Consumer medicine information

Brenda-35 ED

Cyproterone acetate; Ethinylestradiol

BRAND INFORMATION

Brand name

Brenda-35 ED

Active ingredient

Cyproterone acetate; Ethinylestradiol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

This leaflet answers some common questions about Brenda-35 ED.

It does not contain all the available information. It does not take the place of talking to your doctor, pharmacist or health clinic.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking Brenda-35 ED against the benefits expected for you.

If you have any concerns about taking this medicine, talk to your doctor or pharmacist.

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

What Brenda-35 ED is used for

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

  • severe acne when 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. .

Brenda-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. Brenda-35ED contains a progestogen and an oestrogen hormone, and therefore works similarly to the combined oral contraceptive birth control pill, also known as the "Pill" or "birth control pill". It should not be used in combination with another hormonal contraceptive. While taking BRENDA-35ED you may also experience the following benefits:

  • a decrease in the amount of blood you lose each cycle during your period
  • more regular and lighter periods - potentially resulting in a decrease 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 Brenda-35 ED.

Like all oral contraceptives, Brenda-35 ED does not protect against HIV infections (AIDS) or other sexually transmitted diseases (STDs). A barrier form of contraception such as a condom is needed.

Brenda-35 ED is available only with a doctor's prescription.

Ask your doctor if you have any questions about why Brenda-35 ED has been prescribed for you. Your doctor may have prescribed Brenda-35 ED for another reason.

Before you take Brenda-35 ED

When you must not take it

Do not take Brenda-35 ED if you are allergic to:

  • cyproterone and/or ethinylestradiol (the active ingredients in Brenda-35ED)
  • 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
  • rash, itching or hives on the skin

Brenda-35 ED is not for use in men.

Do not take Diane-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 Brenda-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 Brenda-35 ED if you are concerned about an increased risk of blood clots. Blood clots are rare. Very occasionally blood clots may cause serious permanent disabilities, or may even be fatal.

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

Do not take Brenda-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 the Pill, especially if you are older than 35 years of age.

Do not take Brenda-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 for 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)
  • mini-stroke (also known as TIA or transient ischaemic attack)
  • migraine, where you have also had problems with seeing, speaking or had weakness or numbendess 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 levels of fats in your blood.
  • pancreatitis, an inflammation of the pancreas associated with high triglyceride (blood fats) levels in the blood
  • severe liver disease and your liver function has not returned to normal
  • cancer that may grow under the influence of sex hormones (e.g. cancer of the breast or genital organs)
  • benign or malignant liver tumours
  • unexplained vaginal bleeding.

If any of these conditions appear for the first time while using the Brenda-35ED, 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 Brenda-35 ED if you are using another hormonal contraceptive.

Do not take Brenda-35 ED if you are pregnant or think you might be pregnant.

Do not take this medicine if you are breastfeeding.

Do not give this medicine to a child.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

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

Before you start to take it

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives.

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 medical conditions, especially the following:

  • diabetes
  • high blood pressure
  • heart valve disorders or certain heart rhythm disorders
  • migraine
  • cancer
  • polycystic ovary syndrome, a hormonoal 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 - an autoimmune disease affecting different parts of 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 (yellowishbrown pigmentation patches on the skin, particularly of the face) – if so, avoid exposure to the sun or ultraviolet radiation
  • have hereditary angio-oedema – you should see your doctor immediately if you experience symptoms of angio-oedema, 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, or recur or worsen while taking Brenda-35 ED, you should contact your doctor.

Brenda-35 ED contains lactose. If you have been told by your doctor that you have intolerance to some sugars, contact your doctor before you start taking Brenda-35 ED.

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

Taking other medicines

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

Some medicines may interact with Brenda-35 ED. These include:

  • medicines used to treat tuberculosis such as rifampicin, rifabutin
  • medicines used to treat epilepsy such as phenytoin, primidone, barbiturates (e.g. 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
  • cyclosporin, 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 used to relax the body
  • theophyllin, a medicine that helps with breathing
  • herbal medicines containing St John's Wort
  • grapefruit juice.

These medicines may be affected by Brenda-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 Diane-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 a condom or diaphragm) while you are taking any of these medicines with Brenda-35ED for some time after stopping them.

Your doctor or pharmacist will be able to advise you about how long you will need to use additional contraceptive methods.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking Brenda-35 ED.

How to take Brenda-35 ED

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.

How much to take

How to take it

Take one tablet once a day, at about the same time each day. You must take Diane-35 ED every day regardless of how often you have sex. This will also help you remember when to take it.

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

The Brenda-35 ED pack contains 28 tablets. On the pack each tablet is marked with the day of the week on which it is to be taken.

Take your first tablet from the red section marked with the appropriate day of the week, e.g., if starting on Sunday - select SUN in the red section.

Follow the direction of the arrows on the pack until all 28 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 Brenda-35 ED for the first time

If you are starting Brenda-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 diaphragm) for the first 14 days of tablet-taking when having intercourse.

Your doctor will advise you when to start if you:

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

Changing from another contraceptive

  1. Switching from another combined oral contraceptive
Start Brenda-35 ED on the day after the last active tablet from the previous pill pack. Bleeding may not occur until the end of the first pack of Brenda-35 ED.
Ask your doctor or pharmacist if you are not sure which the active tablets were in your previous Pill pack.
Your previous Pill pack may have different coloured tablets to those of Brenda-35 ED.
  1. Changing from a vaginal ring:
Start taking Brenda-35ED on the day of removal of the last vaginal ring.
  1. Changing from progestogen-only pill 'minipill'
Stop taking the minipill on any day and start taking Brenda-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.
  1. Changing from a progestogen only injection, implant, intrauterine system (IUS) or vaginal ring
Start taking Brenda-35 ED when your next injection is due, or on the day that your implant, IUS or vaginal ring 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 it Brenda-35ED

Keep taking Brenda-35 ED for as long as your doctor tells you to.

You may need to take Brenda-35 ED for about 6 months before you notice an improvement in your condition.

You may be advised by your doctor to stop Brenda-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 Brenda-35ED.

Stopping Brenda-35 ED

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

It is possible that acne and excess hair may return when treatment is stopped.

Do not start taking Brenda-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 Brenda-35ED.

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 Brenda-35 ED and not stop until your doctor advises this. Seek advice from 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 it

If you miss a tablet and take the missing tablet within 12 hours of missing it, contraceptive protection is not reduced.

If you are more than 12 hours late follow these detailed instructions:

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

If you have been taking the beige active tablets for 7 uninterrupted days and miss a beige active tablet, take the missed tablet as soon as you remember, then go back to taking your medicine as you would normally, even if it means taking 2 tablets in one day. You will not need to use additional barrier contraceptive precautions.

The chance of pregnancy after missing a beige 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 beige active tablets left in a row, you should finished 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 beige active tablets of the second pack.

You may have spotting or breakthrough bleeding on tablet-taking days.

If you have been taking the beige active tablets for less than 7 days and miss a beige 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 in the preceding 7 days, , 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 beige 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 pharamcist.

If you forget to take a white inactive tablet, you do not need to take them later because they do not contain any active ingredients. However, it is important that you discard the missed white tablet(s) to make sure that the number of days between taking active tablets is not increased as this would increase the risk of pregnancy. Continue with the next tablet at the usual time.

Please see the diagram at the end of this leaflet entitled "Summary of advice if you missed an active tablet more than 12 hours ago".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 (telephone 13 11 26), or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much Brenda-35 ED. Do this even if there are no signs of discomfort or poisoning. You may need medical attention.

If you take several beige 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 medicien may experience such bleeding.

While you are taking Brenda-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 the Brenda-35ED, 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 Brenda-35 ED.

Stop taking Brenda-35 ED and see your doctor immediately or go to the Emergency Department at your nearest hospital if you notice possible 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 Brenda-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 Brenda-35ED, 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 Diane-35ED 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 greather than 4 hours.

Consult your doctor if you develop high blood pressure while taking Brenda-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 beige 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 the Brenda-35ED, usually after about 3 months.

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

  • you have taken the beige active tablets at the right time,
  • you have not vomited or had severe diarrhoea during this cycle,
  • you have not been taking other medicines that interfere with Brenda-35 ED

If this is so, continue to take Brenda-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 Brenda-35ED correctly. Stop taking Brenda-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.

Brenda-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 use Brenda-35 ED to treat any other conditions unless your doctor tells you to.

Do not give Brenda-35 ED to anyone else, even if they have the same condition as you.

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 Brenda-35 ED, or do not take a table every day.

Side effects

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

Like all other medicines, Brenda-35 ED may have unwanted side effects in some people. 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 this list of possible 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 Brenda-35 ED. These are usually mild and lessen with time.

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

  • 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 speech, understanding or eyesight

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

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

Tell your doctor or go to the Emergency Department at your nearest hospital if you experience any of these signs of thrombosis.

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

This is not a complete list of all possible side effects. Other side effects not listed above may also occur in some people.

Some of these side effects (for example, high blood pressure) can only be found when your doctor does tests from time to time to check your progress.

Blood clots and Brenda-35ED

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 Brenda-35 ED.

They can also happen during pregnancy. The risk of having blood clots is higher in Brenda-35ED 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 Brenda-35ED for the first time, or after having a break from the Pill for 4 weeks of more.

Therefore, one should keep the possibility of an increased risk of blood clots in mind, particularly where there is a history of thrombosis.

If you notice possible signs of a blood clot, stop taking Brenda-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 Brenda-35ED, speak to your doctor.

Cancer and Brenda-35ED

Brenda-35ED contains a progestogen and an oestrogen 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 lump.

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.

After taking Brenda-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 will not keep well.

Keep your tablets in a cool dry place where the temperature stays below 25°C.

Do not store Brenda-35 ED or any other medicine in the bathroom or near a sink. Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Keep Brenda-35ED 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 Brenda-35 ED, or your tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Return any unused medicine to your pharmacist.

Product description

What it looks like

Brenda-35 ED is available as a calendar pack and contains 2 different tablets:

  • 21 small beige round active tablets
  • 7 white round non-active tablets.

On the pack each tablet is marked with a day of the week on which it is to be taken.

Ingredients

Each beige active tablet contains two active ingredients: cyproterone acetate 2 mg and ethinylestradiol 35 mcg.

They also contain the following inactive ingredients:

  • lactose monohydrate
  • maize starch
  • povidone
  • magnesium stearate
  • sucrose
  • macrogol 6000
  • calcium carbonate
  • purified talc
  • glycerol montanate
  • titanium dioxide (E171)
  • iron oxide yellow CI77492 (E172)
  • glycol montanate
  • purified water

Each white inactive tablet contains:

  • lactose monohydrate
  • maize starch
  • povidone
  • magnesium stearate
  • sucrose
  • macrogol 6000
  • calcium carbonate
  • glycol montanate
  • titanium dioxide

Brenda-35 ED tablets do not contain gluten, tartrazine or any other azo dyes.

Supplier

Brenda-35 ED is supplied in Australia by:

Alphapharm Pty Limited
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.mylan.com.au

This leaflet was prepared on 14 August 2019.

AUST R 55128

brenda_cmi\Aug19/00

Summary of advice if you missed an active tablet more than 12 hours ago

Before missing your tablet, did you take beige active tablets for the previous 7 days?

NO:

Did you have sex in the 7 days before missing the tablet?

NO

  • Take the tablet missed AND use extra barrier precaution for 7 days. If there are fewer than 7 beige active tablets left in the pack, finish the beige active tablets and go straight to the beige active tablets of the next pack. This means you skip the white inactive tablets

YES

  • See your doctor or pharmacist for advice

YES:

Does your pack still have 7 active beige tablets in a row to follow?

NO

  • Take the tablet you missed and complete taking the beige active tablets. Skip the white inactive tablets. Start your next pack with beige active tablets.

YES

  • Take the tablet you missed AND complete the pack as normal.

Published by MIMS October 2019

BRAND INFORMATION

Brand name

Brenda-35 ED

Active ingredient

Cyproterone acetate; Ethinylestradiol

Schedule

S4

 

1 Name of Medicine

Active ingredient: cyproterone acetate and ethinylestradiol.

6.7 Physicochemical Properties

Cyproterone acetate.

Chemical name: 6-chloro-17α hydroxy-1α,2α-methylene-pregna-4,6-diene-3,20-dione-acetate.
Molecular formula: C24H29ClO4.
Molecular Mass: 416.96.

Chemical structure.


CAS number.

CAS No.: 427-51-0.

Ethinylestradiol.

Chemical name: 19-nor-17α-pregna-1,3,5,(10)-triene-20-yne-3,17β-diol.
Molecular formula: C20H24O2.
Molecular Mass: 296.41.

Chemical structure.


CAS number.

CAS No.: 57-63-6.
Cyproterone acetate is a white to pale yellow crystalline powder. M.P. 206 - 213°C.
Cyproterone acetate is very soluble in chloroform and dioxane, freely soluble in acetone and benzene, soluble in ethanol, methanol and ethyl acetate, sparingly soluble in solvent hexane and almost insoluble in water.
Ethinylestradiol is a white to 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.

2 Qualitative and Quantitative Composition

Brenda-35 ED contains the synthetic progestogen, cyproterone acetate and the synthetic oestrogen, ethinylestradiol.
Each beige active tablet, contains ethinylestradiol 35 microgram and cyproterone 2 mg.
Brenda-35 ED also contains lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

The calendar pack consists of a foil backed blister platform containing:
21 beige active tablets with cyproterone acetate 2 mg and ethinylestradiol 35 microgram;
followed by 7 white placebo tablets.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Brenda-35 ED is a progestogen-oestrogen combination for the treatment of signs of androgenisation in the woman. At the same time, it is a reliable contraceptive for women who suffer primarily from these signs or in whom acne and similar conditions occur or deteriorate under the use of other ovulation inhibitors.
The substance cyproterone acetate contained in Brenda-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 Brenda-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 Brenda-35 ED is indicated in women of childbearing age who exhibit mild forms of hirsutism, and in particular 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, combined oral contraceptives (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

Cyproterone acetate.

Absorption.

Following oral administration, cyproterone acetate (CPA) is completely absorbed over a wide dose range. Peak serum concentrations of 15 nanogram/mL are reached at about 1.6 hours after single ingestion. The absolute bioavailability of cyproterone acetate is unknown. Relative bioavailability was calculated, in a study of eight young women, from a dose corrected comparison of area under the curves (AUC) of serum levels after 100 mg oral and 300 mg intramuscular depot administration and was found to be 80 ± 30% when averaged over all volunteers (range 23%-119%).

Distribution.

Cyproterone acetate is almost exclusively bound to serum albumin. Only 3.5 to 4.0% of the total serum drug concentrations are present as free steroid. The ethinylestradiol induced increase in sex hormone binding globulin (SHBG) does not influence the serum protein binding of cyproterone acetate. The apparent volume of distribution of cyproterone acetate is about 986 ± 437 L.

Metabolism.

Cyproterone acetate is subject to extensive metabolism. The main metabolite in plasma was identified as 15-hydroxy-CPA which is formed possibly via the cytochrome P450 enzyme CYP3A4. The clearance rate from serum is about 3.6 mL/min/kg.

Excretion.

Cyproterone acetate serum levels decrease in two phases which are characterised by half-lives of about 0.8 h and about 2.3 to 3.3 days. Cyproterone acetate is partly excreted in unchanged form. Its metabolites are excreted at a urinary to biliary ratio of about 1:2. The half-life of metabolite excretion is about 1.9 days.

Steady-state conditions.

Cyproterone acetate pharmacokinetics are not influenced by SHBG levels. Following daily ingestion drug serum levels increase about 2.5-fold reaching steady-state conditions during the second half of a treatment cycle.

Ethinylestradiol.

Absorption.

Orally administered ethinylestradiol is rapidly and almost completely absorbed. Peak serum concentrations of about 71 picogram/mL are reached within 1 to 2 hours. Absolute bioavailability, as a result of presystemic conjugation and first-pass metabolism, is approximately 60%.

Distribution.

Ethinylestradiol is highly but nonspecifically bound to serum albumin (approximately 98.5%) and induces an increase in the serum concentrations of SHBG. An apparent volume of distribution of approximately 5 L/kg was determined.

Metabolism.

Ethinylestradiol is subject to presystemic conjugation in both small bowel mucosa and the liver. Ethinylestradiol is primarily metabolised by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed, and these are present as free metabolites and as conjugates with glucuronides and sulfate. The metabolic clearance rate is about 5 mL/min/kg.

Excretion.

Ethinylestradiol serum levels decrease in two phases, the terminal disposition phase is characterised by half-life of approximately 24 hours. Unchanged drug is not excreted, ethinylestradiol metabolites are excreted at a urinary to biliary ratio of 4:6. The half-life of metabolite excretion is about 1 day.

Steady-state conditions.

Steady-state conditions are reached during the second half of a treatment cycle when serum drug levels are higher by 60% as compared to single dose.

5.3 Preclinical Safety Data

Genotoxicity.

There is limited evidence available in the literature suggesting that oestrogens 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 Brenda-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 positive 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 oestrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis and liver.
In a long-term animal 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.

4 Clinical Particulars

4.1 Therapeutic Indications

Brenda-35 ED is indicated 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.
Brenda-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 (i.e. androgen producing tumour or an adrenal enzyme defect) must be clarified by differential diagnosis.

4.3 Contraindications

Preparations containing oestrogen/ 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 venous thromboembolism (VTE) (see Section 4.4 Special Warnings and Precautions for Use):
current VTE (on anticoagulants) or history of deep venous thrombosis or pulmonary embolism;
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 factor(s) for venous or arterial thrombosis may also constitute a contraindication (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. transient ischaemic attack, angina pectoris);
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 involvement, severe hypertension, severe dyslipoproteinaemia.
Pancreatitis or a history thereof if associated with severe hypertriglyceridemia.
Presence or history of severe hepatic disease whereby liver function values have not returned to normal.
Use of direct-acting antiviral (DAA) medicinal products containing ombitasvir, paritaprevir or dasabuvir and combinations of these (see 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).
Concomitant use with another hormonal contraceptive.
Undiagnosed vaginal bleeding.
Known or suspected pregnancy.
Lactation.
Hypersensitivity to any of the ingredients in Brenda-35 ED.
Brenda-35 ED is not for use in men.
Brenda-35 ED is composed of the progestogen cyproterone acetate and the oestrogen 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 oestrogen/progestogen combinations like Brenda-35 ED is predominantly based on combined oral contraceptives (COCs). Therefore, the following warnings related to the use of COCs apply also for Brenda-35 ED.

4.4 Special Warnings and Precautions for Use

If any of the conditions/ risk factors mentioned below are present, the benefits of Brenda-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 whether Brenda-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 myocardial infarction (MI), stroke, deep venous thrombosis (DVT) and pulmonary embolism (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.
Data from a large, prospective 3 armed cohort (EURAS and LASS) suggest that this increased risk is mainly present during the first 3 months.
A large, prospective 3 armed cohort study has shown that the incidence rate of VTE ranged from 8 to 10 per 10,000 woman years (WY) in low oestrogen dose (< 50 microgram ethinylestradiol) COC users. The most recent data suggest that the incidence rate of VTE is approximately 4.4 per 10,000 woman years in nonpregnant non-COC users, and ranged from 20 to 30 per 10,000 WY in pregnancy or the postpartum period.
Overall the risk of VTE in users of low oestrogen dose (< 50 microgram ethinylestradiol) COCs are two to threefold higher than for nonusers of COCs who are not pregnant and remains lower than the risk associated with pregnancy and delivery.
Epidemiological studies have shown that the incidence of VTE is 1.5 to 2 times higher in users of Brenda-35 ED than in users of levonorgestrel-containing COCs.
The user group of Brenda-35 ED is likely to include patients that may have an inherently increased cardiovascular risk such as that associated with polycystic ovarian syndrome.
An additional increase in VTE risk for CHCs containing ≥ 50 microgram ethinylestradiol cannot be excluded.
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 fatal outcome (in 1-2% of the cases).
Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal, 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).
Brenda-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 Brenda-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 Brenda-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 a 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 nonspecific 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 arterial thromboembolism (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. Brenda-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.
A positive family history (ATE ever in a sibling or parent especially at a 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, 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 COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC.
The user group of Brenda-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 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 transient ischaemic attack (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.

Other conditions.

Women with hypertriglyceridaemia, 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 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 oestrogens 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 that occurred first during pregnancy or from 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 women with diabetes taking low dose COCs (containing < 50 microgram ethinylestradiol). However, women with diabetes 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 beige active tablet contains 31.12 mg of lactose monohydrate and each white placebo tablet contains 48.25 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 Brenda-35 ED use, guided by the contraindications and precautions, and should be repeated periodically. In general, an annual examination is recommended. Periodic medical assessment is also of importance because contraindications (e.g. a transient ischaemic attack, 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 AIDS.

Brenda-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 Brenda 35-ED may be reduced in the event of missed beige active tablets (see Section 4.2 Dose and Method of Administration, Management of missed tablets), vomiting, or diarrhoea during beige 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.

Use in hepatic impairment.

Brenda-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.

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

Use in the elderly.

Brenda-35 ED is not indicated after menopause.

Paediatric use.

Brenda-35 ED is only indicated after menarche.

Effects on laboratory tests.

The use of preparations like Brenda-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 Brenda-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.
Enzyme induction can already be observed after a few days of treatment. Maximal enzyme induction is generally seen within a few weeks. After the cessation of drug therapy enzyme induction may be sustained for about 4 weeks.
Women prescribed any of these medicines should temporarily use a barrier method in addition to Brenda-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 beige active tablets in the Brenda-35 ED, the larger white placebo tablets should be omitted and the next pack be started.

Substances increasing the clearance of Brenda-35 ED (diminished efficacy of Brenda-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).

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

When coadministered with COCs, many HIV/ hepatitis C virus (HCV) protease (e.g. ritonavir) and non-nucleoside transcriptase inhibitors (e.g. nevirapine) can increase or decrease plasma concentration of oestrogen 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 oestrogen or the progestogen or both.
Etoricoxib doses of 60 to 120 mg/day have been shown to increase plasma concentrations of ethinylestradiol 1.5 to 1.6-fold, respectively when taken concomitantly with a combined hormonal contraceptive containing 35 microgram ethinylestradiol.

Influence of Brenda-35 ED on other medication.

Oestrogen/ progestogen preparations like Brenda-35 ED may affect the metabolism of certain other medicines. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporin) 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).

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 fetuses if given during the phase of differentiation of the fetal male genital organs. The relevance of these findings to man is not known. Isolated cases of inadvertent use of Brenda-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 Brenda-35 ED during the hormone sensitive phase of differentiation of the genital organs in male fetuses (from about the 45th day of pregnancy) might cause signs of feminisation. For this reason, Brenda-35 ED is contraindicated during pregnancy.
If pregnancy occurs during treatment with Brenda-35 ED, further intake must be stopped.
The use of Brenda-35 ED is contraindicated during lactation as small amounts of cyproterone acetate are excreted in breast milk. Oestrogen containing oral contraceptives may decrease the quantity and quality of breast milk.

4.8 Adverse Effects (Undesirable Effects)

Various adverse effects have been associated with oral contraceptive use. The most serious effects associated with the use of oral contraceptives are discussed with (see Section 4.4 Special Warnings and Precautions for Use).
The most commonly reported adverse reactions with Brenda-35 ED are nausea, abdominal pain, increased weight, headache, depressed mood, altered mood, breast pain, breast tenderness. See Table 1.
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 physician. The physician should then decide on whether its use should be discontinued.

Other adverse effects.

Eye 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.

4.2 Dose and Method of Administration

Combined oral contraceptives, when taken correctly, have a failure rate of approximately 1% per year.
Brenda-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 Brenda-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 Brenda-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 Brenda-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 Brenda-35 ED is stopped.
Brenda-35 ED should be withdrawn 3 to 4 cycles after the treated condition has completely resolved. Repeat course of Brenda-35 ED may be given if the androgen dependent condition(s) recur. In case of a restart with Brenda-35 ED (following a 4 week or great tablet free interval), the increased risk of VTE should be considered (see Section 4.4 Special Warnings and Precautions for Use).

How to take Brenda-35 ED.

One tablet is to be taken daily. The tablets must be taken in the order directed on the pack at about the same time every day, with some liquid as needed. Daily tablet taking should be continuous for 28 consecutive days, starting with a tablet corresponding to that day of the week from the red section of the Brenda-35 ED pack.
If a woman starts on a Monday, Tuesday, Wednesday, Thursday or Friday, her first tablet is a large white placebo tablet, while if she starts on a Saturday or Sunday her first tablet will be a light beige active tablet. Thereafter, one tablet is taken daily, following the arrows marked on the pack, until all tablets have been taken. Each subsequent pack is started the day after the last tablet of the previous pack.
Withdrawal bleeding should usually occur on day 2 to 3 after the last beige active tablet is taken and may not have finished before the next pack is started.

How to start Brenda-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 non-hormonal contraceptive methods must be used for the first 14 days of tablet-taking.

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

The woman should start with Brenda-35 ED on the day after the last active of her previous COC.
In case where a vaginal ring has been used, the woman should start using Brenda-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 from the minipill on any day, from an implant or the IUS on the day of its removal, or from an injectable when the next injection would be due, but in all of these cases she should be advised to additionally use a 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 first 14 days of tablet taking.

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 first 14 days of tablet taking. 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.
Brenda-35 ED should not be used in breastfeeding women (see Section 4.6 Fertility, Pregnancy and Lactation).

Additional contraceptive precautions.

When additional contraceptive precautions are required the woman should be advised to 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.

How to manage reduced reliability.

When Brenda-35 ED is taken according to the directions for use, the occurrence of pregnancy is highly unlikely. However, the reliability of oral contraceptive protection may be reduced under the following circumstances.

Management of missed tablets.

Missed white pills from the last row of the blister are placebo (inactive, hormone free) tablets and thus can be disregarded. However they should be discarded to avoid unintentionally prolonging the placebo tablet phase. The following advice only refers to missed beige active tablets (rows 1-3 of the blister).
If the woman is less than 12 hours late in taking any beige active tablet, contraceptive protection is not reduced. The woman should take the tablet as soon as she remembers and should take further tablets at the usual time.
If the woman is more than 12 hours late in taking any beige active tablet, contraceptive protection may be reduced. The more tablets are missed and the closer they are to the regular placebo tablet interval, the higher the risk of a pregnancy.
The management of missed tablets can be guided by the following two basic rules.
1. Active tablet taking must never be discontinued for longer than 7 days.
2. Seven days of uninterrupted active tablet taking are required to attain adequate suppression of the hypothalamic pituitary ovarian axis.
Accordingly, the following advice can be given in daily practice.

Week 1 of active tablets.

The woman should take the last missed beige active tablet as soon as she remembers, even if this means taking two beige active tablets in one day at the same time, and then continue to take tablets at her usual time. Additional contraceptive precautions should be taken for the next 7 days.
If intercourse took place in the preceding 7 days, the possibility of a pregnancy should be considered.

Week 2 of active tablets.

The woman should take the last missed beige active tablet as soon as she remembers, even if this means taking two beige active tablets at the same time. She then continues to take tablets at her usual time, provided that the woman has taken her tablets correctly in the 7 days preceding the first missed beige active tablet. There is no need to use extra contraceptive precautions. However, if this is not the case, or if she missed more than one beige active tablet, the woman should be advised to use extra precautions for 7 days.

Week 3 of active tablets.

The risk of reduced reliability is imminent because of the forthcoming white placebo tablet interval. However, by adjusting the tablet intake schedule, reduced contraceptive protection can still be prevented. By adhering to either of the following two options, there is therefore no need to use extra contraceptive precautions, provided that in the 7 days preceding the first missed beige active tablet the woman has taken all tablets correctly. If this is not the case, the woman should be advised to follow the first of these two options and to use extra precautions for the next 7 days as well.
1. The woman should take the last beige active missed tablet as soon as she remembers, even if this means taking two beige active tablets at the same time. She then continues to take tablets at her usual time until the beige active tablets are taken. The 7 white placebo tablets must be discarded. The next pack must be started right away. The woman is unlikely to have a withdrawal bleed until the end of the active tablets of the second pack but she may experience spotting or breakthrough bleeding on tablet taking days.
2. The woman may also be advised to discontinue tablet taking from the current pack. She should then have a tablet free interval of up to 7 days, including the days she missed tablets, and subsequently continue with the next pack.
If the woman missed tablets and subsequently has no withdrawal bleed in the placebo tablet interval, the possibility of a pregnancy should be considered.

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 to 4 hours after taking a beige 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.

4.7 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.

4.9 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 beige active tablets are: nausea, vomiting and withdrawal bleeding. Withdrawal bleeding may even occur in girls before menarche, if they have accidentally taken Brenda-35 ED. There are no antidotes and further treatment should be symptomatic.
In cases of overdose, it is advisable to contact the Poisons Information Centre (13 11 26) for recommendations on the management and treatment of overdose.

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each beige active tablet, contains ethinylestradiol 35 microgram and cyproterone 2 mg. As well as the active ingredients, Brenda-35 ED tablets also contain the following excipients: lactose monohydrate, maize starch, povidone, magnesium stearate, sucrose, macrogol 6000, calcium carbonate, purified talc, glycerol, titanium dioxide, iron oxide yellow, glycol montanate and purified water.
Each white placebo tablets contain the following excipients: lactose monohydrate, maize starch, povidone, magnesium stearate, sucrose, macrogol 6000, calcium carbonate, purified talc and glycol montanate.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

The calendar pack consists of a foil backed blister platform containing:
21 beige active tablets with cyproterone acetate 2 mg and ethinylestradiol 35 microgram;
followed by 7 white placebo tablets.
Carton containing blister packs of 1 x 28 and 3 x 28 tablets. Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

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

Summary Table of Changes