Consumer medicine information

Zoely

Nomegestrol acetate; Estradiol

BRAND INFORMATION

Brand name

Zoely

Active ingredient

Nomegestrol acetate; Estradiol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zoely.

SUMMARY CMI

ZOELY®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using ZOELY?

ZOELY contains the active ingredient nomegestrol acetate and estradiol. ZOELY is an oral contraceptive, used to prevent pregnancy.

For more information, see Section 1. Why am I using ZOELY? in the full CMI.

2. What should I know before I use ZOELY?

Do not use if you have ever had an allergic reaction to nomegestrol acetate, estradiol or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use ZOELY? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ZOELY and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use ZOELY?

  • ZOELY needs to be taken every day at the same time, to ensure it works effectively. Follow all instructions given to you by your doctor.

More instructions can be found in Section 4. How do I use ZOELY? in the full CMI.

5. What should I know while using ZOELY?

Things you should do

  • Remind any doctor, dentist or pharmacist you visit that you are using ZOELY.
  • Monitor your health and contact your doctor if you notice any changes.
  • Keep all of your doctor's appointments and go for regular checkups.

Things you should not do

  • Do not stop using this medicine suddenly without telling your doctor.
  • Do not use this medicine if you are pregnant, or fall pregnant while taking this medicine.

Driving or using machines

  • ZOELY is not expected to affect your ability to drive or operate machinery. If you experience any side effects which impact your ability to drive or operate machinery when taking this medicine, act appropriately and contact your doctor.

Drinking alcohol

  • Alcohol is not expected to interact with ZOELY. If you drink alcohol, talk to your doctor about the possible effects of taking alcohol with this medicine.

Looking after your medicine

  • Store ZOELY in a cool dry place, out of direct light, where the temperature is below 30°C.
  • Keep ZOELY in the original packaging, in a safe place, away from children.

For more information, see Section 5. What should I know while using ZOELY? in the full CMI.

6. Are there any side effects?

The most common side effects are changes in menstrual cycle, acne, mood changes and headaches. Serious side effects include blood clots in the veins or blood vessels and breast cancer. See more information under ‘The Pill and Thrombosis’ and ‘The Pill and Cancer’.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

ZOELY®

Active ingredient(s): Nomegestrol Acetate and Estradiol


Consumer Medicine Information (CMI)

This leaflet provides important information about using ZOELY. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using ZOELY.

Where to find information in this leaflet:

1. Why am I using ZOELY?
2. What should I know before I use ZOELY?
3. What if I am taking other medicines?
4. How do I use ZOELY?
5. What should I know while using ZOELY?
6. Are there any side effects?
7. Product details

1. Why am I using ZOELY?

ZOELY contains the active ingredient nomegestrol acetate and estradiol. ZOELY is an oral contraceptive, commonly known as a "Birth Control Pill" or "The Pill" that has been prescribed to prevent you from getting pregnant.

ZOELY prevents pregnancy in several ways:

  • It inhibits the egg release by stopping it maturing.
  • It changes the cervical mucus consistency making it more difficult for sperm to reach the egg.
  • It changes the lining of the uterus making it less suitable for implantation.

Oral contraceptives are an effective method of birth control. When taken correctly (without missing tablets) the chance of becoming pregnant is very low.

The following non-contraceptive health benefits have been associated with the combined Pill:

  • Your periods may be lighter and shorter. As a result, the risk of anaemia may be lower.
  • Your period pains may become less severe or may completely disappear.

2. What should I know before I use ZOELY?

Warnings

Do not use ZOELY if:

  • you are allergic to nomegesterol acetate or estradiol, or any of the ingredients listed at the end of this leaflet.
  • always check the ingredients to make sure you can use this medicine.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or troubled breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Check with your doctor if you:

  • have any other medical conditions
  • take any medicines for any other condition

If you have any of the following conditions, tell your doctor before starting ZOELY. Your doctor may advise you to use a different type of Pill or an entirely different (non-hormonal) method of birth control.

  • a blood clot (venous thrombosis) in a blood vessel of your legs, lungs (embolus) or other organs
  • a heart attack or stroke
  • a condition that may be a first sign of a heart attack (such as angina pectoris which causes severe chest pain) or stroke (such as a transient ischaemic attack)
  • a serious risk factor or several risk factors for developing a blood clot
  • very high blood pressure
  • a very high level of fat in the blood (cholesterol or triglycerides)
  • a disorder affecting your blood clotting - for instance Protein C deficiency
  • if you have major surgery (e.g., an operation) and your ability to move around is limited for a long period of time
  • diabetes mellitus with blood vessel damage
  • a history of migraine accompanied by e.g. visual symptoms, speech disability, or weakness or numbness in any part of the body
  • pancreatitis (an inflammation of the pancreas) associated with high levels of fatty substances in your blood
  • jaundice (yellowing of the skin) or severe liver disease and your liver is not yet working normally
  • a benign or malignant liver tumour
  • a cancer that may grow under the influence of sex hormones (e.g. of the breast or of the genital organs)
  • meningioma or have ever been diagnosed with a meningioma (a generally benign tumour of the tissue layer between the brain and the skull)
  • any unexplained vaginal bleeding
  • you are pregnant or think you might be pregnant.

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 contraceptive measures.

Do not take ZOELY if the expiry date printed on the pack has passed.

Do not take ZOELY if the packaging is torn or shows signs of tampering.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Tell your doctor immediately if you are pregnant or think you are pregnant while you are using ZOELY.

ZOELY must not be used during pregnancy.

ZOELY is not recommended for use during breastfeeding. If you wish to take the Pill while breastfeeding, please seek the advice of your doctor.

Before using ZOELY:

In this leaflet, several situations are described where you should stop taking the Pill, or where the reliability of the Pill may be decreased. In such situations you should not have sex or you should take extra non-hormonal contraceptive precautions, e.g. use a condom or another barrier method.

Do not use rhythm or temperature methods. These methods can be unreliable because the Pill alters the usual changes in temperature and cervical mucus that occur during the menstrual cycle.

If you are concerned about contracting a sexually transmitted infection (STI), ask your partner to wear a condom when having sexual intercourse with you.

ZOELY will not protect you from HIV (AIDS) or any other sexually transmitted infections. To help protect yourself from STIs, you need to use a barrier contraceptive such as a condom, but even barrier contraceptives may not protect you against human papilloma virus (HPV).

You should have a thorough medical check-up, including a Pap smear, breast check, blood pressure check and urine check.

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

You must tell your doctor if you smoke.

The risk of having a heart attack or stroke increases as you get older. It also increases the more you smoke. When using the Pill you should stop smoking, especially if you are older than about 35 years of age.

You must tell your doctor if you have any of the conditions listed below. You may need to be kept under close observation. Your doctor can explain this to you. Tell your doctor if:

  • anyone in your immediate family has had breast cancer
  • you suffer from epilepsy
  • you are overweight
  • you have diabetes
  • you have high blood pressure
  • you have a heart valve disorder or a certain heart rhythm disorder
  • anyone in your immediate family has had a thrombosis, a heart attack, or a stroke
  • you have sickle cell disease you have liver disease (jaundice) or gall bladder disease
  • you have Crohn's disease or ulcerative colitis (chronic inflammatory bowel disease)
  • you have systemic lupus erythematosus (SLE, a disease affecting the skin all over the body)
  • you have haemolytic uraemic syndrome (HUS; a disorder of blood coagulation causing failure of the kidneys)
  • if you have elevated fatty acid levels in the blood (hypertriglyceridaemia) or a positive family history for this condition (familial hypertriglyceridaemia). If so, you may be at an increased risk of developing pancreatitis (inflammation of the pancreas) when using combined pills
  • you 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)
  • you have or have had chloasma (yellow brownish pigmentation patches on the skin, particularly of the face); if so, avoid too much exposure to the sun or ultraviolet radiation
  • you have recently given birth you are at an increased risk of blood clots. You should ask your doctor how soon after delivery you can start using ZOELY
  • You need an operation or if your ability to move around is limited for a long period of time. This includes travelling by plane for greater than 4 hours.

Tell your doctor if any of the above conditions appear for the first time, recur, or worsen while using the Pill.

3. What if I am taking other medicines?

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

Medicines that may reduce the effect of ZOELY include:

  • medicines for epilepsy such as
    - phenytoin,
    - primidone,
    - barbiturates,
    - carbamazepine,
    - oxycarbamazepine,
    - topiramate,
    - felbamate
  • medicines for tuberculosis (e.g. rifampicin and rifabutin)
  • medicines for HIV infections (ritonavir, nevirapine, nelfinavir, efavirenz)
  • medicines for Hepatitis C virus infection (e.g. boceprevir, telaprevir)
  • antibiotics (e.g. penicillin, ampicillin, tetracyclines)
  • antifungals (e.g. griseofulvin)
  • medicines for high blood pressure in the blood vessels of the lungs (bosentan)
  • herbal medicines containing St John's Wort primarily for the treatment of depressive moods

If you are taking medicines or herbal products that might make ZOELY less effective, a barrier contraceptive method should also be used. Since the effect of another medicine on ZOELY may last up to 28 days after stopping the medicine, it is necessary to use the additional barrier contraceptive method for that long.

ZOELY may also interfere with the working of other medicines - such as ciclosporin and the anti-epileptic lamotrigine.

The HCV combination drug regimen ombitasvir/ paritaprevir/ritonavir with or without dasabuvir may cause increases in liver function blood test results (increase in ALT liver enzyme) in women using CHCs containing ethinylestradiol. ZOELY contains estradiol instead of ethinylestradiol. It is not known whether an increase in ALT liver enzyme can occur when using ZOELY with this HCV combination drug regimen. Your doctor will advise you.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect ZOELY.

4. How do I use ZOELY?

How much to take

  • follow the instructions provided and use ZOELY until your doctor tells you to stop.

When to use ZOELY

  • Take your medicine at the same time each day.

Taking ZOELY at the same time each day will have the best effect. It will also help you remember when to take it.

How to take ZOELY

A ZOELY pack contains strips of 28 tablets: 24 white tablets with active substances and 4 yellow tablets that do not contain active substances. Each time you start a new strip of ZOELY, take the first white active tablet in the left-hand top corner (see 'Start').

Choose from the 7 stickers with day indicators the one that begins with your starting day, e.g. if you start on a Wednesday, use the day label sticker that starts 'WED'. Stick it on the strip, just above the row of white active tablets where it reads 'Place day label here'. This allows you to check whether you took your daily tablet.

Take one tablet each day at about the same time, with some liquid if necessary.

Follow the direction of the arrows on the pack taking the white active tablets first followed by the yellow inactive tablets.

A period should begin during the 4 days that you use the yellow inactive tablets (the withdrawal bleed). Usually it will start on day 2-3 after the last white tablet and may not have finished before the next strip is started.

Start taking your next pack immediately after the last yellow inactive tablet, even if your period hasn't finished. This means you will always start new packs on the same day of the week, and also means that you have your period on about the same days, each month.

When no hormonal contraception has been used in the past month

Start taking ZOELY on the first day of your cycle, i.e. the first day of menstrual bleeding. ZOELY will work immediately, it is not necessary to use an additional contraceptive method.

You may also start on days 2-5 of your cycle, but in that case make sure you also use an additional contraceptive method (barrier method) for the first 7 days of tablet-taking in the first cycle.

When changing from another combined hormonal contraceptive (combined oral contraceptive (COC), no problem vaginal ring, or transdermal patch)

You can start taking ZOELY the day after you take the last tablet from your present Pill pack. If your present Pill pack contains inactive tablets (placebo) tablets you can start ZOELY on the day after taking the last active tablet (if you are not sure which this is, ask your doctor or pharmacist). You can also start later, but never later than the day following the tablet-free break of the present Pill (or the day after the last inactive tablet of your present Pill).

In case you use a vaginal ring or transdermal patch, you should start using ZOELY preferably on the day of removal, but at latest when the next ring or patch would have been applied.

If you have used the Pill, patch or ring consistently and correctly and if you are sure that you are not pregnant, you can stop taking the Pill or remove the ring or patch on any day and start using ZOELY immediately.

If you follow these instructions, it is not necessary to use an additional contraceptive method.

When changing from a progestogen-only method (minipill)

You can stop taking the minipill any day and start taking ZOELY the next day, at the same time. But make sure you also use an additional contraceptive method (a barrier method) for the first 7 days of tablet-taking.

When changing from an injectable, an implant or a progestogen-releasing intrauterine device (IUD)

Start using ZOELY when your next injection is due or on the day that your implant or your IUD is removed. Make sure you also use an additional contraceptive method (a barrier method) for the first 7 days of tablet-taking.

After having a baby

If you have just had a baby, your doctor may tell you to wait until after your first normal period before you start taking ZOELY. Sometimes it is possible to start sooner. Your doctor will advise you. If you are breast-feeding and want to take ZOELY, you should discuss this first with your doctor.

After a miscarriage or abortion

Your doctor will advise you.

Additional contraceptive precautions

When additional contraceptive precautions are required you should either abstain from vaginal sex, or use a barrier method of contraception, a condom, or a cap (diaphragm) plus spermicide. Rhythm methods are not advised as the Pill disrupts the cyclical changes associated with the natural menstrual cycle e.g., changes in temperature and cervical mucus.

If you forget to take ZOELY

The following advice only refers to missed white active tablets

If you are less than 24 hours late in taking a tablet,

  • the reliability of the Pill is maintained. Take the tablet as soon as you remember and take further tablets at the usual time.

If you are 24 or more hours late in taking any tablet,

  • the reliability of the Pill may be reduced. The more consecutive tablets you have missed, the higher the risk that the contraceptive efficacy is decreased. There is a particularly high risk of becoming pregnant if you miss white active tablets at the beginning or at the end of the strip. Therefore, you should follow the rules given below.

Picture 1

Day 1-7 (the first 7 days of white active tablet intake, see picture 1 and the schedule at the end of this leaflet)

Take the last white active missed tablet as soon as you remember (even if this means taking two tablets at the same time) and take the next tablets at the usual time. Use a barrier method such as a condom as an extra precaution until you have taken your tablets correctly for 7 days in a row. If you had sexual intercourse in the week before missing the tablets, there is a possibility of becoming pregnant. So tell your doctor immediately.

Days 8 to 17 from the first white active tablet intake (see picture 1 and the schedule at the end of this leaflet)

Take the last missed tablet as soon as you remember (even if this means taking two tablets at the same time) and take the next tablets at the usual time. If you have taken your tablets correctly in the 7 days prior to the missed tablet, the protection against pregnancy is not reduced, and you do not need to use extra precautions. However, if you have missed more than 1 tablet, use a barrier method such as a condom as an extra precaution until you have taken your tablets correctly for 7 days in a row.

Day 18-24 (the last 7 days of white active tablet intake, see picture 1 and the schedule at the end of this leaflet)

There is a particularly high risk of becoming pregnant if you miss white active tablets close to the yellow placebo tablet interval. By adjusting your intake schedule this higher risk can be prevented.

The following two options can be followed. You do not need to use extra precautions if you have taken your tablets correctly in the 7 days prior to the missed tablet. If this is not the case, you should follow the first of these two options and use a barrier method such as a condom as an extra precaution until you have taken your tablets correctly for 7 days in a row.

Option 1

Take the last missed white active tablet as soon as you remember (even if this means taking 2 tablets at the same time) and take the next tablets at the usual time. Start the next strip as soon as the white active tablets in the current strip are finished, so skip the yellow placebo tablets. You may not have your period until you take the yellow placebo tablets at the end of the second strip, but you may have spotting (drops or flecks of blood) or breakthrough bleeding while taking the white active tablets.

Option 2

Stop taking the active white tablets and start taking the placebo yellow tablets so that the total number of placebo plus missed active white tablets is not more than 4. At the end of this interval, start the next blister. For example, if you missed one active white tablet, you should take 3 days of the placebo yellow tablets; if you missed 2 active white tablets, you should take 2 days of the placebo yellow tablets; and if you missed 3 active white tablets, you should take only 1 day of the placebo yellow tablets.

If you cannot remember how many white active tablets you have missed, follow the first option, use a barrier method such as a condom as an extra precaution until you have taken your tablets correctly for 7 days in a row and contact your doctor (as you may not have been protected from becoming pregnant).

If you have forgotten to take white active tablets in a strip and you do not have the expected monthly period while taking the yellow placebo tablets from the same strip, you may be pregnant. Consult your doctor before you start with the next strip.

Yellow tablets missed

The last 4 yellow tablets of the fourth row are placebo tablets which do not contain active substances. If you forgot to take one of these tablets the reliability of ZOELY is maintained.

Throw away the yellow tablet that you missed and continue taking the next tablets at the usual time.

You want to delay your period

You can delay your period if you continue with the white active tablets in your next pack of ZOELY immediately after finishing the white tablets in your current pack. You can continue with this pack for as long as you wish, until this pack is empty. When you wish your period to begin, just stop tablet-taking. While using the second pack you may have some breakthrough bleeding or spotting on active tablet-taking days. Start your next pack after the usual 4-day inactive tablet interval.

You want to change the starting day of your period

If you take your tablets as directed, you will have your period on about the same day every 4 weeks. If you want to change this, just shorten (never lengthen) the next placebo tablet interval. For example, if your period usually starts on a Friday and in future you want it to start on Tuesday (3 days earlier) you should now start your next pack 3 days sooner than you usually do. If you make your placebo tablet interval very short (e.g. 3 days or less), you may not have a bleeding during the interval. You may have some breakthrough bleeding or spotting during the use of the white tablets in the next pack.

If you vomit or have diarrhoea

If you vomit within 3-4 hours of taking an active white tablet, or you have severe diarrhoea, the active ingredients of your ZOELY tablet may not have been completely absorbed into your body. The situation is similar to if you forget an active white tablet. After vomiting or diarrhoea, you must take another active white tablet from a reserve blister as soon as possible. If possible, take it within 24 hours of when you normally take your pill. Take the next tablet at the usual time. If this is not possible or 24 or more hours have passed, you should follow the advice given under "What to do if… you forget to take your tablets". If you have severe diarrhoea, please contact your doctor.

The yellow tablets are placebo tablets which do not contain active substances. If you vomit or have severe diarrhoea within 3-4 hours of taking a yellow tablet, the reliability of ZOELY is maintained.

If you have unexpected bleeding

With all Pills, for the first few months, you can have breakthrough bleeding or spotting between your periods. You may need to use sanitary protection but continue to take your tablets as normal. Breakthrough bleeding or spotting usually stops once your body clock has adjusted to the Pill (usually after about 3 tablet-taking cycles). Tell your doctor if it continues, becomes heavy or starts again.

If you have missed a period

If you have taken all of your tablets at the right time, and you have not vomited, or had severe diarrhoea or used other medicines then you are very unlikely to be pregnant. Continue to take ZOELY as usual.

If you miss your period twice in a row, you may be pregnant. Do not start the next pack of ZOELY until your doctor has checked you are not pregnant.

If you use too much ZOELY

There have been no reports of serious harmful effects from taking too many ZOELY tablets at one time. If you take too much ZOELY you may feel sick, vomit, or have vaginal bleeding.

If you discover a child has taken ZOELY, ask your doctor for advice.

If you are not sure of what to do:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor or go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using ZOELY?

Things you should do

When you are using the Pill, your doctor will tell you to return for regular check-ups. You should have a check-up at least once a year.

Call your doctor straight away if you:

  • notice any changes in your own health, especially involving any of the items mentioned in this leaflet; do not forget about the items related to your immediate family
  • feel a lump in your breast
  • are going to use other medicines
  • notice your ability to move around is limited for a long period of time or you are to have surgery (consult your doctor at least 4 weeks in advance)
  • have unusual, heavy vaginal bleeding
  • forgot tablets at the beginning or end of the pack and had intercourse in the seven days before
  • have severe diarrhoea
  • miss your period twice in a row or suspect you are pregnant. Do not start the next pack until told to by your doctor.

Remind any doctor, dentist, or pharmacist you visit that you are using ZOELY.

Stop taking tablets and see your doctor immediately if you notice possible signs of thrombosis, myocardial infarction, or a stroke such as:

  • an unusual cough
  • severe pain in the chest which may reach the left arm - this discomfort may include the back, jaw, throat, arm, stomach
  • feeling of being full, having indigestion or choking
  • sweating, nausea, vomiting, anxiety
  • breathlessness or rapid breathing
  • any unusual, sudden, severe, or prolonged headache or migraine attack
  • partial or complete loss of vision, or double vision
  • confusion, slurring or speech disability
  • sudden changes to your hearing, sense of smell or taste
  • dizziness or fainting
  • fast or irregular heartbeat
  • weakness or numbness in any part of your body
  • severe pain in your stomach
  • severe pain or swelling in either of your legs
  • pain or tenderness in the leg which may be felt only when standing or walking
  • warmth, red or discoloured skin on the leg
  • sudden pain, swelling and slight blue discoloration of an extremity
  • sudden trouble walking, loss of balance or coordination

Driving or using machines

Be careful before you drive or use any machines or tools until you know how ZOELY affects you.

ZOELY is not expected to affect your ability to drive or operate machinery. If you experience any side effects which impact your ability to drive or operate machinery when taking this medicine, act appropriately and contact your doctor.

Drinking alcohol

Tell your doctor if you drink alcohol.

Alcohol is not expected to interact with ZOELY. If you drink alcohol, talk to your doctor about the possible effects of taking alcohol with this medicine.

Looking after your medicine

Follow the instructions in the carton on how to take care of your medicine properly.

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

Store ZOELY in a cool dry place below 30°C, away from moisture, heat, or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on windowsills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effects

What to do

Changes to mood and feelings:

  • mood changes
  • depression/depressed mood
  • irritability
  • changes to appetite
  • decreased or increased interest in sex
  • disturbance in attention

Changes to skin, hair, and tissues:

  • acne
  • hair loss
  • oily skin
  • dry skin
  • dry mouth
  • dry eyes
  • itching
  • excessive hair growth
  • increased sweating
  • larger breasts
  • golden brown pigment patches, mostly in the face

Changes to menstrual cycle:

  • breakthrough bleeding or spotting
  • absence of menstruation
  • regular but scanty periods
  • premenstrual syndrome

Changes to reproductive system:

  • pelvic pain
  • swollen abdomen
  • milk production while not pregnant
  • pain during intercourse
  • dryness in the vagina or vulva
  • spasms of the uterus
  • vaginal smell
  • discomfort in the vagina or vulva

Other:

  • headache or migraine
  • feeling sick (nausea)
  • weight gain
  • fluid retention
  • sensation of heaviness
  • hot flushes
  • increase in the levels of liver enzymes

Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

Relating to Cancer:

  • breast pain
  • lumps in breast

Relating to Thrombosis:

  • headache or pain elsewhere in the body
  • dizziness
  • fainting
  • disturbances in vision
  • swollen ankles
  • yellowing of the eyes or skin

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

The Pill and Thrombosis

A thrombosis is the formation of a blood clot which may block a blood vessel.

A thrombosis sometimes occurs in the deep veins of the legs(deep venous thrombosis). If this blood clot breaks away from the veins where it is formed, it may reach and block the arteries of the lungs, causing a so-called "pulmonary embolism". Deep venous thrombosis is a rare occurrence. It can develop whether or not you are taking the Pill. The risk is higher in Pill-users than in non-users. The chance of getting a thrombosis is highest during the first year a woman uses the Pill. The risk is also higher if you restart using a combined pill (the same product or a different product) after a break of 4 weeks or more. Thrombosis can also happen if you become pregnant. The risk of thrombosis also increases if you gave birth less than a few weeks ago. ZOELY contains estradiol instead of ethinylestradiol. ZOELY may have a risk of VTE in the same range as observed with a combined hormonal contraceptive that contains levonorgestrel/ethinyl estradiol.

Blood clots can also occur very rarely in the blood vessels of the heart (causing a heart attack) or the brain (causing a stroke). Extremely rarely blood clots can occur in the liver, gut, kidney or eye.

Very occasionally thrombosis may cause serious permanent disabilities or may even be fatal.

If you develop high blood pressure while using the Pill, you may be told to stop using it.

The risk of having deep venous thrombosis is temporarily increased as a result of an operation or immobilisation (for example when you have your leg or legs in plaster or splints). In women who use the Pill, the risk may be yet higher. Tell your doctor you are using the Pill well in advance of any expected hospitalisation or surgery. Your doctor may tell you to stop taking the Pill several weeks before surgery or at the time of immobilisation. Your doctor will also tell you when you can start taking the Pill again after you are back on your feet.

If you notice possible signs of a thrombosis, stop taking the Pill and consult your doctor immediately.

The Pill and Cancer

Regularly examine your breasts.

The information given below was obtained from studies of women who used combined oral hormonal contraceptives, as the combined pill containing ethinylestradiol, and from an additional study that included both oral and non-oral hormonal contraceptive-users.

In studies with the combined Pill, breast cancer has been diagnosed slightly more often in women who use the Pill than in women of the same age who do not use the Pill. This slight increase in the numbers of breast cancer diagnoses gradually disappears during the course of the 10 years after stopping use of the Pill.

In the additional study that included both oral and non-oral hormonal contraceptive-users, the occurrence of breast cancer was reported to increase the longer the women used the contraceptive. The difference in the reported risk of breast cancer between women who have never used the contraceptive and those who had used the contraceptive was small: 13 additional cases of breast cancer per 100,000 women-years.

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

Tell your doctor immediately if you have severe pain in your stomach.

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.

Chronic infection with Human Papilloma Virus (HPV) is the single most important risk factor for cervical cancer. HPV is a sexually transmitted infection. In women who use combined oral contraceptives for a long time the chance of getting cervical cancer may be slightly higher. This finding may not be caused by the Pill itself but may be related to sexual behaviour and other factors.

Meningiomas

Use of nomegestrol acetate (an ingredient in ZOELY), has been linked to the development of a generally benign tumour of the tissue layer between the brain and the skull (meningioma). The risk increases especially when you use it at high doses and for longer duration (several years). If you are diagnosed with meningioma, your doctor will stop your treatment with ZOELY. If you notice any symptoms such as changes in vision (e.g. seeing double or blurriness), hearing loss or ringing in the ears, loss of smell, headaches that worsen with time, memory loss, seizures, weakness in your arms or legs, you must tell your doctor straight away.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What ZOELY contains

Active ingredient

(main ingredient)

In the white tablets:

  • nomegestrol acetate 2.5 milligrams
  • estradiol 1.5 milligrams

In the yellow tablets:

No active ingredients

Other ingredients

(inactive ingredients)

In the white tablets:

  • lactose monohydrate
  • microcrystalline cellulose
  • crospovidone
  • purified talc
  • magnesium stearate
  • colloidal anhydrous silica
  • polyvinyl alcohol
  • titanium dioxide
  • macrogol 3350

In the yellow tablets:

  • lactose monohydrate
  • microcrystalline cellulose
  • crospovidone
  • purified talc
  • magnesium stearate
  • colloidal anhydrous silica
  • poly vinyl alcohol
  • titanium dioxide
  • iron oxide yellow
  • iron oxide black
  • macrogol 3350

Do not take this medicine if you are allergic to any of these ingredients.

What ZOELY looks like

ZOELY is presented in 1 or 3 PVC/Aluminium backed blister strips containing 28 film-coated tablets (24 white active tablets and 4 yellow inactive tablets).

The blister is packed in a carton together with the package leaflet. Each carton also contains a single paper sleeve, designed to carry one strip of tablets when removed from the outer carton.

The white, round active tablets are coded with 'ne' on both sides. The yellow, round inactive tablets are coded with 'p' on both sides.

Australia Registration Number:

ZOELY oral-contraceptive AUST R 168332

Who distributes ZOELY

Theramex Australia Pty Ltd
Level 22, 60 Margaret Street,
Sydney NSW 2000
1800 THERAMEX or 1800 843 726

This leaflet was updated in December 2022.

Published by MIMS May 2023

BRAND INFORMATION

Brand name

Zoely

Active ingredient

Nomegestrol acetate; Estradiol

Schedule

S4

 

1 Name of Medicine

Nomegestrol acetate and estradiol (as hemihydrate).

2 Qualitative and Quantitative Composition

Each blister strip consists of 24 white active tablets each containing 2.5 mg nomegestrol acetate and 1.5 mg estradiol (as hemihydrate) and 4 yellow placebo tablets that do not contain active substances.

List of excipients with known effect.

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

3 Pharmaceutical Form

Each blister of Zoely contains:
24 white, round, active film-coated tablets coded with 'ne' on both sides, each containing 2.5 mg nomegestrol acetate and 1.5 mg estradiol.
4 yellow, round, placebo film-coated tablets coded with 'p' on both sides.

4 Clinical Particulars

4.1 Therapeutic Indications

Oral contraception.

4.2 Dose and Method of Administration

How to take Zoely.

Tablet intake instructions are the same for all users.
Tablets must be taken every day at about the same time without regard to meals. Take tablets with some liquid as needed, and in the order as directed on the package. One tablet is to be taken daily for 28 consecutive days. Each pill pack starts with 24 white active tablets, followed by 4 yellow placebo tablets. A subsequent pack is started immediately after finishing the previous pack, without a break in daily tablet intake and irrespective of presence or absence of withdrawal bleeding. Withdrawal bleeding usually starts on day 2-3 after intake of the last white tablet and may not have finished before the next pack is started. See Section 4.4 Special Warnings and Precautions for Use, Cycle control.

How to start Zoely.

No preceding hormonal contraceptive use.

Tablet taking has to start on day 1 of the woman's natural cycle (i.e. the first day of her menstrual bleeding). When doing so, no additional contraceptive measures are necessary. Starting on days 2-5 is allowed, but during the first pill pack a barrier method should be used until the woman has completed 7 days of uninterrupted white tablet taking.

Changing from a combined hormonal contraceptive (combined oral contraceptive (COC), vaginal ring or transdermal patch).

The woman should start with Zoely preferably on the day after the last active tablet (the last tablet containing the active substances) of her previous COC, but at the latest on the day following the usual tablet free or placebo tablet interval of her previous COC. In case a vaginal ring or transdermal patch has been used, the woman should start using Zoely preferably on the day of removal, but at the latest when the next application would have been due.
If the woman has been using her previous method consistently and correctly, and if it is reasonably certain that she is not pregnant, she may also switch on any day. The hormone free interval of the previous method should never be extended beyond its recommended length.

Changing from a progestagen only method (minipill, implant, injectable) or from a hormone medicated intrauterine system (IUS).

The woman may switch any day from the minipill and Zoely should be started on the next day. An implant or IUS may be removed any day, and Zoely should be started on the day of its removal. When changing from an injectable, Zoely should be started on the day when the next injection would have been due. In all of these cases the woman should be advised to additionally use a barrier method until she has completed 7 days of uninterrupted white active tablet taking.

Following first trimester abortion.

The woman may start immediately. When doing so, no additional contraceptive measures are necessary.

Following delivery or second trimester abortion.

For breastfeeding women see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation.
Women should be advised to start between day 21 and 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 white active 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. The increased risk of thromboembolism in the puerperium must be considered if recommencing Zoely (see Section 4.4 Special Warnings and Precautions for Use).

Management of missed tablets.

The following advice only refers to missed white active tablets.
If the user is less than 24 hours late in taking any active tablet, contraceptive protection is not reduced. The woman should take the tablet as soon as she remembers and should take further tablets at the usual time.
If she is 24 or more hours late in taking any active tablet, contraceptive protection may be reduced. The management of missed tablets can be guided by the following two basic rules:
7 days of uninterrupted white active tablet taking are required to attain adequate suppression of the hypothalamic pituitary ovarian axis;
the more white active tablets are missed and the closer the missed tablets are to the 4 yellow placebo tablets, the higher the risk of a pregnancy.

Day 1-7 of active tablet intake.

The user should take the last missed white tablet as soon as she remembers even if this means taking two tablets at the same time. She then continues to take tablets at her usual time. In addition, a barrier method such as a condom should be used until she has completed 7 days of uninterrupted white tablet taking. If intercourse took place in the preceding 7 days, the possibility of a pregnancy should be considered.

Day 8-17 of active tablet intake.

The user should take the last missed white tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time. Provided that the woman has taken her tablets correctly in the 7 days preceding the first missed tablet, there is no need to use extra contraceptive precautions. However, if she has missed more than 1 tablet, the woman should be advised to use extra precautions until she has completed 7 days of uninterrupted white tablet taking.

Day 18-24 of active tablet intake.

The risk of reduced reliability is imminent because of the forthcoming yellow placebo tablet phase. However, by adjusting the tablet intake schedule, reduced contraceptive protection can still be prevented. By adhering to either of the following two options, there is therefore no need to use extra contraceptive precautions, provided that in the 7 days preceding the first missed tablet the woman has taken all tablets correctly. If this is not the case, she should follow the first of these two options and use extra precautions for the next 7 days as well.
1. The user should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time until the active tablets are used up. The 4 placebo tablets from the last row must be discarded. The next blister pack must be started right away. The user is unlikely to have a withdrawal bleed until the end of the active tablets section of the second pack, but she may experience spotting or breakthrough bleeding on tablet taking days.
2. The woman may also be advised to discontinue active tablet taking from the current blister pack. She should then take placebo tablets from the last row for a maximum of 3 days such that the total number of placebo plus missed active white tablets is not more than 4, and subsequently continue with the next blister pack.
If the woman missed tablets and subsequently has no withdrawal bleed in the placebo tablet phase, the possibility of a pregnancy should be considered.

Please note.

If the user is not sure about the number or colour of tablets missed and what advice to follow, a barrier method should be used until she has completed 7 days of uninterrupted white active tablet taking.

Yellow placebo tablets missed.

Contraceptive protection is not reduced. Yellow tablets from the last (4th) row of the blister can be disregarded. However, the missed tablets should be discarded to avoid unintentionally prolonging the placebo tablet phase.

Advice in case of gastrointestinal disturbances.

In case of severe gastrointestinal disturbance (e.g. vomiting or diarrhoea), absorption of the active substances may not be complete and additional contraceptive measures should be taken. If vomiting occurs within 3-4 hours after white tablet taking, the tablet should be considered as missed and a new tablet should be taken as soon as possible. The new tablet should be taken within 24 hours of the usual time of tablet taking if possible. The next tablet should then be taken at the usual time. If more than 24 hours have passed since last pill intake, the advice concerning missed tablets as given in Management of missed tablets, is applicable. If the woman does not want to change her normal tablet taking schedule, she has to take the extra white tablet(s) from another pack.

How to shift periods or how to delay a period.

To delay a period the woman should continue with another blister pack of Zoely without taking the yellow placebo tablets from her current pack. The extension can be carried on for as long as wished until the end of the white active tablets in the second pack. Regular intake of Zoely is then resumed after the yellow placebo tablets have been taken of the second pack. During the extension the woman may experience breakthrough bleeding or spotting.
To shift her periods to another day of the week than the woman is used to with her current scheme, she can be advised to shorten her forthcoming yellow placebo tablet phase with a maximum of 4 days. The shorter the interval, the higher the risk that she does not have a withdrawal bleed and may experience breakthrough bleeding and spotting during the subsequent pack (just as when delaying a period).

4.3 Contraindications

Combined hormonal contraceptives (COCs) should not be used in the presence of any of the conditions listed below. Zoely should be stopped immediately should any of the following conditions appear for the first time during the use of Zoely.
Presence or risk of venous thromboembolism (VTE) (see Section 4.4 Special Warnings and Precautions for Use):
current VTE (on anticoagulants) or history of deep venous thrombosis [DVT] or pulmonary embolism [PE];
known hereditary or acquired predisposition for venous thromboembolism, such as APC-resistance (including Factor V Leiden), antithrombin-III-deficiency, protein C deficiency, protein S deficiency hyperhomocysteinaemia, antiphospholipid-antibodies (e.g. anticardiolipin-antibodies and lupus anticoagulant);
major surgery with prolonged immobilisation;
a high risk of venous thromboembolism due to the presence of multiple risk factors.
Presence or risk of arterial thromboembolism (ATE) (see Section 4.4 Special Warnings and Precautions for Use):
current ATE or history of ATE (e.g. myocardial infarction or stroke) or prodromal condition (e.g. angina pectoris or transient ischaemic attack [TIA]);
known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and antiphospholipid-antibodies (e.g. anticardiolipin-antibodies and lupus anticoagulant), APC-resistance (including Factor V Leiden), antithrombin-III-deficiency, protein C deficiency, protein S deficiency.
History of migraine with focal neurological symptoms.
A high risk of arterial thromboembolism due to multiple risk factor(s) or the presence of one serious risk factor such as: diabetes mellitus with vascular symptoms, severe hypertension, severe dyslipoproteinemia.
Pancreatitis or a history thereof if associated with severe hypertriglyceridaemia.
Presence or history of severe hepatic disease as long as liver function values have not returned to normal.
Presence or history of liver tumours (benign or malignant).
Known or suspected sex steroid-influenced malignancies (e.g. of the genital organs or the breasts).
Meningioma or history of meningioma.
Known or suspected pregnancy.
Hypersensitivity to any of the active substances of Zoely or to any of the excipients.

4.4 Special Warnings and Precautions for Use

If any of the conditions/risk factors mentioned below is present, the benefits of the use of Zoely should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start using Zoely. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the woman should contact her physician. The physician should then decide on whether its use should be discontinued. All data presented below are based upon epidemiological data obtained with combined oral contraceptives (COCs) containing ethinylestradiol. Zoely contains 17β-estradiol. The warnings are considered applicable to the use of Zoely.

Circulatory disorders.

Risk of venous thromboembolism (VTE). Epidemiological studies have shown an association between the use of combined oral contraceptives (COCs) containing ethinylestradiol and an increased risk of venous thrombotic and thromboembolic diseases such as deep venous thrombosis and pulmonary embolism. These events occur rarely in average risk women.
Use of any ethinylestradiol-containing COC carries an increased risk of venous thromboembolism (VTE) compared with no use. The excess risk of VTE is highest during the first year a woman ever uses a combined oral contraceptive. The risk is also increased after initially starting a COC or restarting the same or different COC after a break in use of 4 weeks or more. This increased risk is less than the risk of VTE associated with pregnancy, which is estimated as 5-20 cases per 10,000 woman-years for pregnant women. This compares with 1-5 cases per 10,000 woman-years for non-users. VTE is fatal in 1%-2% of cases. It is not known how Zoely influences this risk compared with other COCs.
Extremely rarely, thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral or retinal veins and arteries, in COC users. There is no consensus as to whether the occurrence of these events is associated with the use of COCs. The use of any CHC increases the risk of VTE compared with no use.
Products that contain the progestogens levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. Zoely may have a risk of VTE in the same range as observed with CHC containing levonorgestrel.
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. See Table 1.
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 Section 4.4 Special Warnings and Precautions for Use, Risk factors for VTE).
Zoely 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.
The increased risk of thromboembolism in the puerperium must be considered if recommencing Zoely (see Section 4.2 Dose and Method of Administration).
Women using COCs should be specifically pointed out to contact their physician in case of possible symptoms of thrombosis. In case of suspected or confirmed thrombosis, COC use should be discontinued. Adequate contraception should be initiated because of the teratogenicity of anti-coagulant therapy (coumarins).

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: Activated Protein C (APC) resistance (including Factor V Leiden), antithrombin-III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinaemia, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).
Other medical conditions associated with VTE: 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 Zoely (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 Zoely 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;
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. Zoely 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: hyperhomocysteinaemia and antiphospholipid antibodies (e.g. anticardiolipin antibodies, and lupus anticoagulant), APC-resistance (including Factor V Leiden), antithrombin-III-deficiency, protein C deficiency, protein S deficiency.
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 or 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.

Neoplasms.

The most important risk factor for cervical cancer is persistent human papilloma virus (HPV) infection. Epidemiological studies have indicated that long-term use of ethinylestradiol-containing COCs contributes to this increased risk, but there continues to be uncertainty about the extent to which this finding is attributable to confounding effects, like increased cervical screening and difference in sexual behaviour including use of barrier contraceptives, or a causal association.
With the use of the higher-dosed COCs (50 microgram ethinylestradiol) the risk of endometrial and ovarian cancer is reduced. Whether this also applies to 17β-estradiol-containing COCs remains to be confirmed.
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 using ethinylestradiol-containing 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. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.
In another epidemiological study of 1.8 million Danish women followed an average of 10.9 years, the reported RR of breast cancer among COC users increased with longer duration of use compared with women who never used COCs (overall RR = 1.19; RR ranged from 1.17 for 1 to less than 5 years of use to 1.46 after more than 10 years of use). The reported absolute risk difference (number of breast cancer cases between never-users compared with current and recent COC users) was small: 13 per 100,000 woman-years.
Epidemiological 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.
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. Therefore, a hepatic 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.

Meningioma.

The occurrence of meningiomas (single and multiple) has been reported in association with use of nomegestrol acetate, especially at high doses and for prolonged use (several years). Patients should be monitored for signs and symptoms of meningiomas in accordance with clinical practice. If a patient is diagnosed with meningioma, any nomegestrol acetate-containing treatment, must be stopped, as a precautionary measure.

Hepatitis C.

During clinical trials with the Hepatitis C virus (HCV) combination drug regimen ombitasvir/paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medications such as CHCs. Women using medications containing estrogens other than ethinylestradiol, such as estradiol had a rate of ALT elevation similar to those not receiving any estrogens; however, due to the limited number of women taking these other estrogens, caution is warranted for co-administration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Other conditions.

Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.
Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. A relationship between COC use and clinical hypertension has not been established. However, if a sustained clinically significant hypertension develops during the use of a COC then it is prudent for the physician to suspend the intake of the tablets and treat the hypertension. Where considered appropriate, COC use may be resumed if normotensive values can be achieved with antihypertensive therapy. In seven multi-centre clinical trials of up to two years duration, no clinically relevant changes in blood pressure were observed with Zoely.
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; (hereditary) 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.
There is no evidence for a need to alter the therapeutic regimen in diabetics using low-dose COCs (containing < 0.05 mg ethinylestradiol). However, diabetic women should be carefully observed while taking a COC especially in the first months of use. Zoely was shown to have no effect on peripheral insulin resistance and glucose tolerance in healthy women (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Crohn's disease, ulcerative colitis and worsening of depression 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.
Zoely contains < 60 mg lactose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption who are on lactose-free diet should take this amount into consideration.

Medical examination/consultation.

Prior to the initiation or reinstitution of COC use, a complete medical history (including family history) should be taken and pregnancy must be ruled out. Blood pressure should be measured and if clinically indicated a physical examination should be performed, guided by the contraindications and precautions. The woman should also be instructed to carefully read the user leaflet and to adhere to the advice given. The frequency and nature of further periodic checks should be based on established practice guidelines and be adapted to the individual woman.
Women should be advised that oral contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.

Reduced efficacy.

The efficacy of COCs may be reduced in the event of e.g. missed tablets (see Section 4.2 Dose and Method of Administration), gastro-intestinal disturbances during active tablet taking (see Section 4.2 Dose and Method of Administration), or use of concomitant medication that decreases the plasma concentrations of nomegestrol acetate (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Cycle control.

As with all COCs, breakthrough bleeding or spotting may occur, especially during the first months of use. Therefore, the evaluation of any breakthrough bleeding or spotting is only meaningful after an adaptation interval of about three cycles. If bleeding irregularities persist or occur after previously regular cycles, then non-hormonal causes should be considered and adequate diagnostic measures are indicated to exclude malignancy or pregnancy. These may include curettage. Women with undiagnosed abnormal vaginal bleeding should not start treatment with a COC until a possible underlying condition has been excluded.
In the pivotal efficacy and safety trials, women using Zoely experienced overall a low number of bleeding events. Withdrawal bleedings were light and of short duration (on average 3-4 days) and often less painful (dysmenorrhea).
Some users of Zoely have reported absence of withdrawal bleeding during the placebo yellow tablet phase although not being pregnant. In such cases, absence of withdrawal bleeding was not associated with a higher occurrence of breakthrough bleeding or spotting in the subsequent cycle.
If absence of withdrawal bleeding occurs and Zoely is taken according to the instructions as described (see Section 4.2 Dose and Method of Administration) it is unlikely that the woman is pregnant. However, pregnancy must be ruled out before Zoely use is continued, if Zoely has not been taken as directed or if two consecutive withdrawal bleeds are missed.

Use in hepatic impairment.

See Section 4.3 Contraindications; Section 5.2 Pharmacokinetic Properties, Special populations.

Use in renal impairment.

See Section 5.2 Pharmacokinetic Properties, Special populations.

Use in the elderly.

No data available.

Paediatric use.

Warnings and precautions for post-menarcheal adolescents less than 18 years of age and women greater than 50 years of age are expected to be similar to those described for adults between these age groups although this has not been confirmed in clinical trials.

Effect on laboratory tests.

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Effect on laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Note.

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

Influence of other medicinal products on Zoely.

Interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. The following interactions have been reported in the literature for COCs in general.

Hepatic metabolism.

Interactions can occur with medicinal or herbal products that induce microsomal enzymes, specifically cytochrome P450 enzymes (CYP) which can result in increased clearance reducing plasma concentrations of sex hormones and may decrease the effectiveness of combined oral contraceptives, including Zoely. These products include phenytoin, barbiturates, primidone, bosentan, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, products containing St. John's wort and some HIV protease inhibitors (e.g. ritonavir and nelfinavir) and non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine and efavirenz), and combinations of them.
Enzyme induction can occur after a few days of treatment. Maximal enzyme induction is generally observed within a few weeks. After drug therapy is discontinued, enzyme induction can last for about 28 days.
When coadministered with hormonal contraceptives, many combinations of HIV protease inhibitors (e.g. nelfinavir) and non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine), and/or combinations with hepatitis C virus (HCV) medicinal products (e.g. boceprevir, telaprevir), can increase or decrease plasma concentrations of progestins, including nomegestrol acetate, or estrogen. The net effect of these changes may be clinically relevant in some cases.
Women receiving any of the above mentioned hepatic enzyme inducing medicinal or herbal products should be advised that the efficacy of Zoely may be reduced. A barrier contraceptive method should also be used during administration of the hepatic enzyme inducing medicinal product, and for 28 days after discontinuation of the hepatic enzyme inducing medicinal product.
If concomitant drug administration runs beyond the end of the active tablets in the current blister pack, the next blister pack should be started right away without the usual placebo tablet interval.
For women on long-term therapy with microsomal enzyme inducing medicinal products, an alternative method of contraception unaffected by enzyme inducing medicinal products should be considered.
Concomitant administration of strong (e.g. ketoconazole, itraconazole, clarithromycin) or moderate (e.g. fluconazole, diltiazem, erythromycin) CYP3A inhibitors may increase the serum concentrations of estrogens or progestins.

Antibiotics.

Contraceptive failures of ethinylestradiol containing oral contraceptives have been reported with antibiotics, such as ampicillin and tetracyclines. The mechanism of this effect has not been elucidated and it is unknown whether interactions of antibiotics with a 17β-estradiol containing contraceptive occur. Women on treatment with antibiotics (except rifampicin and griseofulvin, see above) should use a barrier method until 7 days after discontinuation. If the period during which the barrier method is used extends beyond the end of the white tablets in the COC pack, the yellow placebo tablets must be discarded and the next COC pack should be started right away.
Drug interaction studies were not performed with Zoely, but two studies with rifampicin and ketoconazole, respectively, were performed with a higher dosed NOMAC-E2 combination (NOMAC 3.75 mg + 1.5 mg E2) in postmenopausal women.

Influence of Zoely on other medicinal products.

Oral contraceptives may affect the metabolism of other drugs. Accordingly, plasma and tissue concentrations may either increase (e.g. ciclosporin) or decrease (e.g. lamotrigine).

Other interactions.

During clinical trials with the HCV combination drug regimen ombitasvir/ paritaprevir/ ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol containing medications such as CHCs. Women using medications containing estrogens other than ethinylestradiol, such as estradiol had a rate of ALT elevation similar to those not receiving any estrogens; however, due to the limited number of women taking these other estrogens, caution is warranted for coadministration with the combination drug regimen ombitasvir/ paritaprevir/ ritonavir with or without dasabuvir.

Paediatric population.

The interactions as described above are expected to be similar in postmenarcheal adolescent women.

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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

See Section 5.1 Pharmacodynamic Properties.
(Category B3)
Zoely is not indicated during pregnancy. If pregnancy occurs during treatment with Zoely, further intake should be stopped. Most epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used ethinylestradiol-containing COCs prior to pregnancy, nor a teratogenic effect when ethinylestradiol-containing COCs were taken inadvertently during early pregnancy.
Clinical data on a limited number of exposed pregnancies indicate no adverse effect of Zoely on the foetus or neonate.
In rats, treatment with nomegestrol acetate and estradiol in combination caused increased post-implantation loss, abortions, decreased foetal weight, feminisation of male foetuses, malformations (cleft palate and bent tail) and increased variations (vertebral and rib abnormalities and incomplete ossification). Nomegestrol acetate, given alone in rats, prolonged or impaired parturition. Post-implantation loss was increased and foetal weight was decreased in rabbits treated with the combination. Systemic exposure to nomegestrol acetate (plasma AUC) at no-effect doses in the animal embryofetal development studies was similar to or less than the expected human exposure level. Nomegestrol acetate was shown to cross the placenta in monkeys, with foetal plasma levels comparable to maternal drug levels.
Lactation may be influenced by COCs as they may reduce the quantity and change the composition of breast milk. Therefore, the use of COCs should not be recommended until the nursing mother has completely weaned her child. Small amounts of the contraceptive steroids and/or their metabolites may be excreted with the milk, but there is no evidence that this adversely affects infant health.

4.7 Effects on Ability to Drive and Use Machines

Zoely has no influence on the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

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

Tabulated summary of adverse reactions.

Seven multicentre clinical trials of up to two years duration were used to evaluate the safety of Zoely. In total 3490 women, aged 18-50, were enrolled and completed 35,028 cycles.
Zoely is well tolerated and demonstrates an overall safety profile similar to other combined oral contraceptives. Possibly related undesirable effects that have been reported in users of Zoely are listed in Table 2.
The adverse reaction rates for Zoely (N = 3490) in comparison to the reference COC containing drospirenone 3 mg and ethinylestradiol 30 microgram (21/7 regimen) (N = 1105) in the integrated safety data set were acne (15.4% versus 7.9%), weight increased (8.5% versus 5.9%) and abnormal withdrawal bleeding (predominantly absence of withdrawal bleeding) (10.2% versus 0.6%).

Description of selected adverse reactions.

A number of undesirable effects have been reported in women using combined oral contraceptives containing ethinylestradiol, which are discussed in more detail, see Section 4.4 Special Warnings and Precautions for Use. These include: venous thromboembolic disorders; arterial thromboembolic disorders; hypertension; hormone dependent tumours (e.g. liver tumours, breast cancer); chloasma.
The frequency of diagnosis of breast cancer is very slightly increased among COC users. As breast cancer is rare in women under 40 years of age the excess number is small in relation to the overall risk of breast cancer. Causation with COC use is unknown. For further information, see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use.

Paediatric population.

Frequency, type and severity of adverse reactions in postmenarcheal adolescents are expected to be the same as in adult women.

Other special populations.

No studies have been performed with renally or hepatically impaired subjects. However, steroid hormones may be poorly metabolized in patients with impaired liver function.

Post-market experience.

In addition to the above mentioned adverse reactions, hypersensitivity reactions have been reported in Zoely users (frequency unknown).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

There have been no reports of serious deleterious effects from overdose. Multiple doses up to five times the daily dose of Zoely and single doses up to 40 times the daily dose of nomegestrol acetate alone have been used in women without safety concern. On the basis of general experience with combined oral contraceptives, symptoms that may occur are nausea, vomiting and, in young girls, slight vaginal bleeding. There are no antidotes and further treatment should be symptomatic.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Nomegestrol acetate is a highly selective progestogen derived from, and structurally similar to, the naturally occurring steroid hormone, progesterone. Nomegestrol acetate has a strong affinity for the human progesterone receptor and has strong antigonadotropic activity, moderate antiandrogenic activity, and is devoid of any estrogenic, androgenic, glucocorticoid or mineralocorticoid activity.
The estrogen contained in Zoely is 17β-estradiol, a natural estrogen identical to the endogenous human 17β-estradiol (E2). This estrogen differs from the estrogen ethinylestradiol used in other combined oral contraceptives (COC) by the lack of the ethinyl group in the 17α position. During use of Zoely, the average E2 levels are comparable to the E2 levels during the early follicular and late luteal phase of the menstrual cycle.
The contraceptive effect of Zoely is based on the interaction of various factors, the most important of which are the inhibition of ovulation and the changes in the cervical secretion. During the use of Zoely, nomegestrol acetate is primarily responsible for the suppression of ovulation, with 17β-estradiol enhancing the suppressive effects of nomegestrol acetate.
After discontinuation of Zoely, rapid return to ovulation was observed in most women.
Folic acid is an important vitamin in the early phase of pregnancy. Folic acid serum levels remained unchanged during and after Zoely treatment for 6 consecutive cycles as compared to baseline.
Pharmacotherapeutic group: progestogens and estrogens, fixed combinations, ATC code: G03AA14.

Clinical trials.

Contraceptive efficacy.

Two randomized, open label, comparative efficacy safety trials (study report 292001 and 292002) were conducted in more than 3200 women treated for 13 consecutive cycles with Zoely. The primary efficacy and safety parameters were contraceptive efficacy, vaginal bleeding pattern (cycle control), general safety and acceptability. Women entering the study were aged between 18 and 50 years and women with a BMI greater than 35 were excluded from the study. Women were excluded from the study if they had conditions which were listed as a contraindication for combined oral contraceptives. The overall pearl index (method failure and user failure) 18-50 years of age was 0.64 (upper limit 95% CI 1.03).
In the pivotal efficacy and safety trials, women using Zoely experienced overall a low number of bleeding events. Withdrawal bleedings were light and of short duration (on average 3-4 days) and often less painful (dysmenorrhea).
A randomized, open label, comparative, multicenter trial (study report 292004) was performed to assess effects of Zoely on haemostasis, lipids, carbohydrate metabolism, adrenal and thyroid function and on androgens. Glucose tolerance and insulin sensitivity remained unaltered and no clinically relevant effects on lipid metabolism and haemostasis were observed with Zoely. The comparator levonorgestrel 150 microgram + ethinylestradiol 30 microgram was associated with more pronounced changes in these parameters. Zoely increased the carrier proteins TBG and CBG, but to lesser extent than LNG-EE. Zoely induced a small increase in SHBG, which was slightly higher than LNG-EE (20 to 30 microgram EE). The androgenic parameters androstenedione, DHEA-S, total and free testosterone were significantly reduced during use of Zoely.
Endometrial histology was investigated in a subgroup of women (n = 32) in one clinical study after 13 cycles of treatment. There were no abnormal results.

5.2 Pharmacokinetic Properties

Nomegestrol acetate (NOMAC).

Absorption.

Orally administered nomegestrol acetate (NOMAC) is rapidly absorbed. Maximum plasma concentrations of NOMAC of about 7 nanogram/mL are reached at 2 h after single administration. The absolute bioavailability of NOMAC after a single dose is 63%. Administration of Zoely with a high fat meal increased the bioavailability of NOMAC by 27-29% which was not considered clinically relevant.

Distribution.

Nomegestrol acetate (NOMAC) is extensively bound to albumin (97-98%), but does not bind to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG). The apparent volume of distribution of NOMAC at steady state is 1645 ± 576 L.

Metabolism.

Nomegestrol acetate (NOMAC) is metabolized into several hydroxylated metabolites without progestagenic activity, by liver cytochrome P450 enzymes, mainly CYP2C8, CYP2C19, CYP3A4 and CYP3A5. NOMAC and its hydroxylated metabolites undergo extensive phase 2 metabolism to form glucuronide and sulphate conjugates. The estrogenic and androgenic activities of the metabolites are unknown. The apparent clearance at steady state is 26 L/h.

Excretion.

The elimination half-life (t1/2) is 46 hours (ranging from 28-83 hours) at steady state. The elimination half-life of metabolites was not determined. NOMAC is excreted via urine and faeces. Approximately 80% of the dose is excreted in urine and faeces within 4 days. Excretion of NOMAC was nearly complete after 10 days and amounts excreted were higher in faeces than in urine.

Linearity.

Dose linearity was observed in the range 0.625-5 mg (assessed in fertile and postmenopausal women).

Steady-state conditions.

The pharmacokinetics of nomegestrol acetate (NOMAC) are not influenced by SHBG. Steady state is achieved after 5 days. Maximum plasma concentrations of NOMAC of about 12 nanogram/mL are reached 1.5 hours after dosing. Average steady-state plasma concentrations are 4 nanogram/mL.

Drug-drug interactions.

From in vitro studies, nomegestrol acetate causes no notable induction or inhibition of any cytochrome P450 enzymes and has no clinically relevant interaction with the P-gp transporter.

Estradiol (E2).

Absorption.

17β-estradiol (E2) is subject to a substantial first-pass effect after oral administration. The absolute bioavailability is approximately 5%. After administration of Zoely with a high fat meal, the mean exposure to estradiol (E2) was only marginally affected. Exposure to the major metabolite of E2, estrone (E1), was increased by about 20% which was not considered clinically relevant.

Distribution.

The distribution of exogenous and endogenous 17β-estradiol (E2) is similar. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estradiol circulates in the blood bound to SHBG (37%) and to albumin (61%), while only approximately 1-2% is unbound.

Metabolism.

Oral exogenous 17β-estradiol (E2) is extensively metabolized. The metabolism of exogenous and endogenous E2 is similar. E2 is rapidly transformed in the gut and the liver in several metabolites, mainly estrone (E1), which are subsequently conjugated and undergo enterohepatic circulation. There is a dynamic equilibrium between E2, E1 and E1-sulfate (E1S) due to various enzymatic activities including E2-dehydrogenases, sulfotransferases and aryl sulfatases. Oxidation of E1 and E2 involves cytochrome P450 enzymes, mainly CYP1A2, CYP1A2 (extra hepatic), CYP3A4, CYP3A5, and CYP1B1 and CYP2C9.

Excretion.

17β-estradiol (E2) is rapidly cleared from the circulation. Due to metabolism and enterohepatic circulation, a large circulating pool of estrogen sulfates and glucuronides is present. This results in a highly variable elimination half-life of E2, which is calculated to be 8.4 ± 6.4 hours, after intravenous administration.

Steady-state conditions.

Maximum serum concentrations of 17β-estradiol (E2) are about 90 picogram/mL and are reached 6 hours after dosing. Average serum concentrations are 50 picogram/mL and these E2 levels correspond with the early and late phase of a woman's menstrual cycle.

Special populations.

Paediatric population.

Whole body physiologically based pharmacokinetic modeling and simulation showed that no difference in the nomegestrol acetate pharmacokinetics is expected between postmenarcheal adolescent women (aged 12-17 years) and adult women.

Effect of renal impairment.

No studies were performed to evaluate the effect of renal disease on the pharmacokinetics of Zoely.

Effect of hepatic impairment.

No studies were conducted to evaluate the effect of hepatic disease on the pharmacokinetics of Zoely. However, steroid hormones may be poorly metabolised in women with impaired liver function.

Ethnic groups.

No formal studies were performed to assess pharmacokinetics in ethnic groups.

5.3 Preclinical Safety Data

Genotoxicity.

No evidence for genotoxicity was found with nomegestrol acetate in assays for bacterial and mammalian mutagenicity, yeast mitotic gene conversion, chromosomal aberrations and unscheduled DNA synthesis in vitro and clastogenicity in vivo (mouse and rat bone marrow micronucleus tests).
There is limited evidence available in the literature suggesting that estradiol may be weakly genotoxic at high doses. No evidence could be found for an increase in the rate of gene mutation in bacterial or mammalian cells, but there was some evidence for the induction of chromosomal aberrations and aneuploidy and an increased incidence of sister chromatid exchanges (indicative of DNA damage) in mammalian cells. None of these effects were induced by estradiol in human lymphocyte cultures. Importantly, there was no evidence for micronuclei formation in rodent bone marrow assays.
The genotoxic potential of the combination of nomegestrol acetate and estradiol has not been investigated.

Carcinogenicity.

Carcinogenicity studies have not been performed with the combination of nomegestrol acetate and estradiol. However, studies have been performed for the two active components separately.
Supraphysiological doses of estradiol have been associated with the induction of tumours in estrogen-dependent target organs in all rodent species tested. The relevance of these findings with respect to humans has not been established. However, it must be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumours.
In a long-term oral (dietary) carcinogenicity study in mice, nomegestrol acetate increased the incidence of mammary gland carcinoma and pituitary adenoma in females at doses ≥ 20 mg/kg/day and 50 mg/kg/day, respectively. Systemic exposure to nomegestrol acetate (plasma AUC) in animals at these doses was 4 to 15 times higher than that of women treated with Zoely. These findings are consistent with extensive endocrine disruption in the species caused by the progestagenic activity of nomegestrol acetate.
No evidence of tumourigenicity was found with nomegestrol acetate in a 2-year study in rats using dietary doses up to 10 mg/kg/day (yielding 30 times the expected human exposure level).

6 Pharmaceutical Particulars

6.1 List of Excipients

The white active tablets contain the inactive ingredients lactose monohydrate, microcrystalline cellulose, crospovidone, purified talc, magnesium stearate, colloidal anhydrous silica, Opadry II complete film coating system 85F18422 White PI (11376).
The yellow placebo tablets contain the inactive ingredients lactose monohydrate, microcrystalline cellulose, crospovidone, purified talc, magnesium stearate, colloidal anhydrous silica, Opadry II complete film coating system 85F32865 Yellow PI (106699).

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Pack sizes: 1 x 28 and 3 x 28 tablets in PVC/Al blisters (transparent PVC thermoforming film with aluminium lidding foil). Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Zoely is a combined oral contraceptive (COC) preparation containing the progestogen nomegestrol acetate and the natural estrogen 17β-estradiol as the active substances.

Chemical structure.

Nomegestrol acetate.


Chemical name: 17α-acetoxy-6-methyl-19-norpregna-4,6-dien-3,20-dione.
Molecular formula: C23H30O4.
Molecular mass: 370.48.
A white to off white crystalline powder that is freely soluble in methylene chloride, acetone and ethyl acetate, soluble in dioxane and acetonitrile and sparing soluble in methanol and ethanol. Melting range is between 177 and 180°C.

Estradiol.


Chemical name: estra-1,3,5(10)-triene-3,17β-diol.
Molecular formula: C18H24O2.
Molecular mass: 281.4.
A white to almost white, crystalline powder and is practically insoluble in water. Melting range is between 173 and 179°C.

CAS number.

Nomegestrol acetate.

58652-20-3.

Estradiol.

50-28-2.

7 Medicine Schedule (Poisons Standard)

Schedule 4.

Summary Table of Changes