Consumer medicine information

Diane-35 ED

Cyproterone acetate; Ethinylestradiol

BRAND INFORMATION

Brand name

Diane-35 ED

Active ingredient

Cyproterone acetate; Ethinylestradiol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Diane-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 Diane-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 DIANE-35 ED IS USED FOR

Diane-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.

Diane-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. Diane-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 Diane-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 Diane-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 DIANE-35 ED

When you must not take it

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

  • cyproterone acetate and/or ethinylestradiol (the active ingredients in Diane-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.

Diane-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 Diane-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 Diane-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 Diane-35 ED, increase the risk of having a blood clot. However, the risk of having a blood clot when taking Diane-35 ED is less than the risk of having a blood clot during pregnancy.

Do not take Diane-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 Diane-35 ED, especially if you are older than 35 years of age.

Do not take Diane-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)
  • 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
  • cancer that may grow under the influence of sex hormones (e.g. of the breast or the genital organs)
  • a benign or malignant liver tumour
  • unexplained vaginal bleeding.

If any of these conditions appear for the first time while using Diane-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 Diane-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. The expiry date is printed on the carton and on each blister after “EXP” (e.g. 11 18 refers to November 2018). The expiry date refers to the last day of that month. 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 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, recur, or worsen while taking Diane-35 ED, you should tell your doctor.

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

If you have not told your doctor about any of the above, tell him/her before you start taking Diane-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 Diane-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. 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 Diane-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 condoms or a diaphragm) while you are taking any of these medicines with Diane-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 DIANE-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 pack 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 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 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 Diane-35 ED for the first time

If you are starting Diane-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 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 Diane-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 Diane-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 Diane-35ED.

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

Changing from a vaginal ring:
Start taking Diane-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 Diane-35 ED at the same time the day after you took your last minipill.

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 Diane-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 Diane-35 ED

You may have to take Diane-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 Diane-35 ED 3 to 4 months after your symptoms have completely resolved.

You should have regular checkups with your doctor to determine how long to keep taking Diane-35 ED.

Stopping Diane-35 ED

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

It is possible that the original condition may recur once Diane-35 ED is stopped. Do not start taking Diane-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 Diane-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 Diane-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 Diane-35 ED

If you miss a tablet and take the missing tablet within 12 hours of missing it, you should still be protected against pregnancy.

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

For Diane-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 this means taking two tablets in one day at the same time. 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 beige 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 finish the active tablets in your pack but skip the white inactive tablets and start a new pack with the beige active tablets corresponding to the correct day of the week. 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 at the same time. 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 pharmacist.

If you miss 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 (Australia: 13 11 26 or New Zealand: 0800 poison or 0800 764 766) 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 Diane-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 medicine may experience such bleeding.

WHILE YOU ARE TAKING DIANE-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 Diane-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 Diane-35 ED.

Stop taking Diane-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 Diane-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 Diane-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 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 greater than 4 hours.

Consult your doctor if you develop high blood pressure while taking Diane-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 Diane-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 beige active tablets at the right time
  • you have not been taking medicine(s) that may interfere with Diane-35 ED.
  • you have not vomited or had severe diarrhoea during this cycle.

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

Diane-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 Diane-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 Diane-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 Diane-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 attention if you get some of the side effects.

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

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

The following list includes the more common side effects of Diane-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 Diane-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 Diane-35 ED.

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

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

Cancer and Diane-35 ED

Diane-35 ED contains a progestogen and an 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.

AFTER TAKING DIANE-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 25°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 Diane-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

Diane-35 ED active tablets are beige and round.

Diane-35 ED inactive tablets are white and round.

Diane-35 ED comes in a box containing either 1 or 3 blister packs. Each blister pack contains 21 beige active tablets and 7 white inactive tablets.

Ingredients

Each beige active tablet contains:

Active ingredients:

  • 2 mg of cyproterone acetate
  • 35 micrograms of ethinylestradiol

Inactive ingredients:

  • lactose monohydrate
  • maize starch
  • povidone
  • magnesium stearate
  • sucrose
  • macrogol 6000
  • calcium carbonate
  • purified talc
  • glycerol
  • titanium dioxide
  • iron oxide yellow
  • 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

Tablets do not contain gluten. Tablets also do not contain tartrazine or any other azo dyes.

Supplier

Made in Germany for:

Bayer Australia Ltd.
ABN 22 000 138 714
875 Pacific Highway
Pymble NSW 2073

Bayer New Zealand Limited
3 Argus Place, Hillcrest,
North Shore
Auckland 0627

Australian Registration Number

Diane-35 ED - AUST R 33647

Date of Preparation

March 2020

See TGA website (www.ebs.tga.gov.au) for latest Australian Consumer Medicine Information.

See MEDSAFE website (www.medsafe.govt.nz) for latest New Zealand Consumer Medicine Information.

® Registered Trademark of the Bayer group, Germany

©Bayer Australia Ltd All rights reserved.

Missed taking Diane-35 ED?

See the end of this leaflet

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Diane-35 ED

Active ingredient

Cyproterone acetate; Ethinylestradiol

Schedule

S4

 

1 Name of Medicine

Cyproterone acetate and ethinylestradiol.

6.7 Physicochemical Properties

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.

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:
Molecular Formula: C24H29ClO4.
Molecular Mass: 416.96.

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: 296.41.

CAS number.

Cyproterone acetate.

427-51-0.

Ethinylestradiol.

57-63-6.

2 Qualitative and Quantitative Composition

Diane-35 ED contains the synthetic progestogen, cyproterone acetate and the synthetic estrogen, ethinylestradiol.
Each beige active tablet contains cyproterone acetate 2 mg and ethinylestradiol 35 microgram.

Excipients with known effect.

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

3 Pharmaceutical Form

Tablet, sugar coated.
Diane-35 ED tablets are available in blister packs of 28 tablets. Each blister contains 21 round beige active tablets followed by 7 round white placebo tablets.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Diane-35 ED is a progestogen/estrogen 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 Diane-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 Diane-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 Diane-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, 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 3.5-4.0% 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 1-2 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 condition.

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 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 Diane-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.

4 Clinical Particulars

4.1 Therapeutic Indications

Diane-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.
Diane-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.

4.3 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 venous thromboembolism (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.
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 Diane-35 ED.
Diane-35 ED is not for use in men.
Diane-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 Diane-35 ED is predominantly based on COCs. Therefore, the following warnings related to the use of COCs apply also for Diane-35 ED.

4.4 Special Warnings and Precautions for Use

If any of the conditions/risk factors mentioned below are present, the benefits of Diane-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 Diane-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.
Data from a large, prospective 3-armed cohort study (EURAS1 and LASS2) suggest that this increased risk is mainly present during the first 3 months.
A large, prospective 3-arm cohort study has shown that the incidence rate of VTE ranged from 8 to 10 per 10,000 woman years (WY) in low estrogen 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 non-pregnant non-COC users, and ranged from 20 to 30 per 10,000 WY in pregnancy or the post-partum period.
Overall the risk of VTE in users of low estrogen dose (< 50 microgram ethinylestradiol) COCs are two to threefold higher than for non-users 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 Diane-35 than in users of levonorgestrel-containing COCs.
The user group of Diane-35 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 post-partum 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 the cases).
Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal 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).
Diane-35 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 Diane-35 (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 Diane-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 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. Diane-35 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 Diane-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 papilloma virus (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 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 angiooedema exogenous estrogens may induce or exacerbate symptoms of angiooedema.
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 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 30.97 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 Diane-35 ED, guided by the Contraindications and Precautions (see 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 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.

Diane-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 Diane-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.

Diane-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.

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

Use in the elderly.

Diane-35 ED is not indicated after menopause.

Paediatric use.

Diane-35 ED is only indicated after menarche.

Effects on laboratory tests.

The use of preparations like Diane-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 Diane-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 Diane-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 Diane-35 ED pack, the white placebo tablets should be omitted and the next pack be started.

Substances increasing the clearance of Diane-35 ED (diminished efficacy of Diane-35 ED by enzyme induction), e.g.

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 Diane-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 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 combined hormonal contraceptive containing 35 microgram ethinylestradiol.

Influence of Diane-35 ED on other medication.

Estrogen/progestogen preparations like Diane-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.

Coadministration 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)1
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 Diane-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 Diane-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, Diane-35 ED is contraindicated during pregnancy.
If pregnancy occurs during treatment with Diane-35 ED, further intake must be stopped.
1 Category B3: drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed.
Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.

The use of Diane-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.

4.8 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, see Section 4.4 Special Warnings and Precautions for Use.
The most commonly reported adverse reactions with Diane-35 ED are nausea, abdominal pain, increased weight, headache, depressed mood, altered mood, breast pain, breast tenderness. They occur in ≥ 1% of users. See Table 1.
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.

Other adverse reactions.

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.
Diane-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 Diane-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 Diane-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 Diane-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 Diane-35 ED is stopped.
Diane-35 ED should be withdrawn 3 to 4 cycles after the treated condition has completely resolved. Repeat course of Diane-35 ED may be given if the androgen dependent condition(s) recur. In case of a restart with Diane-35 ED (following a 4 week or greater tablet free interval), the increased risk of VTE should be considered (see Section 4.4 Special Warnings and Precautions for Use).

How to take Diane-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. 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 Diane-35 ED pack.
If a woman starts on a Monday, Tuesday, Wednesday, Thursday or Friday, her first tablet is a white placebo tablet, while if she starts on a Saturday or Sunday her first tablet will be a 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 Diane-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 first 14 days of tablet taking.

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

The woman should start with Diane-35 ED on the day after the last active tablet of her previous COC.
In case a vaginal ring has been used, the woman should start taking Diane-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.
Diane-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.

How to manage reduced reliability.

When Diane-35 ED is taken according to the directions for use, the occurrence of pregnancy is highly unlikely. However, the reliability of 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 3-4 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 Diane-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).

7 Medicine Schedule (Poisons Standard)

S4.

References

1. Dinger JC, Heinemann LA, Kuhl-Habich D. The safety of a drospirenone-containing oral contraceptive: final results from the European Active Surveillance study on Oral Contraceptives based on 142,475 women-years of observation. Contracept 2007; 75:344-54.
2. Long-term Active Surveillance Study for Oral contraceptives (LASS), 2nd update report based on study status. May 2009.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each beige active tablet contains: lactose monohydrate, maize starch, povidone, magnesium stearate, sucrose, macrogol 6000, calcium carbonate, purified talc, glycerol, titanium dioxide, iron oxide yellow, glycol montanate, purified water.
Each white placebo tablet contains: lactose monohydrate, maize starch, povidone, magnesium stearate, sucrose, macrogol 6000, calcium carbonate, purified talc, glycol montanate.

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 25°C.

6.5 Nature and Contents of Container

Diane-35 ED tablets are available in PVC/Al blister packs and are packaged in cartons containing blister packs of 1 x 28 or 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 to your local pharmacy.

Summary Table of Changes