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham's chorea; herpes gestationis, and otosclerosis related hearing loss.
In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.
Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. Recurrence of cholestatic jaundice which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of COCs.
Although COCs may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics taking low dose COCs (containing < 50 microgram ethinylestradiol). However, diabetic women should be carefully observed while taking COCs.
Crohn's disease and ulcerative colitis have been associated with COC use.
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking COCs.
If in women suffering from hirsutism, symptoms have recently developed or increased substantially, the causes (androgen producing tumour, adrenal enzyme defect) must be clarified by differential diagnosis.
Each yellow active tablet contains 41.19 mg of lactose monohydrate and each white placebo tablet contains 67 mg of lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose galactose malabsorption who are on a lactose free diet should take this amount into consideration.

Medical examination/ consultation.

A complete medical history and physical examination should be taken prior to the initiation or reinstitution of Estelle-35 ED, guided by Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, and should be repeated periodically. In general, an annual examination is recommended. Periodic medical assessment is also of importance because contraindications (e.g. a TIA, etc.) or risk factors (e.g. a family history of venous or arterial thrombosis) may appear for the first time during the use of a COC. The frequency and nature of these assessments should be adapted to the individual woman but should generally include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests.

Sexually transmitted infections (STIs) including human immunodeficiency virus (HIV) infections and acquired immunodeficiency syndrome (AIDS).

Estelle-35 ED does not protect against STIs, including HIV infections (AIDS). The woman should be advised that additional barrier contraceptive measures are needed to prevent transmission of STIs.

Reduced efficacy.

The contraceptive efficacy of Estelle-35 ED may be reduced in the event of missed yellow active tablets, (see Section 4.2 Dose and Method of Administration, Management of missed tablets), vomiting, or diarrhoea during yellow active tablet taking (see Section 4.2 Dose and Method of Administration, Advice in case of gastrointestinal disturbances) or concomitant medication (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Reduced cycle control.

With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. Therefore, the evaluation of any irregular bleeding is only meaningful after an adaptation interval of about three cycles.
If bleeding irregularities persist or occur after previously regular cycles, then nonhormonal causes should be considered and adequate diagnostic measures are indicated to exclude malignancy or pregnancy. These may include curettage.
In some women, withdrawal bleeding may not occur during the placebo tablet interval. If the COC has been taken according to the directions, it is unlikely that the woman is pregnant. However, if the COC has not been taken according to these directions (see Section 4.2 Dose and Method of Administration) prior to the first missed withdrawal bleed or if two withdrawal bleeds are missed, pregnancy must be ruled out before COC use is continued.

Alanine transaminase (ALT) elevations.

In patients treated with hepatitis C antiviral medications including glecaprevir, pibrentasvir ombitasvir, paritaprevir or dasabuvir, ALT elevations may occur in women using ethinylestradiol-containing medications such as CHCs. Prescribers should consult the relevant antiviral medicine product safety information. Patients taking a CHC should therefore be switched to an alternative method of contraception (e.g. progestogen-only contraception or non-hormonal methods) prior to starting therapy.

Use in hepatic impairment.

Estelle-35 ED is contraindicated in women with severe hepatic diseases as long as liver function values have not returned to normal (see Section 4.3 Contraindications).

Use in renal impairment.

Estelle-35 ED has not been specifically studied in renally impaired patients.

Use in the elderly.

Estelle-35 ED is not indicated after menopause.

Paediatric use.

Estelle-35 ED is only indicated after menarche.

Effects on laboratory tests.

The use of preparations like Estelle-35 ED may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of carrier proteins, e.g. corticosteroid binding globulin and lipid/ lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effects of other medicines on Estelle-35 ED.

Interactions can occur with medicines that induce microsomal enzymes which can result in increased clearance of sex hormones and which may lead to breakthrough bleeding and/or contraceptive failure.
Women prescribed any of these medicines should temporarily use a barrier method in addition to Estelle-35 ED or choose another method of contraception. The barrier method should be used during the time of concomitant medicine administration and for 28 days after their discontinuation. If the period during which the barrier method is used runs beyond the end of the yellow active tablets in the Estelle-35 ED pack, the white placebo tablets should be omitted and the next pack be started.

Substances increasing the clearance of Estelle-35 ED (diminished efficacy of Estelle-35 ED by enzyme induction).

Phenytoin, barbiturates, primidone, carbamazepine, rifampicin and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and products containing St John's wort (Hypericum perforatum). The mechanism of this interaction appears to be based on the hepatic enzyme inducing properties of these drugs. Enzyme induction can already be observed after a few days of treatment. Maximal enzyme induction is generally seen within a few weeks but may then be sustained for at least four weeks after the cessation of drug therapy.

Substances with variable effects on the clearance of Estelle-35 ED.

When coadministered with COCs, many HIV/ hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors can increase or decrease plasma concentration of estrogen or progestogen. These changes may be clinically relevant in some cases.

Substances decreasing the clearance of COCs (enzyme inhibitors).

Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g. ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice can increase plasma concentrations of the estrogen or the progestogen or both.
Etoricoxib doses of 60 mg to 120 mg/day have been shown to increase plasma concentrations of ethinylestradiol 1.4 to 1.6-fold, respectively when taken concomitantly with a CHC containing 35 microgram ethinylestradiol.

Influence of Estelle-35 ED on other medication.

Estrogen/progestogen preparations like Estelle-35 ED may affect the metabolism of certain other medicines. Accordingly, plasma and tissue concentrations may either increase (e.g. ciclosporin) or decrease (e.g. lamotrigine).
In clinical studies, administration of a hormonal contraceptive containing ethinylestradiol did not lead to any increase or only to a weak increase in plasma concentrations of CYP3A4 substrates (e.g. midazolam) while plasma concentrations of CYP1A2 substrates can increase weakly (e.g. theophylline) or moderately (e.g. melatonin and tizanidine).

Pharmacodynamic interactions.

Co-administration of ethinylestradiol-containing medicinal products with direct-acting antiviral (DAA) medicinal products containing ombitasvir, paritaprevir or dasabuvir, and combinations of these has been shown to be associated with increases in alanine aminotransferase (ALT) levels to greater than 20 times the upper limit of normal in healthy female subjects and HCV infected women (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use). ALT elevations have also been observed with HCV anti-viral medicinal products including glecaprevir, pibrentasvir. Patients taking a CHC should therefore be switched to an alternative method of contraception (e.g. progestogen-only contraception or non-hormonal methods) prior to starting therapy.

Note.

The product information of concomitant medications should be consulted to identify potential interactions.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category B3)
Animal studies showed that the drug combination of ethinylestradiol and cyproterone acetate or cyproterone acetate alone (given at high doses) can cause signs of feminisation in male foetuses if given during the phase of differentiation of the foetal male genital organs. The relevance of these findings to man is not known. Isolated cases of inadvertent use of Estelle-35 ED during pregnancy have so far given no indications of a corresponding risk in humans. Despite this, the possibility must be considered that the use of Estelle-35 ED during the hormone sensitive phase of differentiation of the genital organs in male foetuses (from about the 45th day of pregnancy) might cause signs of feminisation. For this reason, Estelle-35 ED is contraindicated during pregnancy.
If pregnancy occurs during treatment with Estelle-35 ED, further intake must be stopped.
 The use of Estelle-35 ED is contraindicated during lactation as small amounts of cyproterone acetate are excreted in breast milk. Estrogen containing oral contraceptives may decrease the quantity and quality of breast milk.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Various adverse reactions have been associated with oral contraceptive use. The most serious reactions associated with the use of oral contraceptives are discussed under Section 4.4 Special Warnings and Precautions for Use.
The most commonly reported adverse reactions with Estelle-35 ED are nausea, abdominal pain, increased weight, headache, depressed mood, altered mood, breast pain, breast tenderness. They occur in ≥ 1% of users.
Serious adverse reaction is thromboembolism.
In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the woman should contact her doctor. The doctor should then decide on whether its use should be discontinued.
See Table 2.

Other adverse reactions.

Eyes disorders.

Cataract.

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.

4.9 Overdose

There have been no reports of serious deleterious effects from overdose. On the basis of general experience with COCs, symptoms that may occur in case of overdose of active tablets are: nausea, vomiting and, in young girls, withdrawal bleeding. Withdrawal bleeding may even occur in girls before menarche, if they have accidently taken Estelle-35 ED. There are no antidotes and further treatment should be symptomatic.
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.

The substance cyproterone acetate contained in Estelle-35 ED blocks the effect of endogenously produced and exogenously administered androgens at the target organs by means of competitive inhibition. This results in a gradual regression of signs of androgenisation, irrespective of whether increased androgen values or increased peripheral sensitivity are the cause of the disorder. The decrease in androgen concentration at the target organs has an additional therapeutic effect.
While Estelle-35 ED is being taken, the increased sebaceous gland function, which plays an important role in the development of acne and seborrhoea, is reduced. This leads, usually after 3 to 4 months of therapy, to the healing of existing acne efflorescences. The excessive greasiness of the hair and skin generally disappears earlier. The loss of hair which frequently accompanies seborrhoea likewise diminishes. Treatment with Estelle-35 ED is indicated in women of childbearing age who exhibit mild forms of hirsutism and in particular in slightly increased facial hair; results do not, however, become apparent until after several months of use.
Apart from the described antiandrogen effect, cyproterone acetate has also a pronounced progestational action. The combination of ethinylestradiol and cyproterone acetate prevents a possible pregnancy by the inhibition of ovulation, the inspissation of cervical mucus so as to constitute a barrier to sperm, and the rendering of the endometrium unreceptive to implantation.
As well as protection against pregnancy, COCs have several positive properties which, next to the negative properties (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)), can be useful in deciding on the method of birth control. For the majority of users, the cycle is more regular, the menstruation is often less painful and bleeding is lighter. The latter may result in a decrease in the occurrence of iron deficiency. In addition, with the higher dosed COCs (> 35 microgram ethinylestradiol), there is evidence of a reduced risk of fibrocystic tumours of the breasts, ovarian cysts, pelvic inflammatory disease, ectopic pregnancy, endometrial and ovarian cancer. These additional benefits have only been established in case control and cohort studies. Results from randomised controlled trials are not available.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

In a bioequivalence study Estelle-35 ED was compared to a tablet containing cyproterone acetate and ethinylestradiol. Orally both substances are completely absorbed from the Estelle-35 ED tablet, ethinylestradiol being slightly faster. Maximum plasma levels can be expected within 1 hour to 4 hours. The mean Cmax and median Tmax values were 12.8 nanogram/mL and 1.51 hours respectively for cyproterone and 406 picogram/mL and 1.46 hours, respectively for ethinylestradiol. The course of the postmaximum concentration is characterised by a two phase decrease with half-lives of 3-4 hours and 2 days for cyproterone acetate and 1-3 hours and approx. 1 day for ethinylestradiol.
Because the plasma half-life of cyproterone acetate is twice as long as that of other progestogens, a stable substance level that is scarcely influenced by the individual dose is reached with daily administration.
The two steroids are eliminated mainly as metabolites: cyproterone acetate is eliminated by the kidneys (30%) and with the bile (70%) with a half-life of 2 days, and ethinylestradiol is eliminated by the kidneys (40%) and with the bile (60%) with a half-life of 1 day.
Approximately 0.2% of the maternal progestogen (cyproterone acetate) dose and approx. 0.02% of the estrogen dose can be passed on to the infant with the maternal milk.
After oral administration cyproterone acetate is completely bioavailable, while ethinylestradiol is approx. 40-60% bioavailable.

Carbohydrate metabolism.

Depending on the nature and amount of their active substances, ovulation inhibitors may lead to an excessive glucose and plasma insulin reaction (reduced glucose tolerance), especially on oral glucose loading. The changes are generally reversible after discontinuation of medication.

Lipometabolism.

Studies of serum lipids and lipoproteins conducted by various groups have produced somewhat inconsistent results. Whereas, for example, the majority of workers found normal or even reduced cholesterol levels, others reported an increase. The results on the behaviour of the phospholipids, which generally increased slightly, show greater consistency, as do also the results for the plasma triglyceride values, which all study groups agree are increased. This appears to correlate with the estrogen content of oral ovulation inhibitors.

Other metabolic functions.

A few authors have observed isolated disturbances of folic acid metabolism. The resultant megaloblastic anaemia proved responsive to the administration of folic acid and vitamin B12 even without withdrawal of the oral ovulation inhibitors.
An effect was also observed on tryptophan and vitamin B6 metabolism (increased xanthurenic acid elimination after tryptophan loading). Some authors see an association between this and the occurrence of depressive states.

5.3 Preclinical Safety Data

Genotoxicity.

There is limited evidence available in the literature suggesting that estrogens may be weakly genotoxic at high doses. Ethinylestradiol was negative in studies for DNA adduct formation in cultured human liver slices and in assays for gene mutations (bacterial or mammalian cells in vitro) and gave equivocal results in assays for chromosomal damage (clastogenic effects were not consistently seen and occurred at high doses).
Cyproterone acetate was negative in a standard battery of genotoxicity studies. However, further tests showed that CPA was capable of producing DNA adducts in hepatocytes in rats, dogs and monkeys in vivo and also in freshly isolated rat and human liver cells in vitro following metabolism by hydroxysteroid sulfotransferases. This DNA adduct formation occurred at exposures that might be expected to occur with the recommended dose regimen for Estelle-35 ED.
CPA increased DNA repair activity in rat and human hepatocytes in vitro. CPA was clastogenic in a female rat liver micronucleus test. Other in vivo consequences of CPA treatment were an 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 a target for mutations. In all of these positives in vivo tests, hepatocyte proliferation is likely to have contributed to the results being positive. CPA had mitogenic activity towards rat hepatocytes in vitro, but not human hepatocytes.

Carcinogenicity.

Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis and liver.
In a long-term carcinogenicity study of CPA in rats, 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 the liver pathology), the carcinogenic potential of CPA in animals could not be determined.
The clinical relevance of these findings is presently uncertain. Clinical experience and limited epidemiological data available to date do not appear to have supported an increased incidence of hepatic tumours in humans at the recommended clinical dose of 2 mg/day cyproterone acetate. It should also be borne in mind that sexual steroids can promote the growth of certain hormone dependent tissues and tumours.

6 Pharmaceutical Particulars

6.1 List of Excipients

Yellow active tablets: lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, magnesium stearate, Opadry complete film coating system Y-1R-7000B White Opadry Buff OY-3690, quinoline yellow, Opaglos 6000 and sucrose.
White placebo tablets: lactose monohydrate, microcrystalline cellulose and magnesium stearate.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

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

6.5 Nature and Contents of Container

Blister packs (Al/PVDC) consisting of 21 yellow tablets and 7 white inactive tablets (placebos).
Available in packs of 28 or 3 x 28 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Cyproterone acetate is a white, or almost white, crystalline powder, practically insoluble in water, very soluble in methylene chloride, freely soluble in acetone, soluble in methanol, sparingly soluble in ethanol. It melts at about 210°C.
Ethinylestradiol is a white, or slightly yellowish white, crystalline powder. M.P. 181-185°C.
Ethinylestradiol is practically insoluble in water, freely soluble in ethanol (96%) and ether, sparingly soluble in chloroform. It dissolves in dilute alkaline solutions. It shows polymorphism.

Chemical structure.

Cyproterone acetate.

The chemical name for cyproterone acetate is 6-chloro-17α hydroxy-1α,2α-methylene-pregna-4,6-diene-3,20-dione acetate and has the following chemical structure:
Chemical Formula: C24H29ClO4. Molecular mass: 416.9.

Ethinylestradiol.

The chemical name for ethinylestradiol is 19-nor-17a-pregna-1,3,5,(10)-triene-20-yne-3,17β-diol and has the following chemical structure:
Chemical Formula: C20H24O2. Molecular mass: 296.4.

CAS number.

427-51-0 cyproterone acetate.
57-63-6 ethinylestradiol.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes