Consumer medicine information

Yaz Flex

Ethinyloestradiol; Drospirenone

BRAND INFORMATION

Brand name

Yaz Flex Tablets

Active ingredient

Ethinyloestradiol; Drospirenone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Yaz Flex.

WHAT IS IN THIS LEAFLET

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

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

YAZ Flex is used to prevent pregnancy.

It is also used to treat moderate acne in women seeking oral contraception.

You may also experience the following benefits:

  • improvement in symptoms like bloating, swelling or weight gain related to fluid retention
  • fewer bleeding/spotting days
  • a decrease in anaemia (iron deficiency)
  • a decrease in period pain.

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 various 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.

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 Flex is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted infections.

This means that with YAZ Flex, you may not have a menstrual period every month for up to 4 months. When you start to take YAZ Flex, you must take one tablet daily for 24 days without a tablet free break. This is called the fixed phase.

YAZ Flex allows you to schedule when you want to have your period. You can choose to take a 4 day tablet free break (have your period) during day 25 - 120. This is called the flexible phase.

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 FLEX

When you must not take it

Do not take YAZ Flex if you have an allergy to

  • drospirenone
    and/or ethinyloestradiol , the active ingredients in YAZ Flex
  • 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 Flex 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 Flex 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 Flex if you have or are concerned about or have 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 Flex 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 Flex 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 open the foil containing the cartridge of YAZ Flex tablets until you have a CLYK device and are ready to take your first Pill.

Once opened, the tablets last 40 days, so any unused tablets should be disposed of after this time.

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:

  • depression
  • 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 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 angioedema - you should see your doctor immediately if you experience symptoms of angio-oedema, such as swollen face, tongue and/or pharynx and/or difficulty swallowing, or hives together with difficulty in breathing.

If any of the above conditions appear for the first time, or recur or worsen while taking YAZ Flex, you should tell your doctor.

Tell your doctor if you are breastfeeding.

YAZ Flex is generally not recommended if you are breastfeeding.

YAZ Flex contains lactose.

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

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

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 Flex 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, itraconazole, voriconazole, fluconazole
  • 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
  • some medicines used to treat high blood pressure, chest pain, or irregular heartbeats such as verapamil, diltiazem
  • herbal medicines containing St John’s Wort
  • grapefruit juice.

These medicines may be affected by YAZ Flex, or may affect how well it works. Your doctor may need to alter the dose of these medicines, or prescribe a different medicine.

You might have an increase in potassium in the blood if you are taking YAZ Flex 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 significantdifferences 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 about 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 FLEX

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet. The information contained in this leaflet tells you how you should take the Pill.

A separate set of instructions is enclosed with the CLYK tablet dispenser. Please follow these instructions carefully on how to use the CLYK tablet dispenser.

The CLYK tablet dispenser is a dispensing system for YAZ Flex; it tells you when it is time to take your Pill and helps you keep track of your intake regimen.

If you do not understand the instructions provided, ask your doctor or pharmacist for help.

How to take it

Take your first YAZ Flex tablet by dispensing the Pill from the CLYK tablet dispenser.

Insert the narrow end of the cartridge into the dispenser so that the tablets in the cartridge can be seen through the window of the dispenser (see Fig. 1).

Fig. 1: Preparing the CLYK tablet dispenser for use

Note: There is a grey coloured disc on top of the pink YAZ Flex tablets in the cartridge. This is not a tablet. It is a plastic stopper that is part of the cartridge unit.

Unpack and insert the cartridge on the day you want to start taking your Pill.

Make sure the day and time you release your first Pill is convenient for you.

The dispenser will automatically record when the first tablet is released by setting this time as the reference time.

Slowly press the two soft sides of the dispenser, firmly and completely (at the Bayer logo), at the same time to release the tablet.

Take one tablet daily at about the same time every day. You must take YAZ Flex every day regardless of how often you have sex. This will also help you remember when to take it. Take the tablets for the first 24 days (fixed phase) without a tablet free break.

A 4 day tablet free break can be taken between the flexible phase - days 25 - 120. A tablet free break should not be longer than 4 days.

A 4 day tablet free interval must be taken after taking the Pill for 120 consecutive days.

After each 4 day tablet free interval, a new cycle of Pill taking starts with a minimum of 24 days and a maximum of 120 days.

Swallow the tablet whole with a full glass of water.

It does not matter if you take it before or after food.

If you see an exclamation mark symbol (!) on the CLYK tablet dispenser screen, this means you must use additional barrier contraceptive precautions (e.g. condoms, diaphragm) until this symbol (!) disappears.

If you do not understand the instructions ask your doctor or pharmacist for help.

When to take it

If you are starting YAZ Flex 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 Flex after having a baby
  • have had a miscarriage or an abortion.

Changing from a combined oral contraceptive:
Start taking YAZ Flex on the day after taking the last placebo tablet in your previous Pill pack.

Changing from a vaginal ring:
Start taking YAZ Flex on the day after the removal is due.

Changing from a progestogen-only pill:
Stop taking the minipill on any day and start taking YAZ Flex 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 YAZ Flex 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.

Stopping YAZ Flex

You can stop taking YAZ Flex 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 Flex and not stop until your doctor advises this. Ask your doctor or pharmacist about suitable supplements. It is both safe and recommended that you take folic acid during pregnancy.

If you forget to take 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.The CLYK tablet dispenser will guide you through what to do in this situation. If you want further information follow these instructions:

For YAZ Flex to be effective, the tablets need to be taken uninterrupted for 7 days.

FIXED PHASE: Days 1 – 7

If you miss one or more YAZ Flex tablets during the first 7 days of tablet taking, take the last missed tablet as soon as you remember, even if this means taking two YAZ Flex tablets at the same time. Then, take the next tablet at the usual time when the CLYK prompts you. Use extra contraceptive precautions (barrier method such as a condom) for the next 7 days. If you had sexual intercourse in the week before missing the tablets, there is a possibility of becoming pregnant. Tell your doctor immediately.

The chance of pregnancy after missing a YAZ Flex tablet depends on when you missed the tablet. There is a higher risk of becoming pregnant if you miss a tablet at the beginning of a cycle or directly before or directly after a 4 day tablet free break.

FIXED PHASE: Days 8 – 24

If you miss one or more YAZ Flex tablets during days 8 – 24 of tablet taking, take the last missed YAZ Flex tablet as soon as you remember, even if this means taking two YAZ Flex tablets at the same time. Then, take the next tablet at the usual time when the CLYK prompts you. Use additional contraceptive precautions if the CLYK prompts you.

FLEXIBLE PHASE:
Days 25 - 120

If you have missed one or more YAZ Flex tablets during days 25 – 120, you can choose either option:

  1. Take the last missed tablet as soon as you remember, even if it means taking two YAZ Flex tablets at the same time. Then, take the next tablet at the usual time when the CLYK prompts you until you have taken at least 7 YAZ Flex tablets in a row without interruption.
  2. You can stop taking your Pill, take a 4 day tablet free break, including the days where tablets were missed, and then continue with a new cycle of YAZ Flex. The total tablet free break should be no longer than 4 days. The CLYK may prompt you to use additional contraceptive precautions. It is important that you follow this advice.

If you have forgotten to take your tablets and you do not have your expected menstrual bleed (that should start while having a 4 day Pill free break), you may be pregnant. Contact your doctor before you continue tablet-taking.

Please see the end of this leaflet for “Summary of advice if you missed a 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) 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 Flex.

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 FLEX

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 Flex.

Stop taking YAZ Flex 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 Flex, 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 Flex 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 Flex – 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 YAZ Flex tablet, the active ingredients may not have been completely absorbed. This is like missing a tablet. Follow the advice for missed tablets.

In the event of spotting and/or bleeding on three consecutive days during the flexible phase (days 25 – 120), it is recommended to take the 4 day tablet free interval.

This will reduce the total number of days with bleeding.

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), even during the fixed phase of the cycle between days 1 – 24. 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 tablets at the right time
  • you have not been taking medicine(s) that may interfere with YAZ Flex
  • you have not vomited or had severe diarrhoea during this cycle.

If this is so, continue to take YAZ Flex 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 Flex 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.

YAZ Flex 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 Flex 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 Flex, 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 Flex.

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
  • decrease and loss of libido
  • 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 bad fainting attack, or you collapse
  • unusual headaches or migraines that are worse than usual
  • sudden problems with your speech 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 notice anything else that is making you feel unwell.

Other side effects not listed on the following pages 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 risk of a blood clot is highest during the first year of taking the Pill for the first time, or when re-starting after having a break from the Pill for 4 weeks or more.

If you notice possible signs of a blood clot, stop taking YAZ Flex 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 Flex, 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 FLEX

Storage

Keep the YAZ Flex cartridge in the blister foil until you have a CLYK device and are ready to start taking your Pill.

Once the cartridge is taken out of the foil, YAZ Flex tablets only keep for 40 days, including the time they are in the CLYK device.

Any unused tablets must be disposed of after this time.

Keep your tablets and the CLYK device 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 Flex 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 Flex is available in dispenser packs containing either 1, 3 or 4 refills. Each dispenser pack contains 30 light pink tablets.

Ingredients

Each YAZ Flex light pink tablet contains:

Active ingredients:

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

Inactive ingredients:

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

YAZ Flex 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

Australian Registration Number

YAZ Flex - AUST R 179878

Date of Preparation

February 2018

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

Summary of advice if you missed a tablet more than 24 hours ago.

Always follow the instructions given on the screen of your CLYK tablet dispenser.

If you see an exclamation mark symbol (!) on the CLYK tablet dispenser screen, this means you must use additional barrier contraceptive precautions (e.g. condoms, diaphragm) until this symbol (!) disappears.

If you are concerned, contact your doctor or pharmacist for advice. In addition, you may contact Bayer Medical Information on 1800 673 270.

BRAND INFORMATION

Brand name

Yaz Flex Tablets

Active ingredient

Ethinyloestradiol; Drospirenone

Schedule

S4

 

Name of the medicine

Drospirenone 3 mg and ethinyloestradiol (as betadex clathrate) 20 microgram.

Excipients.

Lactose, maize starch, magnesium stearate, hypromellose, purified talc, titanium dioxide and iron oxide red.

Description

Ethinyloestradiol.

Chemical name: 19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3, 17β-diol. Molecular formula: C20H24O2. MW: 296.41. CAS: 57-63-6. Ethinyloestradiol 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.

Drospirenone.

Chemical name: 6β, 7β, 15β, 16β-dimethylene-3-oxo-17α-pregn-4-ene-21, 17-carbolactone. Molecular formula: C24H30O3. MW: 366.50. CAS: 67392-87-4. Drospirenone is a white to off white crystalline powder. It is freely soluble in methylene chloride, soluble in acetone, methanol, sparingly soluble in ethylacetate and ethanol 96% (v/v) and practically insoluble in hexane and water.
Yaz Flex is a combined oral contraceptive (COC) tablet containing the synthetic progestogen, drospirenone and the synthetic oestrogen, ethinyloestradiol (as betadex clathrate).
Ethinyloestradiol betadex-clathrate is an inclusion complex of the compendially described substances ethinyloestradiol and betadex and when dissolved in water it dissociates into the active moiety ethinyloestradiol and the ligand betadex.
Each Yaz Flex tablet contains drospirenone 3 mg and ethinyloestradiol (as betadex clathrate) 20 microgram and the excipients: lactose, maize starch, magnesium stearate, hypromellose, purified talc, titanium dioxide and iron oxide red.

Pharmacology

Pharmacodynamic properties.

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 Precautions, Adverse 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 oestrogen related sodium retention. In combination with ethinyloestradiol, drospirenone displays a favourable lipid profile with an increase in high density lipoprotein (HDL). Drospirenone exerts antiandrogenic activity. Drospirenone does not counteract the ethinyloestradiol related sex hormone binding globulin (SHBG) increase which is useful for binding and inactivating the endogenous androgens.
Drospirenone is devoid of any androgenic, oestrogenic, 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 ethinyloestradiol), 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 Flex remains to be confirmed.
The flexible extended cycle oral contraceptive regimen of Yaz Flex may reduce bleeding associated problems such as dysmenorrhoea, headache and breast tenderness.

Pharmacokinetics.

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 about 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 ethinyloestradiol 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.

Elimination.

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 about 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.

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).

Ethnic groups.

The impact of ethnic factors on the pharmacokinetics of drospirenone and ethinyloestradiol 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 ethinyloestradiol.

Ethinyloestradiol.

Absorption.

Orally administered ethinyloestradiol is absorbed rapidly and completely. Peak serum concentrations of about 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 ethinyloestradiol was reduced in about 25% of the investigated subjects.

Distribution.

Serum ethinyloestradiol levels decrease in two phases, the terminal disposition phase is characterised by a half-life of approximately 24 hours. Ethinyloestradiol 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 about 5 L/kg was determined.

Metabolism.

Ethinyloestradiol is subject to presystemic conjugation in both small bowel mucosa and the liver. Ethinyloestradiol 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 ethinyloestradiol is approximately 5 mL/min/kg.

Elimination.

Ethinyloestradiol is not excreted in unchanged form to any significant extent. The metabolites of ethinyloestradiol 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 ethinyloestradiol accumulate by a factor of about 1.4 to 2.1.

Clinical Trials

Yaz Flex is a flexible, extended cycle oral contraceptive based on the conventional COC Yaz. Yaz contains 24 hormone tablets and 4 placebo tablets. The contraceptive and therapeutic effects for Yaz also apply to Yaz Flex as both formulations are identical with respect to the hormone tablet.

Contraception.

The contraceptive efficacy and safety of Yaz Flex was examined in two multicentre open trials evaluating the Yaz Flex regimen. The contraceptive reliability was analysed using two different methods, the Pearl index (PI) and a life table analysis.
The first pivotal study A40196 was a randomised, parallel group study to evaluate the bleeding pattern, contraceptive efficacy and safety of the Yaz Flex regimens (Yaz Flex, Yaz extend and Yaz) in 1067 women between the ages of 18 to 35 years. This study was conducted in Europe and Canada. Yaz Flex (group A) women were advised to schedule their withdrawal bleeding between days 25 and 120 of the intake cycle when intracyclic bleeding occurs. The Yaz extend (group B) dosage regimen consisted of 120 active cycle taken without interruption, irrespective of the occurrence of (unintended) bleeding episodes. The Yaz (group C) took 24 active tablets followed by 4 placebo tablets. This was a two year study: year 1 comprised the randomised parallel group treatment and year 2 was an extension period during which all subjects who continued, received Yaz Flex. The Pearl index (PI) was calculated on the Yaz Flex group in both year 1 and year 2, totalling 1268 woman years (WY) of exposure. The PIU (unadjusted PI) was 0.63 with an upper two sided 95% confidence interval of 1.24 based on 8 pregnancies. The PIA (adjusted PI) was 0.59 with an upper two sided 95% confidence interval of 1.22.
The probability of pregnancy was calculated using the Kaplan-Meier estimator. The Kaplan-Meier estimator after one year of treatment with Yaz Flex was 1.42%, the probability of contraceptive protection was 98.58% with a 95% CI of (0.9709; 0.9931).
The number of bleeding and spotting days within the first year of treatment for the Yaz Flex regimen was 41.0 days versus 65.8 days for the Yaz group. The difference was statistically significant (p < 0.0001). When compared against the Yaz extend group, the Yaz Flex group had less bleeding days on average, 41 compared with 60.9 (67%). Table 1 displays the number and proportion of bleeding or spotting days during one year of treatment-FAS.
The mean length of withdrawal bleeding over the first two extended cycles by comparison with the monthly cycles of the Yaz subjects was longer in group A (7.5-9.8 days) and group B (9.8-10.5 days). The mean length of withdrawal bleeding in group C was between 4.4-5.2 days.
Subject satisfaction was 62% with Yaz Flex subjects reporting very satisfied, 33.5% reporting quite satisfied, and 86% indicating preparedness to recommend the regimen to a friend.
The second pivotal study (A48294) was a three arm, active controlled study evaluating the efficacy and safety of the Yaz Flex regimens in 1864 women between the ages of 18 to 45 years. This study was conducted in the United States. The Yaz extend group (group B) in study A40196 was replaced with the Yaz Stop&Go regimen in this study. The Yaz Stop&Go regimen is similar to the Yaz Flex regimen (group A) except that women were allowed to schedule their withdrawal bleeding at any time between days 25 and 120 of the intake cycle independent of the occurrence of intracyclic bleeding. The PIU for Yaz Flex was 1.65 with an upper two sided 95% confidence interval of 2.64 based on 17 pregnancies and 1032 WY of exposure. The PIU for the two flexible extended regimens (Yaz Flex and Yaz Stop&Go) was 1.92.
The probability of pregnancy was calculated using the Kaplan-Meier estimator. For Yaz Flex, the estimation of cumulative failure rate was 1.63% (95% CI; 1.01, 2.61), indicating a probability of contraceptive protection on 98.4%. For the Yaz Flex/ Yaz Stop&Go pooled population, it was 1.83% (95% CI; 1.21, 2.75), and probability of protection 98.2%.
Subjects in the extended flexible treatment regimens had improved bleeding pattern, including reduction in overall bleeding when compared to the conventional Yaz regimen.
The mean number of bleeding and spotting days in the first year of treatment for the Yaz Flex group was 39.9 compared with 51.8 for the Yaz group (p < 0.0001). In the subset of subjects who completed ≥ 350 days of treatment, the mean number of bleeding and spotting days was as follows: Yaz Flex 46.6 days, Yaz Stop&Go 53.0 days and Yaz 65.1 days.
Women were satisfied with the extended cycle length, the ease of following the regimen and the instructions in study A48294. Table 2 displays the satisfaction rates reported in study A48294 for the extended flexible treatment regimens.
A third study (A47505) evaluated the efficacy and safety of the flexible extended (Yaz Flex) in comparison with the conventional Yaz regimen in the treatment of primary dysmenorrhoea in 223 women. This study was a five month multicentre, open label, randomised, controlled, parallel group study. The total number of bleeding and spotting days (first 90 day reference period, mean ± SD) were 19.9 ± 13.0 for Yaz Flex compared with 25.3 ± 9.1 for the Yaz group. Similarly, the number of bleeding episodes was less with Yaz Flex, 2.4 ± 1.7 compared with 3.5 ± 1.0 whereas mean length of bleeding and spotting episodes was greater and more variable at 7.8 ± 9.0 compared with 5.2 ± 1.8 for the Yaz regimen. Table 3 displays the number of days with dysmenorrhoeic pain over 140 days of treatment.

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 4.
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].
There are no clinical data with Yaz Flex.

Indications

Yaz Flex is indicated for use as:
an oral contraceptive;
treatment of moderate acne vulgaris in women who seek oral contraception.

Contraindications

Combined hormonal contraceptives (CHCs) including Yaz Flex 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 Precautions):
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 Precautions):
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 Interactions with Other Medicines).
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 Flex.

Precautions

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 Flex should be discontinued.

Circulatory disorders.

Epidemiological studies have suggested an association between the use of combined oral contraceptives (COCs) containing ethinyloestradiol 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 (EURAS1 and LASS2) 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 ethinyloestradiol/ 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 ethinyloestradiol/ 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 ethinyloestradiol/ 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 ethinyloestradiol/ 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 ethinyloestradiol/ 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 ethinyloestradiol/ drospirenone 30 microgram/3 mg cases was very small (1.2% of all cases making the risk estimates unreliable). The relative risk for ethinyloestradiol/ 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 ethinyloestradiol/ 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 ethinyloestradiol 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 Flex. See Dosage and Administration, Use in pregnancy, and 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 Flex 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 Flex (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 Flex 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 discoloration of an extremity.
If the occlusion occurs in the eye symptoms can range from painless blurring of vision which can progress to loss of vision. Sometimes loss of vision can occur almost immediately.

Risk of arterial thromboembolism (ATE).

Epidemiological studies have associated the use of CHCs with an increased risk for 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 Flex 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 hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when taking COCs.
Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. The antimineralocorticoid effect of drospirenone may counteract ethinyloestradiol 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. 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 oestrogens may induce or exacerbate symptoms of angioedema.
Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. Recurrence of cholestatic jaundice 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 ethinyloestradiol). 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.
Worsening of depression has been observed in patients taking COCs.
Each Yaz Flex tablet contains 48.18 mg of lactose. 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.

Prior to the initiation or reinstitution of Yaz Flex, a complete medical history (including family history) should be taken and pregnancy must be ruled out. This should be repeated at least annually during the use of Yaz Flex. Periodic medical assessment is important 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 taking Yaz Flex. The frequency and nature of these assessments should be adapted to the individual woman but should generally include special attention 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 Yaz Flex tablets, gastrointestinal disturbances or concomitant medication (see Dosage and Administration and Interactions with Other Medicines).

Reduced cycle control.

The flexible regimen is designed to delay menstruation. With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, even during the fixed phase of the cycle especially during the first few months of use. Evaluation of any irregular bleeding is only meaningful after an adaptation interval of about three months. The fixed phase is between days 1-24. Irregular bleeding is unscheduled and cannot be predicted. The hormonal withdrawal bleeding following the 4 day tablet free interval can be scheduled. The flexible regimen of Yaz Flex allows withdrawal bleeding to be scheduled during the flexible phase. The flexible phase is between days 25-120.
If bleeding irregularities persist even after induction of withdrawal bleeding 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 tablet free interval. If the COC has been taken according to the directions described in the section Dosage and Administration, 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.

Information for the patient.

A Consumer Medicine Information leaflet is available. Please advise your patient to read this information carefully.

Carcinogenicity.

Long-term carcinogenicity studies were performed in mice and rats with drospirenone, ethinyloestradiol 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 ethinyloestradiol 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 ethinyloestradiol alone, indicating that ethinyloestradiol was responsible for the increase in neoplastic lesions. Coadministration of drospirenone decreased the carcinogenic potential of ethinyloestradiol in the mouse pituitary and in the mouse and rat uterus and mammary gland.
The ethinyloestradiol induced tumours in rodents have previously been seen with other ethinyloestradiol containing products, and are considered attributable to species specific effects of oestrogens 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 ethinyloestradiol, it should be borne in mind that sex steroids can promote the growth of certain hormone dependent tissues and tumours.

Genotoxicity.

There is limited evidence available in the literature suggesting that oestrogens may be weakly genotoxic at high doses. Ethinyloestradiol 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.

Use in pregnancy.

(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.
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 ethinyloestradiol 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 ethinyloestradiol 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 to 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 oestrogens in rats. When pregnant monkeys received a combination of drospirenone and ethinyloestradiol 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. The data regarding the use of Yaz Flex during pregnancy are limited to permit conclusions concerning negative effects of Yaz Flex on pregnancy, health of the foetus or neonate. No relevant epidemiological data are available yet.
Yaz Flex is contraindicated during pregnancy. The possibility of pregnancy should be considered in any patient who may be experiencing symptoms of pregnancy, especially if the user has not adhered to the prescribed schedule. If pregnancy occurs during treatment with Yaz Flex, further intake must be stopped.
If Yaz Flex is taken according to the instructions as described under Dosage and Administration and conditions possibly impairing contraceptive effectiveness are ruled out, it is unlikely the woman is pregnant. Scheduled withdrawal bleeding does not occur every 4 weeks. The frequency of withdrawal bleeding is reduced when the tablets are taken continuously for up to 120 days depending on when the user decides to have her 4 day tablet free interval. The absence of withdrawal bleeding cannot always be used as an early sign of an unexpected pregnancy and as such may be difficult to recognise. Pregnancy is unlikely if Yaz Flex is taken as directed, if for any reason pregnancy is suspected, a pregnancy test should be performed.

Use in lactation.

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.

Children and adolescents.

Yaz Flex is only indicated after menarche.

Use in the elderly.

Yaz Flex is not indicated after menopause.

Patients with hepatic impairment.

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

Patients with renal impairment.

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

Effect 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 antimineralocorticoid activity.

Interactions

Effects of other medicines on Yaz Flex.

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 on treatment with 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. During the period the barrier method is used, tablet taking should not be interrupted by a tablet free interval.

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 oestrogen or progestogen. These changes may be clinically relevant in some cases.

Substances decreasing the clearance of COCs (enzyme inhibitors).

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

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 ethinyloestradiol 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 ethinyloestradiol 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 Contraindications).

Other interactions.

There is a theoretical potential for an increase in serum potassium in women taking Yaz Flex 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.

Adverse Effects

The most serious adverse reactions associated with the use of oral contraceptives are indicated under Precautions (see also Contraindications).

Clinical trial data.

Table 5 includes the adverse drug reactions for Yaz in combination with the adverse drug reactions reported in the clinical trials with Yaz Flex (N = 2623).
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 oestrogens may induce or exacerbate symptoms of angioedema.

Dosage and 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.
One tablet is to be taken daily at about the same time with some liquid. Tablet taking is continuous for at least 24 consecutive days.
During days 25-120 a woman may decide to take a 4 day tablet free break but not before day 24. A tablet free interval should not be longer than 4 days.
A 4 day tablet free interval has to be taken after 120 days of continuous tablet taking. After each 4 day tablet free interval, a new cycle starts with a minimum of 24 days to a maximum of 120 days.
During the 4 day tablet free interval, bleeding usually occurs and may not have finished before the next Yaz Flex tablet is taken.
In the event of continued spotting and/or bleeding (three consecutive days) during days 25-120, a 4 day tablet free interval is recommended. This will reduce the total number of days of bleeding.
Yaz Flex can only be used in combination with a dedicated Clyk tablet dispenser. Clyk is a tablet dispenser designed to support the user follow the Yaz Flex regimen. The instructions for use is provided with the Clyk tablet dispenser. The instructions for use should be read carefully before and during use.

How to start Yaz Flex.

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).
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 take Yaz Flex on the day following the usual tablet free or placebo tablet interval of her previous COC.
In case a vaginal ring has been used, the woman should start taking Yaz Flex preferably on the day of removal of the ring, but at the latest 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 does not need additional contraceptive measures.

Following delivery or second trimester abortion.

Women should be advised to start on 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 Precautions, Use in lactation.

Management of missed tablets.

If the woman is less than 24 hours late in taking a Yaz Flex tablet, contraceptive protection is not reduced. The woman should take the Yaz Flex tablet as soon as she remembers and continue to take the tablets at the usual time.
If the woman is more than 24 hours late in taking a Yaz Flex tablet, contraceptive protection may be reduced. The management of missed tablets can be guided by the following two basic rules.
1. The recommended tablet free interval is 4 days, tablet taking must never be discontinued for longer than 7 days.
2. Seven days of uninterrupted tablet taking are required to attain adequate suppression of the hypothalamic pituitary ovarian axis.
The following advice can be given in daily practice.

Day 1-7.

The woman should take the last missed Yaz Flex tablet as soon as she remembers, even if this means taking two Yaz Flex tablets at the same time. Subsequent tablets should be taken at the 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 Yaz Flex tablets missed and the closer they are to the tablet free interval the higher the risk of a pregnancy.

Day 8-24.

The woman should take the last missed Yaz Flex tablet as soon as she remembers, even if this means taking two Yaz Flex tablets at the same time. Subsequent tablets should be taken at the usual time. If the woman has taken her tablets correctly in the 7 days preceding the first missed Yaz Flex tablet, there is no need to use extra contraceptive precautions. However, if this is not the case, or if she missed more than one tablet, the woman should be advised to use extra contraceptive precautions until she has taken the tablets continuously for at least 7 days without interruption.

Day 25-120.

Contraceptive efficacy may be reduced if tablets are missed and particularly if the missed tablet extends the 4 day pill break. 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 no need to use extra contraceptive precautions, provided that in the 7 days preceding the first missed Yaz Flex tablet the user has taken the tablets correctly. If this is not the case, the user should be advised to follow one of these options and use extra contraceptive precautions for the next 7 days as well.
1. The woman should take the last missed Yaz Flex tablet as soon as she remembers, even if this means taking two Yaz Flex tablets at the same time. She then continues to take tablets at her usual time until she has taken at least 7 Yaz Flex tablets in a row without interruption.
2. The woman may also decide to have a tablet free interval of 4 days, including the days she missed tablets in order to induce withdrawal bleeding, and subsequently start a new cycle of Yaz Flex.
If the woman missed tablets and subsequently has no withdrawal bleed in the tablet free interval, the possibility of a pregnancy should be considered.

Advice in case of gastrointestinal disturbances.

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

Overdosage

There has not yet been any clinical experience of overdose with Yaz Flex. On the basis of general experience with COCs, symptoms that may occur in case of overdose of Yaz Flex 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.
In cases of overdose, it is advisable to contact the Poisons Information Centre (131 126) for recommendations on the management and treatment of overdose.

Presentation

Tablets, ethinyloestradiol 20 microgram, drospirenone 3 mg (light pink, round, marked DS in a regular hexagon on one side): 1 x 30's (Clyk tablet dispenser + dispenser pack (starter kit)), 1 x 30's, 3 x 30's*, 4 x 30's (dispenser pack). The dispenser pack containing the 30 Yaz Flex tablets are to be inserted into the Clyk tablet dispenser immediately for use. Please see instructions for use provided with the Clyk tablet dispenser.
*Not currently marketed in Australia.

Storage

Store below 30°C.

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 ethinylestradiol/drospirenone and other oral contraceptives. Obstet and 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 Ø, Løkkegaard 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 oestrogen 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 oestrogen 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.

Poison Schedule

S4.