Consumer medicine information

Yaz

Ethinylestradiol; Drospirenone

BRAND INFORMATION

Brand name

Yaz

Active ingredient

Ethinylestradiol; Drospirenone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Yaz.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about YAZ. 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 YAZ 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 YAZ IS USED FOR

YAZ is a combined oral contraceptive, commonly known as a ‘birth control pill’ or ‘the Pill’.

YAZ is used to prevent pregnancy.

It is also used to treat moderate acne and symptoms of premenstrual dysphoric disorder (PMDD) in women seeking oral contraception.

You may also experience the following benefits:

  • more regular and lighter periods – potentially resulting in a decrease in anaemia (iron deficiency)
  • a decrease in period pain
  • improvement in symptoms like bloating, swelling or weight gain related to fluid retention

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 the Pill.

When taken correctly, it prevents you from becoming pregnant in several ways, including:

  • inhibiting the egg release by stopping it maturing
  • changing the cervical mucus consistency, making it more difficult for the sperm to reach the egg.

YAZ has 24 active (hormone) tablets and 4 inactive tablets, rather than the traditional 21 active tablets and 7 inactive tablets. This means that with YAZ, you take the active (hormone) tablets for three more days. This helps your hormone levels to stay even.

When the Pill is taken by women under close observation in clinical trials, it is more than 99% effective in preventing pregnancy.

However, in real life the Pill is around 92% effective. This is because pills might be missed, or taken with medicines that may interfere with their effectiveness, or may not be absorbed due to vomiting and diarrhoea.

Like all oral contraceptives, YAZ is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted infections.

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 YAZ

When you must not take it

Do not take YAZ if you have an allergy to

  • drospirenone and/or ethinylestradiol, the active ingredients in YAZ
  • 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.

Do not take YAZ 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 YAZ 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 YAZ if you have or 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.

You are more at risk of having a blood clot when you take the Pill. But the risk of having a blood clot when taking the Pill is less than the risk during pregnancy.

Do not take YAZ 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 YAZ if you have, or have had:

  • 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)
  • severe kidney insufficiency or an acute failure of your kidney
  • 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 the Pill, 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 this medicine if you are pregnant or think you might be pregnant.

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
  • an increased potassium blood level (e.g. due to problems with your kidney/s) and also use diuretics or other drugs that may increase the potassium in your blood
  • cancer
  • hyperhomocysteinaemia, a condition characterised by high levels of the amino acid homocysteine 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 kidney disease
  • have high potassium in your blood
  • 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 YAZ, you should tell your doctor.

Tell your doctor if you are breastfeeding. YAZ is generally not recommended if you are breastfeeding.

YAZ contains lactose monohydrate. If you have an intolerance to some sugars, tell your doctor before you start taking YAZ.

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

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 YAZ may interfere with each other. These include:

  • medicines used to treat tuberculosis such as rifampicin, rifabutin
  • macrolide antibiotics (e.g. clarithromycin, erythromycin)
  • medicines used to treat fungal infections, such as griseofulvin, ketoconazole
  • medicines used to treat HIV, such as ritonavir or nevirapine
  • some medicines used to treat Hepatitis C Virus (HCV) such as boceprevir, telaprevir,
  • medicines used to treat epilepsy such as phenytoin, primidone, barbiturates (e.g. phenobarbitone), carbamazepine, oxcarbazepine, topiramate, felbamate, lamotrigine
  • 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 medicines that 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 YAZ, or may affect how well it works. Your doctor may need to alter the dose of these medicines, or prescribe a different medicine.

Some medicines

  • can have an influence on the blood levels of YAZ
  • can make it less effective in preventing pregnancy
  • can cause unexpected bleeding.

You might have an increase in potassium in the blood if you are taking YAZ with medicines that may increase potassium levels in the blood. These include:

  • medicines used to treat high blood pressure, such as ACE inhibitors, angiotensin-II-receptor antagonists and diuretics
  • certain anti-inflammatory medicines, such as indomethacin
  • aldosterone antagonists, such as spironolactone and eplerenone.

In a study of women taking drospirenone together with an ACE inhibitor, no significant differences were observed in the potassium levels when compared to the placebo.

You may need to use additional barrier methods of contraception (such as condoms or a diaphragm) while you are taking any of these medicines 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 YAZ

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 each day. You must take YAZ 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 green 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 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 YAZ for the first time

If you are starting YAZ 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 may also start on days 2-5 of your period, but in that case make sure you also use additional barrier contraceptive precautions (e.g. condom) for the first 7 days of tablet-taking.

Your doctor will advise you when to start if you:

  • are taking YAZ after having a baby
  • have had a miscarriage or an abortion.

Changing from another contraceptive

Changing from a combined oral contraceptive:
Start taking YAZ 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 YAZ

You can also switch to YAZ after taking one or more inactive tablets in your previous Pill pack, but no later than the day after taking the last inactive tablet.

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 YAZ.

Changing from a progestogen-only pill (‘minipill’):
Stop taking the minipill on any day and start taking YAZ 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 7 days of tablet-taking when having intercourse.

Changing from a progestogen-only injection, implant or intrauterine system (IUS):
Start taking YAZ 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 7 days of tablet-taking when having intercourse.

Changing from a vaginal ring:
Start on the day of removal of the ring but at the latest when the next application would have been due.

Stopping YAZ

You can stop taking YAZ at any time. 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 YAZ 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 want to delay a period

To delay your period,

  • continue taking the light pink active tablets in the current blister,
  • skip the white placebo tablets in the last row of the same blister, and
  • start a new blister by taking the light pink active tablet from the green area corresponding to the day of the week (to ensure that you take your tablets on the corresponding day of the week as marked on the pack, you may have some extra tablets left over in your current blister which you can discard).

You can continue to delay your period by skipping the white placebo tablet in the second blister. The delay can be extended until the last light pink active tablet in the third blister is taken.

If you wish for your period to begin at any time during the extension, stop taking the light pink active tablets and start taking the white placebo tablets instead.

You should get your period approximately 2 – 3 days after you start taking the white placebo tablet. After taking the last white placebo tablet, start a new blister by taking the light pink active tablet.

During the extension, you may have some breakthrough bleeding or spotting on active tablet-taking days.

If you forget to take it

If you are late taking a tablet but still take it within 24 hours, contraception is maintained. If you are more than 24 hours late, this is called a missed pill. Follow these detailed instructions:

For YAZ to be most effective, light pink active tablets need to be taken uninterrupted for 7 days.

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

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

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

If you forget to take more than one light pink 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.

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 for “Summary of advice if you missed a light pink active tablet more than 24 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 Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much YAZ.

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

If you take several light pink 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 YAZ

Things you must do

Tell any 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 Pill, 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 YAZ.

Stop taking YAZ and see your doctor immediately 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 this medicine. 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 YAZ, 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 YAZ 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 YAZ – 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 light pink 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 Pill, 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 light pink active tablets at the right time
  • you have not been taking medicine(s) that may interfere with YAZ
  • you have not vomited or had severe diarrhoea during this cycle.

If this is so, continue to take YAZ 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 the Pill correctly. Stop taking YAZ 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.

If you choose to delay your period while taking YAZ, your regular bleeding is not expected to occur during the extension period when the intake of the light pink active tablet is uninterrupted. Therefore, the absence of regular bleeding cannot be used as a sign of an unexpected pregnancy and as such, unexpected pregnancy may be difficult to recognise. Although pregnancy is unlikely if YAZ is taken as directed, if for any reason you think you might be pregnant, contact your doctor and do a pregnancy test. This may be of particular importance if you are also using other medications, since some medications are known to be harmful to the foetus.

YAZ 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 YAZ 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 YAZ, 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 YAZ.

This medicine helps most people, but it may have unwanted side effects in a few people.

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 your Pill. 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
  • headache, including migraines
  • mood changes, including depression
  • unscheduled vaginal bleeding
  • abnormal periods
  • irregular bleeding between periods
  • 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
  • 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).

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

Tell your doctor or pharmacist if you feel unwell. Other side effects not listed may also occur in some people.

Blood clots and the Pill

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 (DVT). 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 (PE).

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 the Pill. They can also happen during pregnancy. The risk of having blood clots is higher in Pill users than in non users, but not as high as during pregnancy.

The excess risk of a blood clot is highest during the first year after a woman takes the Pill for the first time or after having a break from the Pill for 4 weeks or more.

If you notice possible signs of a blood clot, stop taking YAZ 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 YAZ, speak to your doctor.

Cancer and 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 YAZ

Storage

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

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

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

Keep YAZ 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

YAZ active tablets are light pink round tablets marked on one side with the letters "DS" in a regular hexagon.

YAZ inactive tablets are white round tablets marked on one side with the letters "DP" in a regular hexagon.

YAZ comes in a box containing either 1 or 3 blister packs. Each blister pack contains 24 light pink active tablets and 4 white inactive tablets.

Ingredients

Each YAZ light pink active tablet contains:

Active ingredients:

  • 3 milligram of drospirenone
  • 20 microgram of ethinylestradiol (as betadex clathrate)

Inactive ingredients:

  • Lactose monohydrate
  • maize starch
  • hypromellose
  • magnesium stearate
  • purified talc
  • titanium dioxide
  • iron oxide red

Each white inactive tablet contains:

  • lactose monohydrate
  • microcrystalline cellulose
  • magnesium stearate
  • hypromellose
  • purified talc
  • 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
New Zealand

Australian Registration Number

YAZ - AUST R 226241

Date of Preparation

July 2019

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.

Missed a pill?
See the end of this leaflet

® Registered Trademark of the Bayer group, Germany

© Bayer Australia Ltd

All rights reserved.

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Yaz

Active ingredient

Ethinylestradiol; Drospirenone

Schedule

S4

 

1 Name of Medicine

Yaz (drospirenone and ethinylestradiol).

6.7 Physicochemical Properties

Drospirenone.

The chemical name for drospirenone is 6β, 7β, 15β, 16β-dimethylene-3-oxo-17α-pregn4-ene-21, 17-carbolactone. Chemical formula: C24H30O3. Molecular weight: 366.50.

Chemical structure.

It has the following structural formula:

CAS number.

67392-87-4.
Drospirenone is a white to off-white crystalline powder. It is freely soluble in methylene chloride, soluble in acetone and methanol, sparingly soluble in ethylacetate and ethanol 96% (v/v), and practically insoluble in hexane and water.

Ethinylestradiol.

The chemical name for ethinylestradiol is 19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3, 17β-diol. Chemical Formula: C20H24O2. Molecular Weight: 296.41.

Chemical structure.

It has the following structural formula:

CAS number.

57-63-6.
Ethinylestradiol betadex clathrate is an inclusion complex of the compendially described substances ethinylestradiol and betadex and, when dissolved in water, it dissociates into the active moiety ethinylestradiol and the ligand betadex.
Ethinylestradiol is a white to creamy white, odourless, crystalline powder. It is insoluble in water and soluble in alcohol, chloroform, ether, vegetable oils and aqueous solutions of alkali hydroxides.

2 Qualitative and Quantitative Composition

Each light pink active tablet contains drospirenone 3 mg and ethinylestradiol (as betadex clathrate) 20 microgram.
Excipients with known effect:
Each light pink active tablet contains 48.18 mg of lactose monohydrate.
Each white placebo tablet contains 23.21 mg of lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Each Yaz active tablet is light pink in colour, marked on one side with the letters "DS" in a regular hexagon.
Each Yaz placebo tablet is white in colour, marked on one side with the letters "DP" in a regular hexagon.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The contraceptive effect of combined oral contraceptives is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation and the changes in the cervical secretion. As well as protection against pregnancy, combined oral contraceptives have several positive properties which, next to the negative properties (see Section 4.4 Special Warnings and Precautions for Use and Section 4.8 Adverse Effects (Undesirable Effects)), can be useful in deciding on the method of birth control. The cycle is more regular and the menstruation is often less painful and bleeding is lighter. The latter may result in a decrease in the occurrence of iron deficiency.
Drospirenone has antimineralocorticoid activity, counteracting estrogen related sodium retention. In combination with ethinylestradiol, drospirenone displays a favourable lipid profile with an increase in high density lipoprotein (HDL). Drospirenone exerts antiandrogenic activity. Drospirenone does not counteract the ethinylestradiol related sex hormone binding globulin (SHBG) increase which is useful for binding and inactivating the endogenous androgens.
Drospirenone is devoid of any androgenic, estrogenic, glucocorticoid and antiglucocorticoid activity. This, in combination with the antimineralocorticoid and antiandrogenic properties, gives drospirenone a biochemical and pharmacological profile closely resembling the natural hormone progesterone. Apart from this, with the higher dosed combined oral contraceptives (COCs) (50 microgram ethinylestradiol), there is evidence of a reduced risk of fibrocystic tumours of the breasts, ovarian cysts, pelvic inflammatory disease, ectopic pregnancy and endometrial and ovarian cancer. Whether this also applies to lower dosed combined oral contraceptives such as Yaz remains to be confirmed.

Clinical trials.

Contraception.

Study A12007 and study A30713 were both large multicentre open trials evaluating contraceptive efficacy of Yaz in 1027 and 1101 women respectively over 13 cycles. The age range was 17 to 36 years. The BMI in these studies ranged from 17 to 37.6 kg/m2 with mean values of 22.4 (A12007) and 21.7 (A30713), respectively. The primary efficacy variable was the number of unintended pregnancies (Pearl index). The Pearl index (PI) is defined as the number of pregnancies divided by the exposure time in woman years (WY) multiplied by 100. Pregnancies attributed to noncompliant use of the contraceptive were considered patient failure; all other pregnancies were considered method failure. In study A12007 the PI was 1.29 with an upper two sided 95% confidence interval of 2.30. When corrected to exclude patient failure the PI was 0.72 with an upper two sided 95% confidence interval of 1.69. In study A30713, the PI was 0.49 with an upper two sided 95% confidence interval of 1.14. When corrected to exclude patient failure the PI was 0.22 with an upper two sided 95% confidence interval of 0.80.
Study A29551 was a multicentre open randomised study to investigate the bleeding pattern, cycle control, contraceptive reliability and general safety of Yaz in 229 women compared to ethinylestradiol 0.02 mg + desogestrel 0.15 mg in 220 women taken for 21 days followed by pill free interval of 7 days over 7 cycles. There were no pregnancies in the Yaz group which lead to a Pearl index of 0 with an upper two sided 95% confidence interval of 3.40 and 3.55 for the Pearl index and corrected index, respectively.
A small fourth study (A09151) evaluated lipid and haemostatic and carbohydrate parameters in 29 women taking Yaz compared to ethinylestradiol 0.02 mg + desogestrel 0.15 mg in 30 women taken for 21 days followed by pill free interval of 7 days over 7 cycles. No significant differences in any of the lipid, haemostatic, or carbohydrate parameters were observed between the two treatments.
The Pearl index from the integrated efficacy analysis from these 4 studies was 0.80 with an upper two sided 95% confidence interval of 1.30. When corrected to exclude patient failure the Pearl index was 0.41 with an upper two sided 95% confidence interval of 0.85.
The Pearl index for Yaz was calculated from data from studies in which the protocol allowed up to 24 hours delay in pill taking without a requirement for additional contraception, and in which the regimen was 24 active pills and 4 inactive pill, taken sequentially over 28 days per cycle.
The parameters of bleeding pattern and cycle control demonstrated a well controlled and regular bleeding sequence for Yaz as compared to the comparator used. No clinically relevant changes in blood pressure or weight were observed. Irrespective of treatment duration, the mean absolute change in bodyweight at the final examination was -0.1 kg for and the mean maximum increase in bodyweight versus baseline was 1.2 kg (n = 1,319). The mean maximum decrease was 1.6 kg. The majority of women treated with Yaz were satisfied or very satisfied with the treatment and reported no change or improvement in their physical or emotional wellbeing. The overall subjective assessment of Yaz treated women was equivalent to the comparator group.

Acne.

Yaz as an acne therapy was evaluated in two pivotal multicentre, double blind, randomised placebo controlled studies of 6 month duration. A total of 451 Yaz and 442 placebo subjects were included in the final integrated analysis. Patients had moderate acne defined in the protocol as a minimum of 40 lesions (i.e. at least 20 inflammatory lesions and at least 20 noninflammatory lesions) and were between ages of 14 to 45. The primary efficacy endpoints were the percent change in total lesions, inflammatory lesions, noninflammatory lesions and the percentage of subjects with a "clear" or "almost clear" rating on the investigator's static global assessment (ISGA) on day 15 of cycle 6. The results for the primary efficacy variables are provided in Table 2.
In addition, there was a statistical difference (p = < 0.0001) in the percentage of patients considered improved at the final assessment by the investigator for Yaz (87.6%) as compared to placebo (66.0%) [odds ratio 3.83, 95% CI 2.58, 5.80].

Premenstrual dysphoric disorder (PMDD).

The essential features of PMDD according to the Diagnostic and Statistical Manual-4th edition (DSM-IV) include markedly depressed mood, anxiety or tension, affective lability and persistent anger or irritability. Other features include decreased interest in usual activities, difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control. Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle pain, bloating and weight gain. In this disorder, these symptoms occur regularly during the luteal phase and remit within a few days following onset of menses. The disturbance markedly interferes with work or school, or with usual social activities and relationships with others. Diagnosis is made by healthcare providers according to DSM-IV criteria, with symptomatology assessed prospectively over at least two menstrual cycles. In making the diagnosis, care should be taken to rule out other cyclical mood disorders.
Two multicentre, double blind, randomised, placebo controlled studies were conducted to evaluate the effectiveness of Yaz in treating the symptoms of PMDD. Women aged 18-42, > 1 year after menarche with no known contraindications for oral contraceptives and who met DSM-IV criteria for PMDD, confirmed by prospective daily ratings of their symptoms, were enrolled. Subjects with past or present psychiatric disorders other than PMDD were excluded. Both studies measured the treatment effect of Yaz using the Daily Record of Severity of Problems scale, a patient rated instrument that assesses the symptoms that constitute the DSM-IV diagnostic criteria. The primary study was a parallel group design that included 384 evaluable reproductive aged women with PMDD who were randomly assigned to receive Yaz or placebo treatment for 3 menstrual cycles. The supportive study, a crossover design, was terminated prematurely prior to achieving recruitment goals due to enrolment difficulties. In the supportive study, a total of 64 women of reproductive age with PMDD were treated initially with Yaz or placebo for up to 3 cycles followed by a washout cycle and then crossed over to the alternate medication for 3 cycles.
Efficacy was assessed in both studies by the change from baseline during treatment using a scoring system based on the first 21 items of the daily record of severity of problems (DRSP). Each of the 21 items was rated on a scale from 1 (not at all) to 6 (extreme); thus a maximum score of 126 was possible. In both trials, women who received Yaz had statistically significantly greater improvement in their daily record of severity of problems scores. In the primary study, the average decrease (improvement) from baseline was 37.5 points in women taking Yaz, compared to 30.0 points in women taking placebo in the full analysis set. The difference between treatment groups (-7.5) was statistically significant (p = 0.0001). In the supportive study, the average decrease from baseline for Yaz (n = 42) was -22.9, compared to -10.5 in women (n = 41) taking placebo (p = 0.0001; difference -12.47; 95% CI: -18.28, -6.66).
A statistical comparison between the treatments for the efficacy variables (full analysis set) in the PMDD pivotal study is presented in Table 3.

5.2 Pharmacokinetic Properties

The impact of ethnic factors on the pharmacokinetics of drospirenone and ethinylestradiol was studied after single and repeated daily oral administration to young healthy Caucasian and Japanese women. The results showed that ethnic differences between Japanese and Caucasian women had no clinically relevant influence on the pharmacokinetics of drospirenone and ethinylestradiol.

Drospirenone.

Absorption.

Orally administered drospirenone is rapidly and almost completely absorbed. Maximum concentrations of the drug in serum of about 35 nanogram/mL are reached at approximately 1-2 h after single ingestion. Bioavailability is between 76 and 85%. The intake of food had no influence on the extent of absorption but the maximum concentration was reduced as compared to drug intake on an empty stomach.

Distribution.

After oral administration, serum drospirenone levels decrease in two phases which are characterised by half-lives of 1.6 ± 0.7 h and 27.0 ± 7.5 h, respectively. Drospirenone is bound to serum albumin and does not bind to SHBG or corticoid binding globulin (CBG). Only 3-5% of the total serum drug concentrations are present as free steroid. The ethinylestradiol induced increase in SHBG does not influence the serum protein binding of drospirenone. The mean apparent volume of distribution of drospirenone is 3.7 ± 1.2 L/kg.

Metabolism.

Drospirenone is extensively metabolised after oral administration. The major metabolites in the plasma are the acid form of drospirenone, generated by opening of the lactone ring, and the 4,5-dihydro-drospirenone-3-sulfate, formed by reduction and subsequent sulfation. Drospirenone is also subject to oxidative metabolism catalysed by cytochrome P450 3A4 and has demonstrated a capacity to inhibit this enzyme and cytochrome P450 1A1, cytochrome P450 2C9 and cytochrome P450 2C19 in vitro.

Excretion.

The metabolic clearance rate of drospirenone in serum is 1.5 ± 0.2 mL/min/kg. Drospirenone is excreted only in trace amounts in unchanged form. The metabolites of drospirenone are excreted with the faeces and urine at an excretion ratio of about 1.2 to 1.4. The half-life of metabolite excretion with the urine and faeces is approximately 40 h.

Steady-state conditions.

During a treatment cycle, maximum steady-state concentrations of drospirenone in serum of about 60 nanogram/mL are reached between day 7 and day 14 of treatment. Serum drospirenone levels accumulated by a factor of about 2 to 3 as a consequence of the ratio of terminal half-life and dosing interval. Further accumulation of drospirenone levels beyond treatment cycles was observed between cycles 1 and 6 but thereafter, no further accumulation was observed.

Special populations.

Effect of renal impairment.

Steady-state serum drospirenone levels in women with mild renal impairment (creatinine clearance CLcr, 50-80 mL/min) were comparable to those of women with normal renal function (CLcr, > 80 mL/min). The serum drospirenone levels were on average 37% higher in women with moderate renal impairment (CLcr, 30-50 mL/min) compared to those in women with normal renal function. Drospirenone treatment was well tolerated by all groups. Drospirenone treatment did not show any clinically significant effect on serum potassium concentration.

Effect of hepatic impairment.

In women with moderate impairment of hepatic function (Child-Pugh B), mean serum drospirenone concentration-time profiles were comparable to those of women with normal hepatic function during the absorption/ distribution phases with similar Cmax values. The mean terminal half-life of drospirenone for the volunteers with moderate hepatic impairment was 1.8 times greater than for the volunteers with normal hepatic function.
About 50% decrease in apparent oral clearance (CL/F) was seen in volunteers with moderate hepatic impairment as compared to those with normal liver function. The observed decline in drospirenone clearance in volunteers with moderate hepatic impairment compared to normal volunteers did not translate into any apparent difference in terms of serum potassium concentrations between the two groups of volunteers. Even in the presence of diabetes and concomitant treatment with spironolactone (2 factors that can predispose a patient to hyperkalaemia) an increase in serum potassium concentrations above the upper limit of the normal range was not observed. It can be concluded that drospirenone is well tolerated in patients with mild or moderate hepatic impairment (Child-Pugh B).

Ethinylestradiol.

Absorption.

Orally administered ethinylestradiol is absorbed rapidly and completely. Peak serum concentrations of approximately 88 to 100 picogram/mL are reached within 1-2 hours after single oral administration. Absolute bioavailability as a result of presystemic conjugation and first pass metabolism is approximately 60%. Concomitant intake of food had a variable effect. The maximum concentration was reduced in all subjects and the bioavailability of ethinylestradiol was reduced in about 25% of the investigated subjects.

Distribution.

Serum ethinylestradiol levels decrease in two phases, the terminal disposition phase is characterised by a half-life of approximately 24 hours. 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 of ethinylestradiol is approximately 5 mL/min/kg.

Elimination.

Ethinylestradiol is not excreted in unchanged form to any significant extent. The metabolites of ethinylestradiol 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 and serum levels of ethinylestradiol accumulate by a factor of about 1.4 to 2.1.

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 in vitro (clastogenic effects were not consistently seen and occurred at high concentrations). In vivo studies did not confirm these results.
Drospirenone was found to induce chromosome aberrations in human peripheral lymphocytes. However, drospirenone was not mutagenic in bacterial and mammalian cell gene mutation assays in vitro, and was not clastogenic in mouse micronucleus assays in vivo. Interactions between drospirenone and the DNA of liver cells which indicate a genotoxic potential were found in in vitro and in vivo studies in rats. No such finding was observed in human liver cells in vitro.

Carcinogenicity.

Long-term carcinogenicity studies were performed in mice and rats with drospirenone, ethinylestradiol and with a combination of both products. After 2 years oral treatment of mice and rats with drospirenone alone there were no increases in the incidence of neoplastic lesions. Exposure to drospirenone (based on AUC) was up to 3-fold (mice) and 8-fold (rats) than that anticipated in humans at the recommended clinical dose. In contrast, treatment with the combination of drospirenone and ethinylestradiol resulted in an increased rate of neoplastic lesions in the mammary glands and uteri of mice and rats and in the pituitary glands of mice. The tumour pattern was similar but the incidence increased even further in animals receiving ethinylestradiol alone, indicating that ethinylestradiol was responsible for the increase in neoplastic lesions. Coadministration of drospirenone decreased the carcinogenic potential of ethinylestradiol in the mouse pituitary and in the mouse and rat uterus and mammary gland.
The ethinylestradiol induced tumours in rodents have previously been seen with other ethinylestradiol containing products, and are considered attributable to species specific effects of estrogens on prolactin secretion in rodents.
Although long-term animal studies did not definitively indicate a tumourigenic potential for the clinical use of either drospirenone or ethinylestradiol, it should be borne in mind that sex steroids can promote the growth of certain hormone dependent tissues and tumours.

4 Clinical Particulars

4.1 Therapeutic Indications

Yaz is indicated for use as:
an oral contraceptive;
treatment of moderate acne vulgaris in women who seek oral contraception;
treatment of symptoms of premenstrual dysphoric disorder (PMDD) in women who have chosen oral contraceptives as their method of birth control. The efficacy of Yaz for PMDD was not assessed beyond 3 cycles. Yaz has not been evaluated for treatment of PMS (premenstrual syndrome) (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.3 Contraindications

Combined hormonal contraceptives (CHCs) including Yaz 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 CHC 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 venous thromboembolism, 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 venous thromboembolism 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 or stroke) or prodromal condition (e.g. angina pectoris or transient ischaemic attack [TIA]);
known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and antiphospholipid-antibodies (e.g. anticardiolipin-antibodies and lupus anticoagulant);
history of migraine with focal neurological symptoms;
a high risk of arterial thromboembolism 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.
Severe renal insufficiency or acute renal failure.
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).
Undiagnosed vaginal bleeding.
Known or suspected pregnancy.
Hypersensitivity to any of the ingredients contained in Yaz.

4.4 Special Warnings and Precautions for Use

If any of the conditions/ risk factors mentioned below are present, the benefits of Yaz 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 Yaz should be discontinued.

Circulatory disorders.

Epidemiological studies have suggested an association between the use of combined oral contraceptives (COCs) containing ethinylestradiol and an increased risk of arterial and venous thrombotic and thromboembolic diseases such as myocardial infarction, stroke, deep venous thrombosis, and pulmonary embolism. 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, multinational, cohort study (EURAS and LASS) on the safety of OC use, suggests that this increased risk is mainly present during the first 3 months.
Two prospective cohort studies (EURAS and Ingenix), each evaluating the risk of venous and arterial thromboembolism and death, were initiated separately at the time of ethinylestradiol/drospirenone 30 microgram/3 mg approval in Europe and the United States. The first (EURAS) showed the risk of thromboembolism (particularly venous thromboembolism) and death in ethinylestradiol/drospirenone 30 microgram/3 mg users to be comparable to that of other oral contraceptive preparations, including those containing levonorgestrel (a so called second generation COC).
In the EURAS study, the VTE incidence rate for all OC users ranged from 8.0 to 9.9 per 10,000 WY. The overall incidence rate for past OC users was 4.7 VTE/10,000 WY, which was further specified to 19.4 VTE/10,000 WY for pregnant past OC users and 2.3 VTE/10,000 WY for nonpregnant past OC users. The second prospective cohort study (Ingenix) also showed a comparable risk of thromboembolism in ethinylestradiol/drospirenone 30 microgram/3 mg users compared to users of other COCs, including those containing levonorgestrel. In this second study, COC comparator groups were selected based on their having similar characteristics to those being prescribed ethinylestradiol/drospirenone 30 microgram/3 mg.
Another large population based study (Heit et al.) found an incidence rate of 20 VTE/10,000 WY in pregnant or postpartal women and 4.6 in nonpregnant women of reproductive age. All of these rates tend to be higher than those reported in the past.
Based on this data it can be assumed that the VTE risk in users of OC users is roughly twice as high for nonpregnant non-OC users. The absolute attributable risk (approximately 4 VTEs per 10,000 WY of use) was found to be slightly higher in these studies than reported in the past. Nevertheless the risk in OC users remains lower than the VTE risk associated with pregnancy and the first weeks following delivery.
Two additional epidemiological studies, one case control study (van Hylckama Vlieg et al.) and one retrospective cohort study (Lidegaard et al., 2009) suggested that the risk of venous thromboembolism occurring in ethinylestradiol/ drospirenone 30 microgram/3 mg users was higher than that for users of levonorgestrel containing COCs and lower than that for users of desogestrel/ gestodene containing COCs (so called third generation COCs). In the case control study, however, the number of ethinylestradiol/ drospirenone 30 microgram/3 mg cases was very small (1.2% of all cases making the risk estimates unreliable). The relative risk for ethinylestradiol/ drospirenone 30 microgram/3 mg users in the retrospective cohort study was greater than that for users of other COC products when considering women who used the products for less than one year. However, these one year estimates may not be reliable because the analysis may include women of varying risk levels. Among women who used the products for 1 to 4 years, the relative risk was similar for users of ethinylestradiol/ drospirenone 30 microgram/3 mg to that of other COC products.
Two further retrospective database studies (Parkin et al., Jick and Hernandez) published in 2011, suggested a greater risk for VTE in users of drospirenone containing COCs compared to levonorgestrel containing COCs. However, the number of drospirenone cases in the Parkin et al. study was very small.
It is important that women understand that VTE associated with CHC use is rare in average-risk women. The risk in pregnancy (5-20 per 10,000 women over 9 months) and the risk in the post-partum period (45-65 per 10,000 women over 12 weeks) is higher than that as associated with CHC use.
Drospirenone containing COCs may be associated with a higher risk of VTE than COCs containing the progestogen levonorgestrel or some other progestogens. Epidemiologic studies that compared the risk of VTE reported that the risk ranged from no increase to a three-fold increase.
An additional increase in VTE risk for CHCs containing ≥ 50 microgram ethinylestradiol cannot be excluded.
The decision to use any product other than one with the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with CHCs, and how her current risk factors influence this risk.
The increased risk of VTE during the postpartum period must be considered if re-starting Yaz. See Section 4.2 Dose and Method of Administration; Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy and Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation.
VTE may be life threatening or may have a fatal outcome (in 1-2% of cases).
Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral or retinal veins and arteries.
The risk for venous thromboembolic complications in CHC users may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see list below).
Yaz 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 (venous thromboembolism 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 Yaz (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 Yaz 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 venous thromboembolism.

Symptoms of VTE (deep vein thrombosis and pulmonary embolism).

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 deep vein thrombosis (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 pulmonary embolism (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 discolouration 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 arterial thromboembolism (e.g. myocardial infarction, 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. Yaz 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 (arterial thromboembolism 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; 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.

Symptoms of ATE.

Women should be informed of the symptoms of ATE and be advised to seek urgent medical attention if ATE symptoms develop and to inform the healthcare professional that she is taking a CHC.
Symptoms of a stroke can include:
sudden numbness or weakness of the face, arm or leg, especially on one side of the body;
sudden trouble walking, dizziness, loss of balance or coordination;
sudden confusion, slurred speech or aphasia;
sudden partial or complete loss of vision; diplopia;
sudden, severe or prolonged headache with no known cause;
loss of consciousness or fainting with or without seizure.
Temporary symptoms suggest the event is a transient ischaemic attack (TIA).
Symptoms of myocardial infarction (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 may have a fatal outcome.

Other conditions.

Potassium excretion capacity may be limited in patients with renal insufficiency. In a clinical study, drospirenone intake did not show an effect on the serum potassium concentration in patients with mild or moderate renal impairment. A theoretical risk for hyperkalaemia can be assumed only for patients whose pretreatment serum potassium is in the upper reference range and who are additionally using potassium sparing medicines.
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. The antimineralocorticoid effect of drospirenone may counteract ethinylestradiol induced increases in blood pressure observed in normotensive women taking other combined oral contraceptives. 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; otosclerosis related hearing loss.
In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.
Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. Recurrence of cholestatic jaundice which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of COCs.
Although COCs may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics taking low dose COCs (containing < 50 microgram ethinylestradiol). However, diabetic women should be carefully observed while taking COCs.
Crohn's disease and ulcerative colitis have been associated with COC use.
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking COCs.
Each light pink active tablet contains 48.18 mg of lactose monohydrate and each white placebo tablet contains 23.21 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 COC use, guided by the contraindications and warnings, and should be repeated at least annually during the use of COCs. 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 acquired immune deficiency syndrome (AIDS).

Women should be advised that oral contraceptives do not protect against HIV infections (AIDS) and other STIs. Women should be advised that additional barrier contraceptive measures are needed to prevent transmission of STIs.

Reduced efficacy.

The efficacy of COCs may be reduced in the event of missed light pink active tablets, gastrointestinal disturbances during active tablet taking or concomitant medication (see Section 4.2 Dose and Method of Administration and Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). The more light pink active tablets are missed and the closer they are to the white placebo tablet phase the higher the risk of a pregnancy.

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 prior to the first missed withdrawal bleed or if two withdrawal bleeds are missed, pregnancy must be ruled out before COC use is continued.
In women who choose to use Yaz with a continuous regimen, withdrawal bleeding is not expected to occur during the extension period when active tablet taking is uninterrupted. Therefore, the absence of withdrawal bleeding cannot be used as a sign of an unexpected pregnancy and as such, unexpected pregnancy may be difficult to recognise. This may be of particular importance to women using teratogenic drugs. Although pregnancy is unlikely if Yaz is taken as directed, if for any reason, pregnancy is suspected, a pregnancy test should be performed.

Use in hepatic impairment.

Yaz is contraindicated in women with severe hepatic disease as long as liver function values have not returned to normal (see Section 4.3 Contraindications).

Use in renal impairment.

Yaz is contraindicated in women with severe renal insufficiency or acute renal failure (see Section 4.3 Contraindications).

Use in the elderly.

Yaz is not indicated after menopause.

Paediatric use.

Yaz is only indicated after menarche.

Effects on laboratory tests.

The use of contraceptive steroids 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. Drospirenone causes an increase in plasma renin activity and plasma aldosterone induced by its mild anti-mineralocorticoid activity.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effects of other medicines on Yaz.

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 oral 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 the COC 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 in which the barrier method is used runs beyond the end of the active tablets in the COC pack, the white placebo tablets should be omitted and the next COC pack started.

Substances increasing the clearance of COCs (diminished efficacy of COCs 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 COCs.

When coadministered with COCs, many HIV/ hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors can increase or decrease plasma concentrations 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 by 1.4 to 1.6-fold respectively, when taken concomitantly with a COC containing 35 microgram ethinylestradiol.

Effects of COCs on other medicines.

COCs may affect the metabolism of certain other medicines. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporin) or decrease (e.g. lamotrigine).
Based on in vitro inhibition studies and in vivo interaction studies in female volunteers taking omeprazole, simvastatin or midazolam as a marker substrates, an interaction of drospirenone at doses of 3 mg, with the cytochrome P450 mediated metabolism of other medicines is unlikely.
In clinical studies, administration of a hormonal contraceptive containing ethinylestradiol led to no, or a weak increase in CYP3A4 substrates (e.g. midazolam) and a weak (e.g. theophylline) to moderate (e.g. melatonin, tizanidine) increase in CYP1A2 substrates.

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).

Other interactions.

There is a theoretical potential for an increase in serum potassium in women taking Yaz with other medicines that may increase serum potassium levels. Such medicines include angiotensin II receptor antagonists, potassium sparing diuretics and aldosterone antagonists. However, in studies evaluating the interaction of drospirenone (combined with oestradiol) with an ACE inhibitor or indomethacin, no clinically or statistically significant differences in serum potassium concentrations were observed.

Note.

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

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category B31)
Drospirenone and/or its metabolites crossed the placenta and entered the foetus when administered orally to pregnant rats and rabbits. Treatment of pregnant rats with a combination of drospirenone and ethinylestradiol resulted in a dose dependent increased incidence of embryolethality due to increased preimplantation and postimplantation losses. There was no indication of teratogenic effects of drospirenone in rats or rabbits.
Dose dependent feminisation of male foetuses and virilisation of female foetuses were seen following administration of a combination of drospirenone and ethinylestradiol to female rats in the last third of pregnancy. Feminising effects in male foetuses were consistent with drospirenone's antiandrogenic activity and were observed at an estimated systemic exposure approximately 8-13-fold than that anticipated clinically (based on AUC). Virilisation of female foetuses was seen following systemic drospirenone exposure of approximately 2 to 5-fold than that anticipated clinically (based on AUC). This effect has previously been described for estrogens in rats. When pregnant monkeys received a combination of drospirenone and ethinylestradiol by daily oral administration during the major period of organogenesis and sexual organ differentiation, abortion rates were increased in a dose dependent manner. However, there were no indications of teratogenicity.
Extensive epidemiological studies have revealed neither an increased risk of birth defects in children born to women who take COCs prior to pregnancy, nor a teratogenic effect when COCs were taken inadvertently during early pregnancy. Yaz is contraindicated during pregnancy. Pregnancy should be ruled out before the start of therapy. Should pregnancy occur during the use of Yaz, the preparation must be discontinued immediately (see Section 4.3 Contraindications).
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.
Lactation may be influenced by COCs as they may reduce the quantity and change the composition of breast milk. Small amounts of the contraceptive steroids and/or their metabolites may be excreted in the milk. Therefore, the use of COCs should generally not be recommended until the nursing mother has completely weaned her child.

4.8 Adverse Effects (Undesirable Effects)

The most serious adverse reactions associated with the use of oral contraceptives are indicated under Section 4.4 Special Warnings and Precautions for Use (see Section 4.3 Contraindications).

Clinical trial data.

Adverse drug reactions which have been associated with the use of Yaz as an oral contraceptive or in the treatment of moderate acne vulgaris. (See Table 1.)
In addition, the following undesirable effects have been reported in users of COCs and the association has been neither confirmed nor refuted.
Common: breast tenderness. Uncommon: breast hypertrophy, fluid retention. Rare: vaginal discharge, breast discharge, contact lens intolerance.
In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.
Erythema multiforme has been reported in postmarketing surveillance. The frequency cannot be estimated from the available data and is therefore unknown.

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 http://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. The failure rate may increase when pills are missed or taken incorrectly.
Tablets must be taken in the order directed on the package every day at about the same time with some liquid as needed. Tablet taking is continuous. One tablet is taken daily for 28 consecutive days. Each subsequent pack is started the day after the last tablet of the previous pack. A withdrawal bleed usually starts on day 2-3 after starting the white placebo tablets and may not have finished before the next pack is started.

How to start Yaz.

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). The women should be instructed to take a light pink active tablet from the green section of the pack, corresponding to that day of the week. If started on day 1 in this way, protection against pregnancy is immediate and no additional methods of contraception are required.
Starting on days 2-5 of the menstrual cycle is allowed, but during the first 7 days of the first cycle, a barrier method is recommended in addition to tablet taking.

Changing from another combined hormonal contraceptive (combined oral contraceptive/COC) or vaginal ring.

The woman should start with Yaz preferably on the day after the last active tablet of her previous COC, but at the latest on the day following the usual tablet free or placebo tablet interval of her previous COC. Yaz should be started by taking a light pink active tablet from the green section of the pack.
In case a vaginal ring has been used, the woman should start taking Yaz preferably on the day of removal of the ring, but at least when the next application would have been due.

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 IUS on the day of its removal or from an injectable when the next injection would be due. However, in all of these cases the woman must be advised to additionally use a barrier method for the first 7 days of tablet taking.

Following first trimester abortion.

The woman may start tablet taking immediately. When doing so, she need not take additional contraceptive measures.

Following delivery or second trimester abortion.

Women should be advised to start at day 21 to 28 after delivery or second trimester abortion. When starting later, the woman should be advised to additionally use a barrier method for the first 7 days of tablet taking. However, 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.
For breastfeeding women see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation.

Management of missed tablets.

Missed white pills from the last row of the blister are placebo tablets and thus can be disregarded. However they should be discarded to avoid unintentionally prolonging the placebo tablet phase.
The risk of pregnancy increases with each light pink tablet missed. The following advice only refers to missed light pink active tablets.
If the woman is less than 24 hours late in taking any light pink 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 24 hours late in taking any light pink active tablet, contraceptive protection may be reduced. The management of missed tablets can be guided by the following two basic rules.
1. The placebo tablet interval for Yaz is 4 days. Active tablet taking must never be discontinued for longer than 7 days. Please note: Yaz is registered in Australia for use as a contraceptive using a continuous 28 day regimen consisting of 24 active tablets followed by 4 inactive tablets; the stated efficacy in preventing pregnancy is based on this regimen.
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.

Day 1-7.

The woman should take the last missed light pink active tablet as soon as she remembers, even if this means taking two light pink active tablets at the same time. She then continues to take tablets at her usual time. In addition, a barrier method such as a condom should be used for the next 7 days.
If intercourse took place in the preceding 7 days, the possibility of a pregnancy should be considered. The more light pink active tablets are missed and the closer they are to the white placebo tablet phase the higher the risk of a pregnancy.

Days 8-14.

The woman should take the last missed light pink active tablet as soon as she remembers, even if this means taking two light pink 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 light pink 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 light pink active tablet, the woman should be advised to use extra precautions for 7 days.

Day 15-24.

The risk of reduced reliability is imminent because of the forthcoming placebo tablet phase. 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 light pink active tablet the user has taken all tablets correctly. If this is not the case, the user 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 missed light pink active tablet as soon as she remembers, even if this means taking two light pink active tablets at the same time. She then continues to take tablets at her usual time until all the light pink active tablets are taken. The 4 white placebo tablets from the last row must be discarded. The next pack must be started right away. The user 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 4 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.

How to delay a withdrawal bleed.

Use of continuous ethinylestradiol and drospirenone without placebo tablets for up to three packs is associated with similar efficacy in terms of contraception. There is no data on the efficacy of this regimen on acne or PMDD.
During the extension period, the woman may experience breakthrough bleeding or spotting. This is best managed by taking the placebo tablets to induce a withdrawal bleed than continuing active tablets. If the woman wishes to resume the 28 day dosing cycle, this may be done following the placebo tablet phase and starting a new pack.
There is no data about the long term safety of this regimen in terms of risk of VTE, endometrial safety, or cancer.

Advice in case of gastro-intestinal disturbances.

In case of severe gastro-intestinal disturbances, absorption may not be complete and additional contraceptive measures should be taken.
If vomiting occurs within 3-4 hours after tablet taking, absorption may not be complete. In such an event, the advice concerning missed tablets, (see above), 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 has not yet been any clinical experience of overdose with Yaz. On the basis of general experience with COCs, symptoms that may occur in case of overdose of active tablets are: nausea, vomiting and withdrawal bleeding. The last may even occur in girls before their menarche, if they have accidentally taken the medicinal product. 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. Contraception 2007; 75:344-54.
2. Long-term Active Surveillance Study for oral contraceptives (LASS), 2nd update report based on study status May 2009.
3. Seeger JD, Loughlin J, Eng PM, Clifford CR, Cutone J, Walker AM. Risk of thromboembolism in women taking ethinlyestradiol/ drospirenone and other oral contraceptives. Obstet Gynecol 2007; 100: 587-593.
4. Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton LJ. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30 year population based study. Ann Intern Med 2005; 143:697-706.
5. Lidegaard O, Lokkegaard E, Svendsen AL, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow up. BMJ 2009; 339:b2890.
6. Van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen CJM, Rosendaal FR. Effects of estrogen dose and progestogen type on venous thrombotic risk associated with oral contraceptives: results of the MEGA case-control study. BMJ 2009; 339:b2921.
7. Parkin L, Sharples K, Hernandez RK, Jick SS. Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel nested case-control study based on UK General Practice Research Database. BMJ 2011; 340:d2139.
8. Jick SS, Hernandez RK. Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data. BMJ 2011; 340:d2151.
9. Lidegaard O, Nielsen LH, Skovlund CW, Skjeldestad FE, Lokkegaard, E. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and estrogen doses: Danish cohort study, 2001-9. BMJ 2011; 343:d6423.
10. FDA 2011 Ouellet-Hellstrom R, Graham DJ, Staffa JA, Sidney S, Cheetham TC, Cooper WO, Connell, F. Combined hormonal contraceptives (CHCs) and the risk of cardiovascular disease endpoints. CHC-CVD Final Report 111022v2 (available at http://www.fda.gov/downloads/drugs/drugsafety/ucm277384.pdf, addendum available at http://www.fda.gov/downloads/drugs/drugsafety/ucm287762.pdf).
11. Dinger J, Bardenheuer K, Heinemann K. Cardiovascular and general safety of a 24-day regimen of drospirenone-containing combined oral contraceptives: Final results from the international active surveillance study of women taking oral contraceptives. Contraception 2014; 89(4):253-63.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each light pink active tablet contains: lactose monohydrate, maize starch, magnesium stearate, hypromellose, purified talc, titanium dioxide and iron oxide red.
Each white placebo tablet contains: lactose monohydrate, microcrystalline cellulose, magnesium stearate, hypromellose, purified talc and titanium dioxide.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Yaz tablets are supplied in PVC/Aluminium blister packs. Each blister contains 24 light pink tablets followed by 4 white placebo tablets.
Cartons contain memo packs of 1 x 28, 2 x 28, 3 x 28, 4 x 28 or 6 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