Consumer medicine information

Madeline

Desogestrel; Ethinylestradiol

BRAND INFORMATION

Brand name

Madeline

Active ingredient

Desogestrel; Ethinylestradiol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Madeline.

What is in this leaflet

This leaflet answers some common questions about this medicine. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

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

Read this information carefully before you start taking Madeline® tablets.

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

What this medicine is used for

The name of your medicine is Madeline®. It contains the active ingredients desogestrel and ethinylestradiol.

It is a combined oral contraceptive, commonly known as a "birth control pill" or "the Pill".

It is used to prevent pregnancy. You may also experience the following benefits:

  • more regular periods, lighter bleeding
  • a decrease in the occurrence of anaemia (iron deficiency)
  • a decrease in period pain.

There is also evidence that some medical conditions such as benign breast disease, ovarian cysts, pelvic inflammatory disease (pelvic infections), ectopic pregnancy (pregnancy in which the embryo implants outside of the womb) and cancer of the endometrium (lining of the womb) and ovaries may be less common in women using combined oral contraceptives containing 50 micrograms of ethinylestradiol (high-dose Pills). This may also be the case for low-dose Pills but so far this has only been confirmed for endometrial and ovarian cancer.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

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

How it works

When taken correctly, this medicine prevents pregnancy in several ways:

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

There is no evidence that this medicine is addictive.

Before you take this medicine

When you must not take it

Do not use the combined Pill if you have or have had any of the conditions listed below. If any of these conditions apply to you, tell your doctor before starting to use this medicine. Your doctor may advise you to use a different type of Pill or an entirely different (non-hormonal) method of birth control.

  • a disorder affecting the blood circulation; in particular, those conditions relating to thrombosis (the formation of a blood clot) in the blood vessels of the legs (deep vein thrombosis), the lungs (pulmonary embolism), the heart (heart attack) or other parts of the body (see also the section later in this leaflet called 'The Pill and Thrombosis')
  • a stroke (caused by a clot in or a rupture of a blood vessel in the brain)
  • a condition that may be the first sign of a heart attack (such as angina pectoris or chest pain) or stroke (such as transient ischaemic attack or small reversible stroke)
  • 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)
  • if you have major surgery (e.g., an operation) and your ability to move around is limited for a long period of time (see also the section later in this leaflet called "The Pill and Thrombosis")
  • if you know that you have Activated Protein C resistance, (including Factor V Leiden), antithrombin-III, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant), and hyperhomocysteinaemia.
  • a history of migraine accompanied by e.g. visual symptoms, speech disability, or weakness or numbness in any part of the body
  • diabetes mellitus with blood vessel damage
  • 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
  • a cancer that may grow under the influence of sex hormones (e.g. of the breast or of the genital organs)
  • a benign or malignant liver tumour
  • 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 this medicine, stop taking it at once and tell your doctor.

In the meantime use non-hormonal contraceptive measures. See also 'General Notes' in the next section.

Do not use this medicine if you have Hepatitis C and are taking the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir and medicinal products including glecaprevir and pibrentasvir (see "Taking Other Medicines").

Do not take this medicine if:

  • You are hypersensitive to, or have had an allergic reaction to, desogestrel, ethinylestradiol or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include: cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin; fainting; or hay fever-like symptoms.
    If you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.
  • The expiry date (EXP) printed on the pack has passed.
  • The packaging is torn, shows signs of tampering or it does not look quite right.

General notes

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. This medicine 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).

Before you start to take it

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

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 are overweight
  • you or anyone in your immediate family has had blood clots in the legs (thrombosis), a heart attack, a stroke, breast cancer or high cholesterol.

Before you start taking this medicine, tell your doctor if:

  1. You have allergies to:
  • any other medicines
  • any other substances, such as foods, preservatives or dyes.
  1. You have or have had any medical conditions, especially the following:
  • diabetes
  • high blood pressure
  • 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 or someone in your immediate family has or has had high levels of cholesterol or triglycerides (fatty substances) in the blood
  • anyone in your immediate family has had breast cancer
  • inflammation of your veins (superficial phlebitis)
  • varicose veins
  • migraine
  • epilepsy
  • liver disease
  • gall bladder disease
  • Crohn's disease or ulcerative colitis (chronic inflammatory bowel disease)
  • systemic lupus erythematosus (SLE, a disease affecting the skin, joints and kidneys)
  • haemolytic uraemic syndrome (HUS, a disorder of blood coagulation causing failure of the kidneys)
  • sickle cell disease
  • 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); hereditary and acquired angioedema (you should see your doctor immediately if you experience symptoms of angioedema such as swollen face, tongue and/or throat and/or difficulty swallowing or hives, potentially difficulty breathing). Products containing estrogens may cause or worsen hereditary and acquired angioedema.
  • 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 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.
  • if 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 this medicine (see also the section in this leaflet called 'The Pill and Thrombosis').
  • lactose intolerant.
    If any of the above conditions appear for the first time, or recur or worsen while taking this medicine, you should contact your doctor.
  1. You are currently breastfeeding or you plan to breastfeed. This medicine is generally not recommended whilst breastfeeding.
  2. You are planning to have surgery or an anaesthetic.
  3. You are currently receiving or are planning to receive dental treatment.
  4. You are taking or are planning to take any other medicines. This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

Taking other medicines

Some medicines and herbal products may interact with desogestrel and/or ethinylestradiol. These include:

  • medicines for epilepsy (such as phenytoin, primidone, phenobarbital, barbiturates, carbamazepine, oxcarbazepine, topiramate, felbamate, lamotrigine)
  • medicines for tuberculosis (e.g. rifampicin and rifabutin)
  • medicines for HIV infections (ritonavir, nelfinavir, nevirapine, efavirenz)
  • medicines for Hepatitis C virus infection (e.g. boceprevir, telaprevir)
  • certain antibiotics (e.g. penicillin, and tetracyclines)
  • antifungals (e.g. griseofulvin)
  • ciclosporin, a medicine used for suppressing the immune system (i.e. during and after organ transplants)
  • 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 any of these you may need a different dose or you may need to take different medicines.

You may also need to use an additional barrier method of contraception (such as a condom or a diaphragm) while you are taking any of these medicines and for some time after stopping them. Your doctor will be able to advise how long you will need to use additional barrier contraceptive methods.

Do not use the Pill if you have Hepatitis C and are taking the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir as this may cause increases in liver function blood test results (increase in ALT liver enzyme). The Pill can be restarted approximately 2 weeks after completion of treatment with the combination drug regimen. (See "When you must not take it").

If you are taking other Hepatitis C drug combinations (such as glecaprevir/pibrentasvir) you may experience increased levels of the liver enzyme “alanine aminotransferase” (ALT) in the blood.

Other medicines not listed above may also interact with desogestrel and ethinylestradiol.

Your doctor has more information on medicines that you need to be careful with or avoid while taking this medicine.

How to take this medicine

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

The pack contains 28 tablets: 21 white tablets with active substances and 7 green placebo tablets that contain inactive substances.

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

How much to take

Take one tablet daily.

Do not stop taking your medicine or change your dosage without first checking with your doctor.

How to take it

Swallow each tablet whole with a glass of water.

When to take it

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

Take one tablet daily in the order directed on the blister, at about the same time every day. This will help you remember when to take it. It does not matter if you take this medicine before or after food.

You must take this medicine every day even if you do not have sex very often.

A period should begin during the 7 days that you use the inactive tablets (the withdrawal bleed). Usually it will start on day 2-3 after the last white active tablet.

How to start this medicine

Start with a tablet from the blue zone marked with that day of week.

When no hormonal contraception has been used in the past month:
Start on the first day of your period (i.e. the first day of menstrual bleeding). Take a tablet from the blue zone marked with that day of the week. For example, if your period starts on a Wednesday, then take a tablet marked Wednesday. Then follow the days in order.

If your period starts on a Thursday or Friday, make sure you also use an additional barrier method of contraception (e.g. condom) for the first 7 days of white active tablet taking, as the Thursday and Friday tablets in the blue zone are green placebo (inactive) tablets.

Changing from another combined oral contraceptive, vaginal ring or transdermal patch:
Start the day after taking the last active tablet in your previous Pill pack (or at the latest on the day following the last placebo tablet or tablet free interval of your previous Pill pack), taking a tablet from the blue zone marked with that day of the week.

Ask your doctor or pharmacist if you are not sure which the active tablets were in your previous Pill pack. Your previous Pill pack may have had different colour tablets to those of this medicine.

If a vaginal ring or transdermal patch has been used, start on the day of removal (but at the latest when the next application would have been due), taking a tablet from the blue zone marked with that day of the week.

Changing from a progestogen-only pill (minipill):
You may change any day, taking a tablet from the blue zone marked with that day of the week, but make sure you also use an additional barrier method of contraception (e.g. condom) for the first 7 days of white active tablet taking.

Changing from a progestogen-only implant or progesterone-releasing intrauterine system (IUS):
Change on the day of its removal, taking a tablet from the blue zone marked with that day of the week, and make sure you also use an additional barrier method of contraception (e.g. condom) for the first 7 days of white active tablet taking.

Changing from a progestogen-only injectable:
Change when the next injection would be due, taking a tablet from the blue zone marked with that day of the week, and make sure you also use an additional barrier method of contraception (e.g. condom) for the first 7 days of white active tablet taking.

After having a baby, miscarriage or abortion:
Your doctor will advise you. Please note that there is an increased risk of thrombosis (venous thrombosis embolism, VTE) during the postpartum period and this risk should be considered when restarting this medicine.

How long to take it for

Daily tablet taking should be continuous. One tablet is taken daily for 28 consecutive days in the order directed on the blister.

Start a new blister pack on the day after the last green placebo (inactive) tablet of the previous pack.

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

If you forget to take it

Missed green placebo (inactive) tablets
Missed green placebo (inactive) tablets should be discarded to avoid accidentally extending the placebo tablet phase. Take the next tablet at the usual time. You are still protected against pregnancy because the green placebo (inactive) tablets do not contain any active ingredients.

Missed white active tablets
For this medicine to be most effective, white active tablets need to be taken every day without interruption for 7 days.

If you missed a white active tablet and take the missed tablet within 12 hours, you will be protected against pregnancy and should continue taking the tablets as normal.

If you missed a white active tablet (or several white active tablets - in which case also speak to your doctor for advice) and are more than 12 hours late, take the last missed white active tablet immediately, even if it means taking two tablets in one day. Make sure you also use an additional barrier method of contraception (e.g. condom) for the next 7 days and complete the pack as normal.

However, if these next 7 days include the taking of green placebo (inactive) tablets, the white active tablets of the next pack should be started as soon as the white active tablets from the current pack are finished.

If you missed one or more of the first 7 white active tablets and sexual intercourse has taken place, there is a possibility you may be pregnant. See your doctor for advice.

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

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much of this medicine. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

While you are taking this medicine

Things you must do

Tell your doctor that you are taking this medicine if:

  • you are about to be started on any new medicine
  • you are pregnant or are planning to become pregnant
  • you are breastfeeding or are planning to breastfeed
  • you are about to have any blood tests
  • you are going be immobilised, have surgery or an anaesthetic or are going into hospital (consult your doctor at least 4 weeks in advance)
  • Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

When you are taking the Pill, your doctor will tell you to return for regular check-ups, including getting a pap smear test. Your doctor will advise how often you need a pap smear test. A pap smear test can detect abnormal cells lining the cervix. Sometimes abnormal cells can progress to cancer.

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 take the Pill, the risk may be higher.

The excess risk of thrombosis is highest during the first year a woman takes a combined oral contraceptive. Your doctor may tell you to stop taking the Pill several weeks before surgery, or at the time of immobilisation, and when you can start taking the Pill again. If you notice possible signs of a thrombosis (see side effects), stop taking the Pill and consult your doctor immediately.

Consult your doctor if you develop high blood pressure while taking this medicine – you may be told to stop taking it.

If you vomit within 3-4 hours or have severe diarrhoea after taking a white active tablet, the active ingredients may not have been completely absorbed. This is like missing a tablet. Follow the advice for missed tablets.

If you have unexpected bleeding and it continues, becomes heavy, or occurs again, tell your doctor. When taking these tablets for the first few months, you can have irregular vaginal bleeding (spotting or breakthrough bleeding) between your periods. You may need to use sanitary protection, but continue to take your tablets as normal. Irregular vaginal bleeding usually stops once your body has adjusted to the Pill, usually after about 3 months.

This medicine will not protect you from HIV-AIDS or any other Sexually Transmitted Diseases (STDs), such as chlamydia, genital herpes, genital warts, gonorrhoea, hepatitis B, human papilloma virus and syphilis.

To protect yourself from STDs, you will need to use an extra barrier method of contraception (e.g. condom).

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.

Things you must not do

Do not:

  • Give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Take your medicine to treat any other condition unless your doctor tells you to.
  • Stop taking your medicine, or change the dosage, without first checking with your doctor. You may become pregnant if you are not using any other contraceptive and you stop taking this medicine, or do not take a tablet every day.

Side effects

Tell your doctor as soon as possible if you do not feel well while taking this medicine.

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Tell your doctor if you notice any of the following:

Common/uncommon (occurring in more than one per 1000 users):

  • nausea, vomiting, abdominal pain or diarrhoea
  • increase in body weight or fluid retention
  • headache or migraine
  • decreased sexual drive, increased sexual drive
  • depressed mood or mood changes
  • breast pain, breast tenderness or breast enlargement
  • rash, hives

Rare (occurring in less than one per 1000 users):

  • contact lens intolerance
  • decrease in body weight
  • breast secretion
  • vaginal secretion
  • male-pattern hair growth or loss
  • acne
  • erythema nodosum, erythema multiforme (these are skin conditions)

Unknown (frequency cannot be estimated from the available data):

  • angioedema, particularly in patients who already have a (family) history of angioedema

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

These are very serious side effects and you may need urgent medical attention or hospitalisation.

  • jaundice (yellowing of the eyes or skin).

See 'Thrombosis and the Pill'. Possible signs of a blood clot, heart attack or a stroke can include:

  • an unusual cough
  • severe pain in the chest which may reach the left arm
  • breathlessness
  • any unusual, severe or prolonged headache or migraine attack
  • partial or complete loss of vision, or double vision
  • slurring or speech disability
  • sudden changes to your hearing, sense of smell or taste
  • dizziness or fainting
  • weakness or numbness in any part of your body
  • severe pain in your stomach
  • severe pain or swelling in either of your legs.

Other side effects not listed above may occur in some patients.

When to contact your doctor

Regular check-ups
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.

Contact your doctor as soon as possible if:

  • you notice any changes in your own health, especially involving any of the items mentioned in this leaflet (see also 'When you must not take it' and 'Before you start to take it'); do not forget about the items related to your immediate family
  • you feel a lump in your breast
  • you experience symptoms of angioedema such as swollen face, tongue and/or throat and/or difficulty swallowing or hives potentially with difficulty breathing (see also section ‘Taking other medicines’)
  • you are going to use other medicines (see also 'Taking other medicines')
  • you are going to be immobilised or are to have surgery (consult your doctor at least 4 weeks in advance)
  • you have unusual, heavy vaginal bleeding
  • you forgot tablets in the first week of the pack and had intercourse in the seven days before
  • you have severe diarrhoea
  • you miss your period twice in a row or suspect you are pregnant. Do not start the next pack until told to by your doctor.

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

The situations and symptoms mentioned above are described and explained in more detail in section ‘Before you take this medicine’.

Thrombosis and the Pill

Thrombosis is the formation of a blood clot that may block a blood vessel.

Thrombosis sometimes occurs in the deep veins of the legs (deep venous thrombosis (DVT)). If a blood clot breaks away from the veins where it has formed, it may reach and block the arteries of the lungs, causing pulmonary embolism (PE).

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 after you started using the Pill for the very first time. The risk is also higher if you restart using the Pill (the same product or a different product) after a break of 4 weeks or more. Thrombosis can also occur during pregnancy.

The risk of getting a blood clot in the deep veins of the legs for women using Pills with desogestrel (in Madeline®) may be slightly higher than for women using Pills with levonorgestrel, norgestimate or norethisterone. The absolute numbers remain very small. If 10,000 women use a Pill with levonorgestrel for one year, 2 women would get a thrombosis. If 10,000 women use a Pill with desogestrel for a year approximately 3 to 4 women would get a thrombosis. For comparison, if 10,000 women get pregnant, approximately 6 would get a thrombosis. These findings are based on the results of some studies. Other studies did not find a higher risk for Pills with desogestrel.

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.

Cancer and the Pill

Regularly examine your breasts.

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

Breast cancer has been diagnosed slightly more often in women who take the Pill than in women of the same age who do not take the Pill. This slight increase in the numbers of breast cancer diagnoses gradually disappears during the course of the 10 years after women stop taking the Pill.

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 the difference is caused by the Pill. It may be that these women were examined more often, so that the breast cancer was noticed earlier.

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, but may be related to sexual behaviour and other factors.

Allergic reactions

If you think you are having an allergic reaction to this medicine, do not take any more and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • cough, shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hay fever-like symptoms.

Storage and disposal

Storage

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

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

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

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What Madeline® looks like

21 active tablets: round, biconvex, white, film-coated tablet with "MI" debossed on one side and "7" debossed on the other.

7 placebo tablets: round, biconvex, plain, green, film-coated tablet with no markings.

MADELINE® desogestrel 150 micrograms and ethinylestradiol 30 micrograms tablet blister pack: AUST R 202833.

Ingredients

Each white active tablet contains 150 micrograms of desogestrel and 30 micrograms of ethinylestradiol as the active ingredients.

This medicine also contains the following:

  • lactose monohydrate
  • maize starch
  • povidone
  • colloidal anhydrous silica
  • hypromellose
  • triacetin
  • polysorbate 80
  • titanium dioxide
  • d-alpha-tocopherol (white active tablets only)
  • silicon dioxide (white active tablets only)
  • stearic acid (white active tablets only)
  • magnesium stearate (green placebo tablets only)
  • indigo carmine aluminium lake (green placebo tablets only)
  • iron oxide yellow (green placebo tablets only).

This medicine contains lactose. It also contains d-alpha-tocopherol.

This medicine is gluten-free, sucrose-free, tartrazine-free and free of other azo dyes.

Sponsor

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel
St Cremorne VIC 3121

MADELINE® is a registered trademark of Apotex Pty Ltd.

This leaflet was last updated in:
July 2023.

Published by MIMS September 2023

BRAND INFORMATION

Brand name

Madeline

Active ingredient

Desogestrel; Ethinylestradiol

Schedule

S4

 

1 Name of Medicine

Desogestrel and ethinylestradiol.

2 Qualitative and Quantitative Composition

Madeline is a combined oral contraceptive (COC) tablet containing the synthetic progestogen, desogestrel and the synthetic estrogen, ethinylestradiol.
Each white active tablet contains 150 microgram desogestrel and 30 microgram ethinylestradiol.

Excipients with known effect.

Active tablets.

Lactose monohydrate, d-alpha-tocopherol.

Placebo tablets.

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

3 Pharmaceutical Form

Madeline is available in blister packs. Each blister contains 28 tablets consisting of 21 active tablets and 7 placebo tablets.

Active tablet.

Round, biconvex, white, film-coated tablets with "MI" debossed on one side, and "7" debossed on the other.

Placebo tablet.

Round, biconvex, plain, green, film-coated tablets.

4 Clinical Particulars

4.1 Therapeutic Indications

Oral contraception.

4.2 Dose and Method of Administration

Madeline is intended for oral administration.

Dosage.

How to take this medicine. One tablet is to be taken daily. The tablets must be taken in the order directed on the package at about the same time each day, with some liquid as needed. Daily tablet taking should be continuous, starting with the tablet marked with the corresponding day from the blue zone. Each subsequent pack is to be started immediately following the last placebo (green) tablet. During the placebo days a withdrawal bleed usually occurs. This usually starts on day 2-3 after the last active (white) tablet and may not have finished before the next pack is started.
How to start this medicine. The tablets are taken starting with the tablet marked with the corresponding day from the blue zone of the pack. This way, the woman will virtually always have a menstruation free weekend.

No preceding hormonal contraceptive use (in the past month).

Tablet taking has to start on day 1 of the woman's natural cycle (i.e. the first day of her menstrual bleeding). If the woman starts on a Thursday or Friday (although these tablets are in the blue zone, they are inactive tablets) additional contraceptive precautions are necessary for the first 7 days of active tablet taking.

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

The woman should start with this medicine 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 interval or following the last placebo tablet of her previous COC.
In case a vaginal ring or transdermal patch has been used, the woman should start using this medicine preferably on the day of removal, but at the latest when the next application would have been due.
The hormone free interval of the previous method should never be extended beyond its recommended length.

Changing from a progestogen only method (minipill, injection, implant) or from a progestogen releasing intrauterine system (IUS).

The woman may switch any day from the minipill (from an implant or the IUS on the day of its removal, from an injectable when the next injection would be due), but in all of these cases should be advised to additionally use a barrier method for the first 7 days of active tablet taking.

Following a first trimester abortion.

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

After childbirth or a second or third trimester abortion.

For breastfeeding women see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation.
Women should be advised to start 21 to 28 days after delivery or second trimester abortion (no later than day 26 if starting on a Thursday or day 27 if starting on a Friday). When starting later than day 28, the woman should be advised to additionally use a barrier method for the first 7 days of 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 VTE during the postpartum period should be considered when restarting this medicine (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

Management of missed tablets.

When this medicine is taken according to the directions for use, the occurrence of pregnancy is highly unlikely. However, the reliability of oral contraceptives may be reduced under the following circumstances:
If the user is less than 12 hours late in taking any 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 more than 12 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:
1. Active tablet taking must never be discontinued for longer than 7 days.
2. Seven days of uninterrupted 'active tablet' taking are required to attain adequate suppression of the hypothalamic pituitary ovarian axis.
Accordingly the following advice can be given in daily practice:
If the user is more than 12 hours late in taking any white active tablet (or several white active tablets) from the pack, she should take the last forgotten tablet, even if this means taking two tablets in one day, and then continue to take tablets at the normal time. Additional contraceptive precautions should be taken for the next 7 days.
If these 7 days would usually include the taking of green placebo tablets, the white active tablets of the next pack should be started as soon as the white active tablets from the current pack are finished. This prevents an extended break in taking active tablets, which may increase the risk of the ovaries releasing an egg and thus reducing contraceptive protection. The woman will not have a period until the end of the second pack of tablets, but this is not harmful, nor does it matter if she experiences some bleeding on the days she is taking this medicine.
Whenever white active tablets are missed at the beginning of the pack (that is, missing one or more of the first 7 white active tablets), and sexual intercourse has taken place, the possibility of pregnancy should be considered.

Advice in case of gastrointestinal disturbances.

In case of severe gastrointestinal disturbance, absorption may not be complete and additional contraceptive measures should be taken.
If vomiting occurs within 3-4 hours after tablet taking, the advice concerning missed tablets, as given previously, is applicable. If the woman does not want to change her normal tablet taking schedule, she has to take the extra tablet(s) needed from another pack.

Additional contraceptive precautions.

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

How to shift periods or how to delay a period.

To delay a period the woman should continue with another pack of this medicine without having the green placebo tablet interval. The extension can be carried on for as long as wished until the end of the second pack. During the extension the woman may experience breakthrough bleeding or spotting. Regular intake of this medicine is then resumed after the usual 7 day placebo tablet interval.
To shift her period to another day of the week than the woman is used to with her current scheme, she can be advised to shorten her forthcoming placebo tablet interval by as many days as she likes. The shorter the interval, the higher the risk that she does not have a withdrawal bleed and will experience breakthrough bleeding and spotting during the second pack (just as when delaying a period).

4.3 Contraindications

Combined oral contraceptives (COCs) should not be used in the presence of any of the conditions listed below. Should any of the conditions appear for the first time during COC use, the product should be stopped immediately.
Presence or risk of venous thromboembolism (VTE) (see Section 4.4 Special Warnings and Precautions for Use):
current VTE (on anticoagulants) or history of deep venous thrombosis (DVT) or pulmonary embolism (PE);
known hereditary or acquired predisposition for venous thromboembolism, such as APC resistance (including factor V Leiden), antithrombin III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinaemia and antiphospholipid-antibodies;
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, cerebrovascular accident or stroke) or prodromal conditions (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 factors or to the presence of one serious risk factor such as diabetes mellitus with vascular symptoms, severe hypertension, severe dyslipoproteinaemia.
Pancreatitis or a history thereof if associated with severe 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).
Undiagnosed vaginal bleeding.
Known or suspected pregnancy.
Sickle cell anaemia.
Hypersensitivity to the active substances or to any of the excipients.
Madeline is contraindicated for use with the Hepatitis C virus combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir and medicinal products including glecaprevir and pibrentasvir (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

If any of the conditions/risk factors mentioned below is present, the benefits of COC use should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start using it. 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 COC use should be discontinued. All data presented below are based upon epidemiological data obtained with combined oral contraceptives (COCs) containing ethinylestradiol. Madeline contains 17β-estradiol. No epidemiological data are available with estradiol containing COC but the warnings are considered applicable to the use of this medicine.

Circulatory disorders.

Risk of venous thromboembolism (VTE). Epidemiological studies have suggested an association between the use of 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.
The use of any ethinylestradiol containing COC is associated with 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 COC. 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 to 20 per 10,000 pregnant woman years. This compares with 1 to 5 cases per 10,000 woman years for nonusers. VTE is fatal in 1% to 2% of cases.
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.
The risk of VTE with the COC is greatest for products containing over 50 microgram of ethinylestradiol. There is less risk for products containing less than 35 microgram ethinylestradiol. Madeline contains the progestogen desogestrel which has an increased risk of VTE compared to other progesterones such as levonorgestrel, norgestimate or norethisterone which are associated with the lowest risk of VTE (see Table 1).
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 COCs, and how her current risk factors influence this risk.
The increased risk of VTE during the postpartum period should be considered if restarting a COC (see Section 4.2 Dose and Method of Administration).
The risk for venous thromboembolic complications in COC users may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see list below).
Madeline 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 COC should not be prescribed.

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, 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 Madeline (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 this medicine 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 COC 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 COC.
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 lightheadedness or dizziness;
rapid or irregular heartbeat.
Some of these symptoms (e.g. "shortness of breath", "coughing") are nonspecific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections).
Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discolouration of an extremity.
If the occlusion occurs in the eye symptoms can range from painless blurring of vision which can progress to loss of vision. Sometimes loss of vision can occur almost immediately.
Risk of arterial thromboembolism (ATE). Epidemiological studies have associated the use of COCs 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 COC users increases in women with risk factors. Madeline 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 COC should not be prescribed.

Risk factors for ATE.

Increasing age, particularly above 35 years.
Smoking.
Hypertension.
Obesity (BMI over 30 kg/m2).
Positive family history (i.e. arterial thromboembolism ever in a sibling or parent especially at a relatively early age, e.g. below 50).
Biochemical factors: hyperhomocysteinaemia and antiphospholipid antibodies (e.g. anticardiolipin antibodies, and lupus anticoagulant), Activated Protein C (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, valvular heart disease, atrial fibrillation, dyslipoproteinaemia, systemic lupus erythematosus.
Women should be advised not to smoke if they wish to use a COC. 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 COC use.
An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation.

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 COC.
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, trouble speaking or understanding;
sudden trouble seeing in one or both eyes;
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.

Several epidemiological studies suggest that use of combined oral contraceptives, in particular if used for 5 years or longer, has been associated with an increased risk of cervical intra-epithelial neoplasia or invasive cervical cancer. After cessation of use of oral contraceptives the risk gradually decreases over time to that of nonusers in about 8 years. Human papilloma virus is believed to be the most important cause of cervical cancer, but the independent association with the use of hormonal contraceptives suggests a contributing effect. These findings must be balanced against evidence of significant effects attributable to sexual behaviour, smoking, parity and other factors. See Section 4.4 Special Warnings and Precautions for Use, Medical examination/consultation.
An increased risk of cervical cancer in long-term users of COCs has been reported in some epidemiological studies, but there continues to be controversy about the extent to which this finding is attributable to the confounding effects of sexual behaviour and other factors such as human papilloma virus (HPV).
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 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 intraabdominal haemorrhages. 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. (Also see Section 5.3 Preclinical Safety Data, Genotoxicity, Carcinogenicity.)

Hepatitis C.

During clinical trials with some HCV combination drug regimens, ALT elevations were observed in women using ethinylestradiol containing medications (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). For example, 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. ALT elevations have also been observed with HCV anti-viral medicinal products including glecaprevir/pibrentasvir.
Madeline must be discontinued prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Madeline can be restarted approximately 2 weeks following completion of treatment with the combination drug regimen.

Other conditions.

Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.
Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.
Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. However, if a sustained clinically significant hypertension develops during the use of a COC then it is prudent for the physician to withdraw the COC and treat the hypertension. Where considered appropriate, COC use may be resumed if normotensive values can be achieved with antihypertensive therapy.
The following conditions have been reported to occur or deteriorate with both pregnancy and COC use, but the evidence of an association with COC use is inconclusive: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham's chorea; herpes gestationis; otosclerosis related hearing loss; (hereditary) angioedema.
Although COCs may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics using low dose COCs (containing < 50 microgram ethinylestradiol). However, diabetic women should be carefully observed while taking COCs.
Crohn's disease and ulcerative colitis have been associated with COC use.
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking COCs.
Madeline tablets contain lactose. Each white active tablet contains 54.9 mg lactose; each green placebo tablet contains 55.5 mg lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption who are on a lactose free diet should take these amounts into consideration.
When counselling the choice of contraceptive method(s), all of the above information should be taken into account.

Check the following before use.

Medical examination/consultation.

A complete medical history and physical examination should be taken prior to the initiation or reinstitution of COC use, guided by Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, and should be repeated periodically during the use of COCs. In general, an annual examination is recommended. Periodic medical assessment is also of importance because contraindications (e.g. a transient ischaemic attack, etc.) or risk factors (e.g. a family history of venous or arterial thrombosis) may appear for the first time during the use of a COC. The frequency and nature of these assessments should be based on established guidelines and be adapted to the individual woman but should generally include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology. Women who have ever been sexually active, including current and past users of hormonal contraceptives, should have scheduled Pap smear examinations in accordance with current public health guidelines.

Sexually transmitted disease including HIV infections and AIDS.

Women should be advised that this medicine does not protect against sexually transmitted diseases (STDs), including HIV infections (AIDS) and human papilloma virus (HPV). The woman should be advised that additional barrier contraceptive measures are needed to prevent transmission of STDs, but that even barrier contraceptives may not protect against HPV.

Reduced efficacy.

The efficacy of COCs may be reduced in the event of missed active tablets, gastrointestinal disturbances during active tablet taking or concomitant medication that decrease the plasma concentration of etonogestrel, the active metabolite of desogestrel.

Reduced cycle control.

With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. Therefore, the evaluation of any irregular bleeding is only meaningful after an adaptation interval of about three cycles. If bleeding irregularities persist or occur after previously regular cycles, then nonhormonal causes should be considered and adequate diagnostic measures are indicated to exclude malignancy or pregnancy. These may include curettage.
In some women withdrawal bleeding may not occur during the placebo tablet interval. If the COC has been taken according to the directions, it is unlikely that the woman is pregnant. However, if the COC has not been taken according to these directions prior to the first missed withdrawal bleed or if two withdrawal bleeds are missed, pregnancy must be ruled out before COC use is continued.

Use in hepatic impairment.

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.
See Section 4.3 Contraindications.

Use in the elderly.

No data available.

Paediatric use.

No data available.

Effects on laboratory tests.

The use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins, e.g. corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.
See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Note.

The prescribing information of concomitant medicines should be consulted to identify potential interactions.
Interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or oral contraceptive failure. The following interactions have been reported in the literature.

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. These products include: hydantoins, phenytoin, phenobarbital, primidone, bosentan, carbamazepine, rifampicin, rifabutin and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, some HIV protease inhibitors (e.g. ritonavir) and non-nucleoside reverse transcriptase inhibitors (e.g. efavirenz) and products containing St. John's wort.
Enzyme induction can occur after a few days of treatment. Maximum enzyme induction is generally observed within a few weeks. After drug therapy is discontinued enzyme induction can last for about 28 days.
When co-administered 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 etonogestrel, the active metabolite of desogestrel, or estrogens. 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 Madeline may be reduced. A barrier contraceptive method should be used in addition to Madeline 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 COC pack, the next COC pack should be started right away without the usual placebo tablet interval.
For women on long-term therapy with 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) CYP 3A4 inhibitors may increase the serum concentrations of estrogens or progestins, including etonogestrel, the active metabolite of desogestrel.
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).
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. Madeline must be discontinued prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use). Madeline can be restarted approximately 2 weeks following completion of treatment with the combination drug regimen.
Concomitant use with some other HCV antiviral medicinal products, such as those containing glecaprevir/pibrentasvir, may increase the risk of ALT elevations (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use). Prescribers should consult the relevant anti-viral medicine product safety information. Patients taking a CHC should therefore be switched to an alternative method of contraception (e.g. progestogen-only contraception or non-hormonal methods) prior to starting therapy.

Interference with enterohepatic circulation.

Some clinical reports suggest that enterohepatic circulation of estrogens may decrease when certain antibiotic agents are given, which may reduce ethinylestradiol concentrations (e.g. penicillins, tetracyclines).
Women on treatment with any of these drugs should temporarily use a barrier method in addition to the COC or choose another method of contraception. With microsomal enzyme inducing drugs, the barrier method should be used during the time of concomitant drug administration and for 28 days after their discontinuation. Women on treatment with antibiotics (except rifampicin and griseofulvin) should use the barrier method until 7 days after discontinuation. If the period during which the barrier method is used runs beyond the end of the active tablets in the COC pack, the next COC pack should be started without the usual placebo tablet interval.
Oral contraceptives may interfere with the metabolism of other drugs. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporin) or decrease (e.g. lamotrigine).

Note.

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

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category B3)
Madeline is contraindicated during pregnancy. If pregnancy occurs during treatment, further intake should be stopped. However, extensive epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used COCs prior to pregnancy, nor a teratogenic effect when COCs were taken inadvertently during early pregnancy.
The increased risk of thromboembolism during the puerperium must be considered.
In animal studies, maternal administration of high doses of estrogens has produced urogenital malformations in the offspring. The relevance of the animal findings for the clinical use of ethinylestradiol is not certain. However, there was no evidence for teratogenic activity when ethinylestradiol/desogestrel was given orally to pregnant rats (up to 0.2/0.5 mg/kg) or rabbits (0.04/0.1 mg/kg) during organogenesis. These doses correspond to exposure levels (based on body surface area) 15 to 60 times human exposure at the maximum recommended dose. The combination had no adverse peri/post natal effects in rats at similarly high exposure 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 generally 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

No effects on ability to drive and use machines have been observed.

4.8 Adverse Effects (Undesirable Effects)

Various adverse reactions have been associated with oral contraceptive use. The most serious adverse reactions associated with the use of oral contraceptives are indicated under Section 4.4 Special Warnings and Precautions for Use (also see Section 4.3 Contraindications).
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.
Possibly related undesirable effects that have been reported in clinical trials or observational studies with desogestrel/ethinylestradiol and COCs are listed in Table 2.
A number of undesirable effects have been reported in women using COCs, which are discussed in more detail in 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); exacerbations of hereditary and acquired angioedema; chloasma.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems and contact Arrotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

There have been no reports of serious deleterious effects from overdose. Symptoms that may occur in this case 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.

The contraceptive effect of COCs is based on the interaction of various factors. The primary mechanisms are inhibition of ovulation (by suppression of gonadotropins) and changes in the cervical secretion (blocking the entry of sperm into the uterus). Besides protection against pregnancy, COCs have several positive properties which, next to the negative properties (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)), can be useful in deciding on the method of birth control. For the majority of users, the cycle is more regular, the menstruation is often less painful and bleeding is lighter. The latter may result in a decrease in the occurrence of iron deficiency. Apart from this, there is evidence of a reduced risk of endometrial cancer and ovarian cancer. Furthermore, the higher dosed (0.050 mg ethinylestradiol) COCs have been shown to reduce the incidence of ovarian cysts, pelvic inflammatory disease, benign breast disease and ectopic pregnancy. Whether this also applies to lower dosed COCs remains to be confirmed.
Receptor binding studies as well as studies in animals and humans have shown that etonogestrel, the biologically active metabolite of desogestrel, combines high progestational activity with low intrinsic androgenicity. As a result, desogestrel does not counteract the estrogen-induced increase in sex hormone binding globulin (SHBG), resulting in lower serum levels of free testosterone.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

In a study comparing this product with the reference product, the two products were shown to be bioequivalent. The 90% confidence intervals for the ratio of AUC0-72 and Cmax were found to be between 91.07-112.45% and 87.46-113.28% respectively for desogestrel. The 90% confidence intervals for the ratio of AUC0-t and Cmax were found to be between 95.24-102.94% and 85.77-95.00% respectively for ethinylestradiol.

Desogestrel.

Absorption.

After oral dosing, desogestrel is rapidly absorbed and converted to 3-keto-desogestrel (etonogestrel). Peak serum concentrations of approximately 2 nanogram/mL are reached after 1.5 h after single ingestion and absolute bioavailability is 62-81%.

Distribution.

Etonogestrel is bound to serum albumin and to SHBG. Only 2-4% of the total serum drug concentrations are present as free steroid, 40-70% are specifically bound to SHBG. The ethinylestradiol induced increase in SHBG influences the distribution over the serum proteins, causing an increase of the SHBG bound fraction and a decrease of the albumin bound fraction. The apparent volume of distribution of desogestrel is 1.5 L/kg.

Metabolism.

Etonogestrel is completely metabolised by the known pathways of steroid metabolism. The metabolic clearance rate from serum is about 2 mL/min/kg. No interaction was found when coadministered with ethinylestradiol.

Excretion.

Etonogestrel serum levels decrease in two phases. The terminal disposition phase is characterised by a half-life of approximately 30 hours. Desogestrel and its metabolites are excreted at a urinary to biliary ratio of about 6:4.

Steady-state conditions.

Etonogestrel pharmacokinetics are influenced by SHBG levels, which are increased threefold by ethinylestradiol. Following daily ingestion, drug serum levels increase about two to threefold, reaching steady-state conditions during the second half of the treatment cycle.

Ethinylestradiol.

Absorption.

Orally administered ethinylestradiol is rapidly and almost completely absorbed. Peak serum concentrations of about 80 picogram/mL are reached within 1-2 hours. Absolute bioavailability, as a result of presystemic conjugation and first pass metabolism, is approximately 60%.

Distribution.

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

Metabolism.

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

Excretion.

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

Steady-state conditions.

Steady-state concentrations are reached after 34 days when serum drug levels are higher by 30-40% as compared to single dose.

5.3 Preclinical Safety Data

Genotoxicity.

Assays for gene mutations (S. typhimurium) and chromosomal damage (in vivo mouse micronucleus test) performed with desogestrel or the combination did not provide any evidence of a genotoxic potential.

Carcinogenicity.

Carcinogenicity studies for human risk estimation were performed for both components of the preparation, ethinylestradiol and desogestrel, and the combination.
Long-term studies with ethinylestradiol/desogestrel in rats and mice at oral doses up to 0.2/0.5 mg/kg elicited an increased incidence of pituitary and mammary gland tumours. The tumours occurred at exposure levels (based on body surface area) 30 to 60 times human exposure at the maximum recommended dose. The mechanism involved estrogen and prolactin sensitive pathways in rodents. These pathways have no direct counterpart in humans; therefore the clinical significance of these findings is uncertain.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, maize starch, povidone, colloidal anhydrous silica, hypromellose, triacetin, polysorbate 80, titanium dioxide, d-alpha-tocopherol (white active tablets only), silicon dioxide (white active tablets only), stearic acid (white active tablets only), magnesium stearate (green placebo tablets only), indigo carmine aluminium lake (green placebo tablets only), iron oxide yellow (green placebo tablets only).

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Madeline is available in PVC/PVDC/AL blister packs of 28 tablets (21 active tablets and 7 placebo tablets). AUST R 202833.
Madeline is a registered trade mark of Apotex Pty Ltd.

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

Desogestrel.

A white or almost white crystalline powder, it is a progestogen, semi synthetically produced from naturally occurring plant steroids. It is optically pure, is practically insoluble in water, and slightly soluble in ethanol and ethyl acetate.

Ethinylestradiol.

A white or slightly yellowish white crystalline powder. Melting point: 181-185°C. It is practically insoluble in water, freely soluble in ethanol (96%) and in ether, sparingly soluble in chloroform. It dissolves in dilute alkaline solutions.

Chemical structure.

Desogestrel.


Chemical Name: 13-ethyl-11-methylidene-18,19-dinor-17α-pregn-4-en-20-yn-17-ol.
Molecular Formula: C22H30O.
Molecular Weight: 310.5.

Ethinylestradiol.


Chemical Name: 19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol.
Molecular Formula: C20H24O.
Molecular Weight: 296.4.

CAS number.

Desogestrel: 54024-22-5.
Ethinylestradiol: 57-63-6.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes