Consumer medicine information

Qlaira

Estradiol valerate; Dienogest

BRAND INFORMATION

Brand name

Qlaira

Active ingredient

Estradiol valerate; Dienogest

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Qlaira.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Qlaira. 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 Qlaira against the benefits they expect it will have for you.

If you have any concerns, or are unsure about taking this medicine, ask your doctor or pharmacist for more advice.

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

WHAT QLAIRA IS USED FOR

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

Qlaira is used to prevent pregnancy. It is also used for the treatment of heavy and/or prolonged menstrual bleeding (not caused by any underlying disease) in women who wish to use oral contraception.

While taking Qlaira you may also experience the following benefits:

  • More regular and lighter periods – potentially resulting in a decrease in anaemia (iron deficiency)
  • a decrease in period pain

Some conditions such as pelvic inflammatory disease, ovarian cysts, ectopic pregnancy (where the foetus is carried outside of your womb), lumpy breasts and cancer of the uterus (womb) and ovaries may be less common in women taking Qlaira.

Qlaira contains two female sex hormones called estradiol valerate (an estrogen) and dienogest (a progestogen).The estrogen in Qlaira (estradiol valerate) is broken down in the body into a hormone called 17β-estradiol, which is identical to the natural estrogen produced by the female body. The estrogen in Qlaira is therefore different from the synthetic estrogen (known as ethinylestradiol) usually used in other forms of the Pill.

When taken correctly, Qlaira prevents you from becoming pregnant by:

  • inhibiting ovulation (egg release)
  • changing the cervical mucus consistency, making it more difficult for the sperm to reach the egg
  • changing the lining of the uterus, making it less suitable for implantation.

When the Pill is taken by women under close observation in clinical trials, it is more than 99% effective in preventing pregnancy. However, in real life the Pill is around 92% effective. This is because pills might be missed, or taken with medicines that may interfere with their effectiveness, or may not be absorbed due to vomiting and diarrhoea.

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

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

BEFORE YOU TAKE QLAIRA

When you must not take it

Do not take Qlaira if you have an allergy to:

  • any medicine containing estradiol valerate and/or dienogest
  • any of the ingredients in Qlaira listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

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

Do not take Qlaira if you have, or have had a blood clot in:

  • the blood vessels of the legs (deep vein thrombosis - DVT)
  • the lungs (pulmonary embolism - PE)
  • the heart (heart attack)
  • the brain (stroke)
  • other parts of the body.

Do not take Qlaira if you are concerned about an increased risk of blood clots. Blood clots are rare. Very occasionally blood clots may cause serious permanent disability, and may even be fatal.

All combined oral contraceptive pills, including Qlaira, increase the risk of having a blood clot. However the risk of having a blood clot when taking Qlaira is less than the risk of having a blood clot during pregnancy.

Do not take Qlaira if you are concerned about an increased risk of blood clots because of age or smoking. The risk of having a heart attack or stroke increases as you get older. It also increases if you smoke. You should stop smoking when taking Qlaira, especially if you are older than 35 years of age.

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

  • blood clots in your legs
  • any blood clotting disorders such as Protein C deficiency, Protein S deficiency, Leiden Factor V mutation, Antithrombin III deficiency or other inherited blood clotting conditions
  • A confirmed blood test showing:
    - increased levels of homocysteine
    - antiphospholipid antibodies (APLAs) e.g. anticardiolipin-antibodies and lupus anticoagulant. These may increase your risk for blood clots or pregnancy losses (miscarriage).
  • major surgery after which you have not been able to move around for a period of time
  • angina (chest pain)
  • a mini-stroke (also known as TIA or transient ischaemic attack)
  • migraine, where you have also had problems with seeing, speaking or had weakness or numbness in any part of your body
  • high risk of blood clots due to conditions such as diabetes with blood vessel damage, severe high blood pressure or severe high or low level of fats in your blood
  • pancreatitis (an inflammation of the pancreas) associated with high levels of fatty substances in your blood
  • severe liver disease and your liver function has not returned to normal
  • cancer that may grow under the influence of sex hormones (e.g. of the breast or the genital organs)
  • a benign or malignant liver tumour
  • unexplained vaginal bleeding.

If any of these conditions appear for the first time while using Qlaira, stop taking it at once and tell your doctor. In the meantime use non-hormonal (barrier) methods of contraception (such as condoms or a diaphragm).

Do not take this medicine if you are pregnant or think you might be pregnant.

Do not give this medicine to a child. Qlaira is not intended for use in females whose periods have not yet started.

Do not take this medicine after the expiry date printed on the packet. The expiry date is printed on the packet after “EXP” (e.g. 11 18 refers to November 2018). The expiry date refers to the last day of that month. If it has expired return it to your pharmacist for disposal.

Do not take this medicine if the packaging is torn or shows signs of tampering. If the packaging is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if:

  • you smoke
  • you or anyone in your immediate family has had blood clots in the legs (DVT) or lungs (PE), a heart attack, a stroke, breast cancer or high cholesterol.

Tell your doctor if you have, or have had any of the following medical conditions:

  • diabetes
  • high blood pressure
  • heart valve disorders or certain heart rhythm disorders
  • migraine
  • cancer

Ask your doctor to check if you:

  • are overweight
  • have any hereditary or acquired conditions that may make it more likely for you to get blood clots
  • have high cholesterol or triglycerides
  • have liver disease
  • have jaundice (yellowing of the skin) and/or pruritus (itching of the skin) related to cholestasis (condition in which the flow of bile from the liver stops or slows)
  • have gall bladder disease
  • have Crohn’s disease or ulcerative colitis (chronic inflammatory bowel disease)
  • have systemic lupus erythematosus (SLE - a disease affecting the skin, joints and kidneys)
  • have haemolytic uraemic syndrome (HUS - a disorder of blood coagulation causing failure of the kidneys)
  • have sickle cell disease
  • have a condition that occurred for the first time, or worsened during pregnancy or previous use of sex hormones (e.g. hearing loss, a metabolic disease called porphyria, a skin disease called herpes gestationis, a neurological disease called Sydenham’s chorea)
  • have chloasma (yellowish-brown pigmentation patches on the skin, particularly of the face) – if so, avoid exposure to the sun or ultraviolet radiation
  • have hereditary angioedema – you should see your doctor immediately if you experience symptoms of angioedema, such as swollen face, tongue and/or pharynx and/or difficulty swallowing, or hives together with difficulty in breathing

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

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

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

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

Taking other medicines

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

Some medicines/foods and Qlaira may interfere with each other. These include:

  • medicines used to treat tuberculosis such as rifampicin, rifabutin
  • medicines used to treat epilepsy such as phenytoin, primidone, barbiturates (e.g. phenobarbitone), carbamazepine, oxcarbazepine, topiramate, felbamate, lamotrigine
  • medicines used to treat HIV, such as ritonavir or nevirapine
  • some medicines used to treat Hepatitis C Virus (HCV) such as boceprevir, telaprevir
  • macrolide antibiotics such as clarithromycin and erythromycin
  • medicines used to treat fungal infections, such as ketoconazole, itraconazole,voriconazole, fluconazole and griseofulvin
  • herbal medicines containing St John’s Wort
  • blood pressure medication such as verapamil, diltiazem
  • medicines used to treat depression such as nefazodone, fluvoxamine
  • antacids such as cimetidine
  • grapefruit juice.

These medicines/foods may be affected by Qlaira, or may affect how well it works. Your doctor may need to alter the dose of your medicine, or prescribe a different medicine.

You may need to use an additional barrier method of contraception (such as condoms or a diaphragm) while you are taking any of these medicines with Qlaira and for some time after stopping them.

Your doctor will be able to tell you how long you will need to use additional contraceptive methods.

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

HOW TO TAKE QLAIRA

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

If you do not understand the instructions printed on the packet or in this leaflet, ask your doctor or pharmacist for help.

How to take it

Take one tablet daily at about the same time each day. You must take Qlaira every day regardless of how often you have sex. This will also help you remember when to take it.

Swallow the tablet whole with a full glass of water. It does not matter if you take it before or after food.

Each packet contains 26 coloured active tablets and 2 white inactive tablets.

Usually your period will start when you are taking the second dark red tablet or the white tablets and may not have finished before you start the next packet. Some women still experience bleeding after taking the first tablets of the new packet.

Tablets should be taken continuously so the next packet should be started even if bleeding has not stopped. This means that you should start your following packet on the same day of the week as the current packet and that your period should occur on the same days each month.

Preparation of the packet

To help you keep track, there are 7 weekday sticker strips marked with the 7 days of the week.

Choose the weekday sticker strip that starts with the day you begin taking the tablets. For example, if you start on a Wednesday, use the weekday sticker strip that starts with “WED”. Remember to use the same weekday sticker strip (for example, “WED”) for your next packet.

Stick the weekday sticker strip along the top of the Qlaira packet where it reads “Place weekday sticker strip here”, so that the first day is above the tablet marked “1”.

There is now a day shown above every tablet and you can see whether you have taken a tablet on a particular day. Follow the direction of the arrow on the packet until all 28 tablets have been taken.

Discard the unused weekday sticker strips.

Taking Qlaira for the first time

If you are starting Qlaira after a natural cycle, and you have not used a hormonal contraceptive during the previous month, start on the first day of your period, i.e. on the first day of your menstrual bleeding. If you take Qlaira in this way, you are protected against pregnancy immediately.

Your doctor will advise you when to start if you:

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

Changing from another contraceptive

Changing from a combined oral contraceptive:
Start taking Qlaira on the day after taking the last active tablet in your previous Pill pack. If you are not sure which were the active/inactive tablets in your previous Pill pack, ask your doctor or pharmacist. Your previous Pill pack may have different colour tablets to those of Qlaira.

Changing from a progestogen-only pill (‘minipill’):
Stop taking the minipill on any day and start taking Qlaira at the same time the day after you took your last minipill.

You must also use additional barrier contraceptive precautions (e.g. condoms or a diaphragm) for the first 9 days of tablet-taking when having intercourse.

Changing from a progestogen-only injection, implant or intrauterine system (IUS):
Start taking Qlaira when your next injection is due, or on the day that your implant or IUS is removed.

You must also use additional barrier contraceptive precautions (e.g. condoms or a diaphragm) for the first 9 days of tablet-taking when having intercourse.

Changing from a vaginal ring:
Start Qlaira on the day of removal of the vaginal ring or follow the advice of your doctor.

Ask your doctor what to do if you are not sure when to start.

Stopping Qlaira

You can stop taking Qlaira at any time. If you are considering becoming pregnant, it is recommended that you begin taking a vitamin supplement containing folic acid. It is best that you start taking folic acid before you stop taking Qlaira and not stop until your doctor advises this. Ask your doctor or pharmacist about suitable supplements. It is both safe and recommended that you take folic acid during pregnancy.

If you forget to take Qlaira

Inactive tablets:
If you miss a white tablet (2 tablets at the end of the packet), you do not need to take them later because they do not contain any active ingredients. However, it is important that you discard the missed white tablet(s) to make sure that the number of days between taking active tablets is not increased as this would increase the risk of pregnancy. Continue with the next tablet at the usual time.

Active tablets:
Depending on the day of the cycle on which one active tablet has been missed, you may need to take additional contraceptive precautions, for example a barrier method such as a condom or diaphragm.

Take the tablets according to the following principles. See also the ‘Summary of advice if you missed a tablet’ chart at the end of this leaflet.

  • If you are less than 12 hours late taking a tablet, protection against pregnancy is not reduced. Take the tablet as soon as you remember and then continue taking further tablets again at the usual time.
  • If you are more than 12 hours late taking a tablet, protection against pregnancy may be reduced. Depending on the day of the cycle on which one tablet has been missed, use additional contraceptive precautions e.g. a barrier method such as a condom or diaphragm. You may also need to start a new packet immediately. You must refer to the ‘Summary of advice if you missed a tablet’ chart at the end of this leaflet for details.
  • If more than one tablet is forgotten in a packet, contact your doctor.

Do not take more than 2 active tablets on a given day.

If you have forgotten to start a new packet, or if you have missed one or more tablets during Days 3-9 of your packet, there is a risk that you are already pregnant (if you had sex in the 7 days before forgetting the tablet).

In that case, contact your doctor. The more tablets you have forgotten (especially those on days 3-24) and the closer they are to the inactive tablet phase, the greater the risk of becoming pregnant.

If you have forgotten any of the active tablets in a packet, and you have no bleeding at the end of a packet, you may be pregnant. Contact your doctor before you go on to the next packet.

Please see the chart at the end of this leaflet for the ‘Summary of advice if you missed a tablet’.

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

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (Australia: 13 11 26 or New Zealand: 0800 POISON or 0800 764 766) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Qlaira.

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

WHILE YOU ARE TAKING QLAIRA

Things you must do

Tell any doctors, dentists and pharmacists who treat you that you are taking this medicine.

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Have regular check-ups with your doctor. When you are taking Qlaira, your doctor will tell you to return for regular check-ups, including getting a Cervical Screening Test. Your doctor will advise how often you need a Cervical Screening Test. A Cervical Screening Test can detect abnormal cells lining the cervix. Sometimes abnormal cells can progress to cancer.

If you are about to start on any new medicine, remind your doctor and pharmacist that you are taking Qlaira.

Stop taking Qlaira and see your doctor immediately if you notice the following signs:

  • one-sided swelling of the leg and/or foot or along a vein in the leg
  • pain or tenderness in the leg which may be felt only when standing or walking
  • increased warmth in the affected leg; red or discoloured skin on the leg
  • sudden onset of unexplained shortness of breath or rapid breathing
  • sudden coughing or coughing up of blood
  • sharp chest pain or sudden severe pain in the chest which may increase with deep breathing
  • severe light headedness or dizziness
  • rapid or irregular heartbeat
  • sudden pain, swelling and slight blue discoloration of an extremity
  • sudden numbness or weakness of the face, arm or leg, especially on one side of the body
  • sudden trouble walking, dizziness, loss of balance or coordination
  • sudden confusion, slurred speech or aphasia; sudden partial or complete loss of vision, double vision, painless blurring of vision which can progress to loss of vision
  • sudden, severe or prolonged headache with no known cause
  • loss of consciousness or fainting with or without seizure
  • pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest arm, or below the breastbone
  • discomfort radiating to the back, jaw, throat, arm, stomach
  • feeling of being full, having indigestion or choking
  • sweating, nausea, vomiting
  • extreme weakness and anxiety.

If you are going to have surgery, tell the surgeon or anaesthetist beforehand that you are taking Qlaira. The risk of having blood clots is temporarily increased as a result of major surgery, any surgery to the legs or pelvis, neurosurgery or major trauma. In women who take Qlaira, the risk may be higher.

In women at risk of prolonged immobilisation (including major surgery, any surgery to the legs or pelvis, neurosurgery, or major trauma), your doctor may tell you to stop taking (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation. Another method of contraception should be used to avoid unintentional pregnancy. Your doctor may prescribe other treatment (e.g. treatment for blood clots) if Qlaira has not been discontinued in advance.

Other risk factors for blood clotting include temporary immobilisation including air travel of greater than 4 hours, particularly in women with other risk factors. Consult your doctor if you plan to air travel for greater than 4 hours.

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

If you become pregnant while taking this medicine, tell your doctor immediately.

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

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

If you have missed a period, but you have taken all your tablets, it is unlikely that you are pregnant as long as:

  • you have taken the active tablets at the right time
  • you have not been taking medicine(s) that may interfere with Qlaira
  • you have not vomited or had severe diarrhoea during this cycle

If this is so, continue to take Qlaira as usual. If you have any concerns consult your doctor or pharmacist.

If you miss your period twice in a row, you may be pregnant even if you have taken Qlaira correctly. Stop taking Qlaira and seek advice from your doctor. You must use a non-hormonal method of contraception (such as condoms or a diaphragm) until your doctor rules out pregnancy.

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

To protect yourself from STIs, you will need to use condoms.

What you must not do

Do not take Qlaira to treat any other conditions, unless your doctor tells you to.

Do not give your medicine to anyone else.

Do not stop taking your medicine or change the dosage without checking with your doctor. You may become pregnant if you are not using any other contraceptive and you stop taking Qlaira, or do not take a tablet every day as directed.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Qlaira.

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

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

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

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

The following list includes the more common side effects of Qlaira. These are usually mild and lessen with time.

If you notice any of the following side effects and they worry you, tell your doctor or pharmacist:

  • headache, including migraines
  • stomach pain
  • acne
  • no periods, painful periods, irregular bleeding, spotting or discharge
  • breast tenderness or pain
  • changes in weight
  • mood changes, including depression
  • sleeping problems
  • decreased libido
  • nausea
  • fatigue

The following list includes very serious but rare side effects. You may need urgent medical attention or hospitalisation.

If you experience any of the following, tell your doctor immediately, or go to Accident and Emergency at the nearest hospital:

  • pain in the chest, arm, or below the breastbone
  • pain or discomfort that goes to your back
  • breathlessness and/or difficulty breathing
  • swelling, pain or tenderness of one leg or along a vein in the leg
  • sudden weakness, numbness or bad ‘pins and needles’ of the face, arm or leg, especially on one side of the body
  • sudden trouble walking, dizziness, loss of balance or coordination
  • severe, sudden stomach pains
  • a fainting attack or you collapse
  • unusual headaches or migraines that are worse than usual
  • sudden problems with speaking, seeing or understanding what people are saying to you.

The side effects listed above are possible signs of a blood clot.

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

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed may also occur in some people.

Blood clots and the Pill

Blood clots may block blood vessels in your body. This type of blood clot is also called thrombosis.

Blood clots sometimes occur in the deep veins of the legs. If a blood clot breaks away from the veins where it has formed, it may reach and block the blood vessels of the lungs, causing pulmonary embolism.

Blood clots can also occur in the blood vessels of the heart (causing a heart attack) or the brain (causing a stroke).

Blood clots are a rare occurrence and can develop whether or not you are taking the Pill. They can also happen during pregnancy. The risk of having blood clots is higher in the Pill users than in non users, but not as high as during pregnancy.

The risk of a blood clot is highest during the first year of taking the Pill for the first time, or when re-starting after having a break from the Pill for 4 weeks or more.

Nonetheless, if you notice possible signs of a blood clot, stop taking Qlaira and consult your doctor immediately.

To prevent pregnancy, you must also use additional barrier contraceptive precautions (e.g. condoms or a diaphragm).

If you are concerned about an increased risk of blood clots while taking Qlaira, speak to your doctor.

Cancer and the Pill

Breast cancer has been diagnosed slightly more often in women who take the Pill than in women of the same age who do not take the Pill.

This slight increase in the numbers of breast cancer diagnoses gradually disappears during the course of the 10 years after women stop taking the Pill.

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

It is important that you check your breasts regularly and contact your doctor if you feel any lumps.

In rare cases benign liver tumours and, even more rarely, malignant liver tumours have been reported in users of the Pill. These tumours may lead to internal bleeding.

Contact your doctor immediately if you have severe pain in your abdomen.

Cervical cancer has been reported to occur more often in women who have been taking the Pill for a long time. This finding may not be caused by the Pill, but may be related to sexual behaviour and other factors.

AFTER TAKING QLAIRA

Storage

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

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

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

Keep Qlaira 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.

Return any unused medicine to your pharmacist.

PRODUCT DESCRIPTION

What it looks like

Qlaira tablets are film-coated tablets. The core of the tablet is covered with a coating. The tablets are either dark yellow, medium red, light yellow, dark red or white. They are round with one side embossed with the letters ‘DD’ or ‘DJ’ or ‘DH’ or ‘DN’ or ‘DT’, respectively in a regular hexagon.

Qlaira comes in a pack containing either 1 or 3 packets (also called a ‘wallet’). Each packet of Qlaira contains 26 coloured active (hormone) tablets in rows 1, 2, 3 and 4 and 2 white inactive tablets in row 4.

Ingredients

Composition of the differently coloured tablets containing one or two active ingredients:

  • 2 dark yellow tablets each containing 3 mg estradiol valerate
  • 5 medium red tablets each containing 2 mg estradiol valerate and 2 mg dienogest
  • 17 light yellow tablets each containing 2 mg estradiol valerate and 3 mg dienogest
  • 2 dark red tablets each containing 1 mg estradiol valerate.

Other ingredients in the coloured active tablets are:

  • lactose monohydrate
  • maize starch
  • pregelatinised maize starch
  • povidone
  • magnesium stearate
  • hypromellose
  • macrogol 6000
  • talc
  • titanium dioxide
  • iron oxide yellow and/or iron oxide red.

The white inactive tablets do not contain active ingredient. The ingredients are:

  • lactose monohydrate
  • maize starch
  • povidone
  • magnesium stearate
  • hypromellose
  • talc
  • titanium dioxide.

Tablets do not contain sucrose, gluten, tartrazine or azo dyes.

Supplier

Made in Germany for:

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

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

Australian Registration Number

Qlaira - AUST R 149319

Date of Preparation

July 2020

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

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

®Registered Trademark of the Bayer Group, Germany

© Bayer Australia Ltd. All rights reserved.

Missed taking Qlaira?

See the last page of this leaflet.

Published by MIMS September 2020

BRAND INFORMATION

Brand name

Qlaira

Active ingredient

Estradiol valerate; Dienogest

Schedule

S4

 

1 Name of Medicine

Estradiol valerate/ dienogest.

6.7 Physicochemical Properties

Estradiol valerate exists as white to yellowish white crystals or crystalline powder. The substance is freely soluble in acetone and dichloromethane, soluble in ethanol, methanol, dioxane and diethylether, very slightly soluble in n-hexane and practically insoluble in petroleum ether and water. The melting point is 143°C to 150°C.
Dienogest exists as a white to off white crystalline powder. The substance is freely soluble in dimethylsulfoxide, sparingly soluble in acetone and methanol, slightly soluble in ethanol and ethyl acetate and practically insoluble in water. The melting point is 210°C to 218°C.

Estradiol valerate.

The chemical name for estradiol valerate is 1,3,5(10)-estratriene-3,17β-diol-17-valerate.
Chemical formula: C23H32O3.
Molecular weight: 356.50.

Dienogest.

Dienogest is a progestogen. The chemical name for dienogest is 17α-cyanomethyl-17β-hydroxy-4,9-estradien-3-one.
Chemical formula: C20H25NO2.
Molecular weight: 311.42.

Chemical structure.


CAS number.

Estradiol valerate: 979-32-8.
Dienogest: 65928-58-7.

2 Qualitative and Quantitative Composition

Qlaira is a combined oral contraceptive (COC) pill containing the estrogen estradiol valerate and the progestogen dienogest.
Each dark yellow active tablet contains 3 mg estradiol valerate.
Each medium red active tablet contains 2 mg estradiol valerate and 2 mg dienogest.
Each light yellow active tablet contains 2 mg estradiol valerate and 3 mg dienogest.
Each dark red active tablet contains 1 mg estradiol valerate.

Excipients with known effect.

All Qlaira active and placebo tablets contain lactose monohydrate. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film-coated tablets.
Each wallet contains 28 tablets consisting of:
2 dark yellow, round, biconvex film-coated tablet, one side embossed with the letters "DD" in a regular hexagon;
5 medium red, round, biconvex film-coated tablet, one side embossed with the letters "DJ" in a regular hexagon;
17 light yellow, round, biconvex film-coated tablet, one side embossed with the letters "DH" in a regular hexagon;
2 dark red, round, biconvex film-coated tablet, one side embossed with the letters "DN" in a regular hexagon; and
2 white, round, biconvex film-coated placebo tablet, one side embossed with the letters "DT" in a regular hexagon.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The contraceptive effect of COCs is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation and the changes in cervical secretions. As well as 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. The cycle is more regular, menstruation is often less painful and bleeding is lighter. The latter may result in a decrease in the occurrence of iron deficiency. In addition, there is evidence of a reduced risk of endometrial cancer and ovarian cancer. The higher dosed COCs (0.05 mg ethinylestradiol) have been shown to reduce the incidence of ovarian cysts, pelvic inflammatory disease, benign breast disease and ectopic pregnancy. Whether this also applies to estradiol valerate containing COCs remains to be confirmed.
The estrogen in Qlaira is estradiol valerate, a prodrug of the natural human 17β-estradiol. The estrogenic component used in this COC is therefore different from the estrogens usually used in COCs which are the synthetic estrogens ethinylestradiol or its prodrug mestranol both containing an ethinyl group in the 17 alpha position.
Qlaira leads to lower hepatic effects when compared to a triphasic ethinylestradiol/ levonorgestrel (EE/LNG) containing COC. The impact on sex hormone binding globulin (SHBG) levels and haemostasis parameters was shown to be lower. In combination with dienogest, estradiol valerate displays an increase in HDL, while LDL cholesterol levels are slightly decreased.
Dienogest is an orally and parenterally potent progestogen which has additional antiandrogenic partial effects. Its estrogenic, antiestrogenic and androgenic properties are negligible. As a result of the special chemical structure, a pharmacological spectrum of action is obtained which combines the most important advantages of the 19-nor progestogens and of the progesterone derivatives. Endometrial histology was investigated in a small subgroup of women in one clinical study after 20 cycles of treatment. There were no abnormal results. Findings were in accordance with the typical endometrial changes described for EE containing COCs.

Clinical trials.

The contraceptive efficacy and safety of Qlaira was examined in three multicenter phase III studies that included healthy women aged 18 to 50 years requesting contraception. The contraceptive reliability was analysed using 2 different methods, the PI (Pearl Index) and a life table analysis.
The first of these studies, the pivotal Pearl Index study 306660/A35179, was an open, uncontrolled, one arm study to evaluate the contraceptive efficacy and the safety of estradiol valerate/ dienogest (Qlaira) for 20 cycles. The PI served as primary criterion for the assessment of contraceptive reliability. The PIU (unadjusted Pearl Index) was 0.7257 with an upper limit of the two sided 95% CI of 1.2410 based on 13 pregnancies considered as having occurred during treatment in the entire study population of women aged 18 to 50 years. Six pregnancies assessed as method failure were taken into account for the calculation of the PIA (adjusted Pearl Index). The PIA was 0.3370 with an upper limit of the two sided 95% CI of 0.7335.
The second study (304004/A35644) was pivotal with regard to bleeding patterns and cycle control and was a double blind, double dummy, controlled, randomised study to evaluate bleeding patterns, cycle control, and safety of Qlaira in comparison to a reference COC containing 0.02 mg EE and 0.10 mg levonorgestrel, over a treatment period of 7 cycles. Only 1 pregnancy occurred during the treatment phase of the study. This occurred in the comparator group and was assessed as method failure.
The third study (304742/ A39818) was an open, uncontrolled, one arm study to evaluate the contraceptive efficacy, cycle control, safety and tolerability of Qlaira over a period of 13 treatment cycles, which was extended to a maximum of 28 cycles. The primary efficacy variable was the number of observed pregnancies, i.e. unintended pregnancy during study treatment. Of the 6 confirmed pregnancies that occurred during treatment, 4 pregnancies were considered as method failures and 2 pregnancies as subject failures.
The analysis of the pooled data from the three efficacy studies described above supported the contraceptive reliability of Qlaira: the PIU in women aged 18 to 50 years was 0.7878, with an upper limit of the two sided 95% CI of 1.2302. The PIA calculated on the basis of 10 pregnancies rated as method failure was 0.4193, with an upper two sided 95% confidence limit of 0.7711. Compliance was high throughout these studies.
As a decrease in fertility in women beyond 35 is known, a separate PI calculation was presented for the younger age group of women (18 to 35 years). In the subgroup of women aged 18 to 35 years, there were 18 pregnancies considered as having occurred during treatment. The corresponding PIU was 1.0064 and the upper limit of the two sided 95% CI was 1.5906. There were 9 pregnancies assessed as method failure. The corresponding PIA was 0.5102 and the upper limit of the two sided 95% CI was 0.9685.
In addition to the calculation of the PI, a life table analysis was performed for the time up to the occurrence of a pregnancy. The cumulative failure rate, i.e. the probability of becoming pregnant, was calculated using the Kaplan-Meier estimator on the basis of unintended pregnancies considered to have occurred during treatment. In the first study, the Kaplan-Meier estimate for the cumulative failure rate over an exposure time to the study drug of 545 days was 0.0109 (95% CI = 0.0063 to 0.0188) in 18 to 50 year old women and 0.0142 (95% CI = 0.0080 to 0.0251) in 18 to 35 year old women. The Kaplan-Meier estimate for the cumulative failure rate over an exposure time to the study drug of 545 days based on pooled data from the three studies was 0.0117 (95% CI = 0.0074 to 0.0186) for women 18 to 50 years of age and 0.0152 (95% CI = 0.0094 to 0.0243) in the subgroup of women 18 to 35 years of age. These findings are in line with a failure rate of approximately 1% per year for COCs when correctly taken.
The majority of women were satisfied with the study medication and compliance was high.
The safety profile of Qlaira was not different from that of established low dose COCs even though a considerable number of women older than 35 years of age were included in the clinical studies.

Treatment of heavy and/or prolonged menstrual bleeding in women without organic pathology who desire oral contraception.

The efficacy and safety of Qlaira for treating symptoms of dysfunctional uterine bleeding (DUB) were evaluated in two pivotal phase III multicenter, double blind, randomised, parallel group, placebo controlled clinical trials (308960/ A29849 and 308961/ A42568). The placebo controlled design was chosen because no oral contraceptive is approved for treatment of heavy and/or prolonged menstrual bleeding. Both studies were identical in design. Women, 18 years of age or older, with a diagnosis of dysfunctional uterine bleeding characterised by heavy (defined as two or more bleeding episodes each with menstrual blood loss of at least 80 mL during a 90 day interval), prolonged (defined as two or more bleeding episodes each lasting 8 or more days during a 90 day interval) and/or frequent bleeding (defined as more than 5 bleeding episodes with a minimum of 20 bleeding days overall during a 90 day interval) without organic pathology who desire oral contraception were included. Overall, a total of 421 women were randomised to the two clinical studies, i.e. 269 women in the Qlaira group and 152 women in the placebo group for seven 28 day cycles.
The primary efficacy variable was the proportion of subjects who were completely relieved of symptoms, which was defined by the number of subjects with the absence of any DUB symptom and who had met all the relevant criteria for success during the 90 day efficacy assessment phase. In both studies, Qlaira was effective in treating the symptoms of dysfunctional uterine bleeding with a point estimate of the proportion of subjects with complete symptom relief of 29% in the Qlaira group compared to 2% in the placebo group (difference 27%; CI of the difference 21%-33%; p < 0.0001). In subjects with evaluable response, i.e. excluding nonresponders due to missing data, the point estimate for the proportion of subjects with complete symptom relief was 42% (CI = 35% to 49%) in the Qlaira group compared to 3% (CI = 1% to 8%) in the placebo group (p < 0.0001).
Both studies demonstrated a clinically significant decrease in menstrual blood loss (MBL). In the Qlaira group, the median decrease in the 90 day efficacy phase compared to the 90 day run-in phase was 343 mL. The decrease in the placebo group was 62 mL. The difference between the groups was statistically significant (p < 0.0001). After 6 months of treatment the median MBL was decreased by 88% (from 142 mL to 17 mL) in the Qlaira group compared to 24% (from 154 mL to 117 mL) in the placebo group. The decrease in MBL achieved with Qlaira is rapid (in cycle 2 the median MBL was 41 mL in the Qlaira group compared to 140 mL in the placebo group) and sustained with no loss of the effect (in cycle 7 the median MBL in the Qlaira group was 17 mL compared to 117 mL in the placebo group). The data show that even nonresponders in the Qlaira group had a marked decrease in MBL volume (in cycle 2 and cycle 7 the median MBL was 55 mL and 27 mL respectively in the Qlaira group compared to 143 mL and 124 mL respectively in the placebo group). Figure 1 displays the median MBL volume by cycle based on pooled data from studies 308960/A29849 and 308961/A42568.
The decrease in menstrual blood loss in the Qlaira group was accompanied by a statistically significant improvement in iron metabolism parameters (haemoglobin, haematocrit and ferritin). After 196 days of treatment the adjusted mean change from baseline in haemoglobin, haematocrit and ferritin concentrations were 0.640 g/dL, 1.47% and 7.036 nanogram/mL respectively in the Qlaira group compared to 0.121 g/dL, 0.068% and 1.043 nanogram/mL respectively in the placebo group (p < 0.0001, p = 0.0002 and p < 0.0001 respectively).
The decrease from baseline in the median number of bleeding days for the efficacy phase was 4 days in the Qlaira group and 2 days in the placebo group.
The mean numbers of total sanitary protection items used during the 90 day run-in phase (baseline) were 85 in the Qlaira group and 89 in the placebo group. The decrease in mean numbers during the efficacy phase was larger in the Qlaira group than in the placebo group. In the Qlaira group, the decrease was 41 (SD 35); in the placebo group, the decrease was 19 (SD 37). The difference between treatment groups in adjusted means (-22) was statistically significant (p < 0.0001; 95% CI = -31 to -14).
The proportion of patients with improvements in DUB symptoms, on a scale of 1 (very much improved) to 7 (very much worse), at treatment day 196 as compared to study admission, was statistically significantly higher in the Qlaira group than in the placebo group, according to both the investigator's global assessment (83% vs. 41%, p < 0.0001) and the patient's overall assessment (79% vs. 42%, p < 0.0001).
The impact of Qlaira on quality of life (QoL) and overall wellbeing was assessed using the Psychological General Well-Being Index (PGWBI), the McCoy Female Sexuality Questionnaire (MFSQ) and the EuroQoL 5 Dimensional Health Questionnaire (EQ-5D). In all QoL instruments used, only small differences from baseline and between treatment groups were observed and the differences were not considered clinically relevant.
Overall, Qlaira treatment was associated with a clinically and statistically significant disappearance of symptoms of dysfunctional uterine bleeding, essentially manifested as heavy and/or prolonged bleeding. These results were consistent and reproducible across both pivotal studies. The decreased menstrual blood loss experienced by subjects on Qlaira was significantly better than placebo and was associated with a decrease in the number of bleeding days. The decreased menstrual blood loss was rapid, as soon as the second cycle of treatment, and sustained over 7 cycles with no signs of waning, and was positively felt by subjects. Qlaira subjects experienced a significant decrease in the use of sanitary protection as well as a statistically significant, reproducible, and consistent improvement in parameters of iron metabolism.

5.2 Pharmacokinetic Properties

Dienogest.

Absorption.

Orally administered dienogest is rapidly and almost completely absorbed. Maximal serum concentrations of 90.5 nanogram/mL are reached at about 1 hour after oral administration of the Qlaira tablet containing 2 mg estradiol valerate + 3 mg dienogest. Bioavailability is about 91%. The pharmacokinetics of dienogest are dose proportional within the dose range of 1-8 mg.

Distribution.

A relatively high fraction (10%) of circulating dienogest is present in the free form, with approximately 90% being bound nonspecifically to albumin. Dienogest does not bind to the specific transport proteins SHBG and CBG (corticosteroid binding globulin), therefore there is no possibility of testosterone being displaced from its SHBG binding or cortisol from its CBG binding. Any influence on physiological transport processes for endogenous steroids is consequently unlikely. The volume of distribution at steady state (Vd,ss) of dienogest is 46 L after the intravenous (IV) administration of 85 microgram 3H-dienogest.

Metabolism.

Dienogest is nearly completely metabolised by the known pathways of steroid metabolism (hydroxylation, conjugation), with the formation of endocrinologically mostly inactive metabolites. The metabolites are excreted very quickly so that in plasma, unchanged dienogest is the dominating fraction. CYP3A4 was identified as the predominant isoenzyme catalysing the metabolism of dienogest. The total clearance following the IV administration of 3H-dienogest was calculated as 5.1 L/h.

Excretion.

The plasma half-life of dienogest is approximately 11 hours. Dienogest metabolites are excreted in the urine and faeces in a ratio of about 3:1 after oral administration of 0.1 mg/kg. Following oral administration, 42% of the dose is eliminated within the first 24 h and 63% within 6 days by renal excretion. A combined 86% of the dose is excreted via urine and faeces after 6 days.

Steady-state conditions.

Pharmacokinetics of dienogest are not influenced by SHBG levels. Steady state is reached after 3 days of the same dosage of 3 mg dienogest in combination with 2 mg estradiol valerate. Trough, maximum and average dienogest serum concentrations at steady state are 11.8 nanogram/mL, 82.9 nanogram/mL and 33.7 nanogram/mL, respectively. The mean accumulation ratio for AUC (0-24 h) was determined to be 1.24.

Estradiol valerate.

Absorption.

After oral administration estradiol valerate is completely absorbed. Cleavage to estradiol and valeric acid takes place during absorption by the intestinal mucosa or in the course of the first liver passage. Further metabolism of estradiol gives rise to its metabolites estrone and estriol. Maximal serum estradiol concentrations of 70.6 picogram/mL are reached between 1.5 and 12 hours after single ingestion of the tablet containing 3 mg estradiol valerate on day 1.

Distribution.

In serum 38% of estradiol is bound to SHBG, 60% to albumin and 2-3% circulate in free form. Estradiol can slightly induce the serum concentrations of SHBG in a dose dependent manner. On day 21 of the treatment cycle, SHBG was approximately 148% of the baseline, it decreased to about 141% of the baseline by day 28 (end of placebo phase). An apparent volume of distribution of approximately 1.2 L/kg was determined after IV administration.

Metabolism.

The valeric acid undergoes very fast metabolism. After oral administration approximately 3% of the dose is directly bioavailable as estradiol. Estradiol undergoes an extensive first-pass metabolism and a considerable part of the dose administered is already metabolised in the gastrointestinal mucosa. Together with the presystemic metabolism in the liver, about 95% of the orally administered dose becomes metabolised before entering the systemic circulation. CYP3A4 is involved in the metabolism of estradiol. The main metabolites are estrone, estrone sulfate and estrone glucuronide.

Excretion.

The plasma half-life of circulating estradiol is about 90 minutes. After oral administration, however, the situation differs. Because of the large circulating pool of estrogen sulphates and glucuronides, as well as enterohepatic recirculation, the terminal half life of estradiol after oral administration represents a composite parameter which is dependent on all of these processes and is in the range of about 13-20 h. Estradiol and its metabolites are mainly excreted in urine, with about 10% being excreted in the faeces.

Steady-state conditions.

Pharmacokinetics of estradiol are influenced by SHBG levels. In young women, the measured estradiol plasma levels are a composite of the endogenous estradiol and the estradiol generated from Qlaira. During the treatment phase of 2 mg estradiol valerate + 3 mg dienogest, maximum and average estradiol serum concentrations at steady state are 66.0 picogram/mL and 51.6 picogram/mL, respectively. Throughout the 28 day cycle, stable minimum estradiol concentrations were maintained and ranged from 28.7 picogram/mL to 64.7 picogram/mL.

5.3 Preclinical Safety Data

Genotoxicity.

There is limited evidence available in the literature suggesting that 17β-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 in mammalian cells, and two groups reported an increased incidence of sister chromatid exchanges, indicative of DNA damage. Neither of these latter effects were induced by 17β-estradiol in human lymphocyte cultures. Importantly, there was no evidence of micronuclei formation in well controlled rodent bone marrow assays.
Dienogest did not exhibit any evidence of genotoxic potential in assays for gene mutations in bacterial or mammalian cells, in in vitro and in vivo assays for clastogenicity and in an unscheduled DNA synthesis assay.

Carcinogenicity.

The most important risk factor for cervical cancer is persistent human papillomavirus (HPV) infection. Some epidemiological studies have indicated that long-term use of COCs may further contribute to this increased risk but there continues to be controversy about the extent to which this finding is attributable to confounding effects, e.g. cervical screening and sexual behaviour including use of barrier contraceptives.
A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently taking COCs. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. These studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both. The breast cancers diagnosed in ever users tend to be less advanced clinically than the cancers diagnosed in never users.
In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been reported in users of COCs. In isolated cases, these tumours have led to life threatening intra-abdominal haemorrhages. A liver tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage occur in women taking COCs.
Malignancies may be life threatening or may have a fatal outcome.
No long-term animal studies on the carcinogenic potential of Qlaira have been performed. However, studies have been performed for 17β-estradiol and dienogest, the active components of Qlaira.
Supraphysiological doses of 17β-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.
Long-term studies in rats and mice with dienogest showed increased incidences of pituitary adenomas, fibroepithelial mammary tumours, stromal polyps of the uterus and malignant lymphoma, at doses corresponding to exposure levels about 9-12 times that anticipated at the maximum recommended clinical dose, based on AUC. Similar tumours have been shown to develop with other estrogenic/ progestogenic compounds. The tumours are thought to result from marked species differences in the optimal estrogen:progestogen ratio for reproductive function. Dienogest showed no tumour promoter activity in the rat liver foci assay at exposure levels corresponding to about 100 times the estimated human exposure at the clinical dose, based on AUC.

4 Clinical Particulars

4.1 Therapeutic Indications

Qlaira is indicated for use as:
Oral contraception.
Treatment of heavy and/or prolonged menstrual bleeding in women without organic pathology who desire oral contraception.

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;
major surgery with prolonged immobilisation;
a high risk of venous thromboembolism due to the presence of multiple risk factors.
Presence or risk of arterial thromboembolism (ATE) (see Section 4.4 Special Warnings and Precautions for Use):
current ATE or history of ATE (e.g. myocardial infarction or stroke) or prodromal condition (e.g. angina pectoris or transient ischaemic attack [TIA]);
known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and antiphospholipid-antibodies (e.g. anticardiolipin-antibodies and lupus anticoagulant);
history of migraine with focal neurological symptoms;
a high risk of arterial thromboembolism due to multiple risk factors or to the presence of one serious risk factor such as: diabetes mellitus with vascular symptoms, severe hypertension, severe dyslipoproteinaemia.
Pancreatitis or a history thereof if associated with severe hypertriglyceridemia.
Presence or history of severe hepatic disease as long as liver function values have not returned to normal.
Presence or history of liver tumours (benign or malignant).
Known or suspected sex-steroid influenced malignancies (e.g. of the genital organs or the breasts).
Undiagnosed vaginal bleeding.
Known or suspected pregnancy.
Hypersensitivity to any of the ingredients contained in Qlaira.

4.4 Special Warnings and Precautions for Use

If any of the conditions/ risk factors mentioned below are present, the benefits of Qlaira should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start taking it. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the woman should contact her doctor. The doctor should then decide whether Qlaira should be discontinued.
Qlaira is indicated for treatment of heavy and/or prolonged menstrual bleeding only in women without organic pathology.
All the following precautions are derived from clinical and epidemiological data of ethinyloestradiol containing combined hormonal contraceptive (CHCs). Whether these precautions apply to Qlaira is unknown.

Circulatory disorders.

Epidemiological studies have suggested an association between the use of combined oral contraceptives (COCs) containing ethinylestradiol and an increased risk of arterial and venous thrombotic and thromboembolic diseases such as myocardial infarction, stroke, deep venous thrombosis and pulmonary embolism. These events occur rarely in average-risk women.

Risk of venous thromboembolism (VTE).

The use of any combined hormonal contraceptive (CHC) increases the risk of VTE compared with no use. The woman should be advised that her VTE risk is highest in the first ever year of use and that there is some evidence that the risk is increased when a CHC is re-started after a break in use of 4 weeks or more.
Data from a large, prospective 3 armed cohort study1,2 suggest that this increased risk is mainly present during the first 3 months.
Overall the risk for VTE in users of low estrogen dose (< 0.05 mg ethinylestradiol) COCs is two to threefold higher than for nonusers of COCs who are not pregnant and remains lower than the risk associated with pregnancy and delivery.
VTE, manifesting as DVT and/or PE, may occur during the use of all COCs. A large, prospective 3-armed cohort study1 has shown that the frequency of VTE diagnosis ranges between 8 to 10 per 10,000 woman years (WY) in low estrogen dose (< 0.05 mg ethinylestradiol) COC users. The most recent data suggest that the frequency of VTE diagnosis is approximately 4.4 per 10,000 WY in nonpregnant non-COC users1, and ranges between 20 to 30 per 10,000 WY in pregnancy or the postpartum period1,3.
One post approval commitment study has been completed specifically for Qlaira. In this prospective active surveillance study, the incidence of VTE in women with or without other risk factors for VTE who used Qlaira is in the same range as that for users of levonorgestrel-containing COCs.
It is important that women understand that VTE associated with CHC use is rare in average-risk women. The risk in pregnancy (5-20 per 10,000 women over 9 months) and the risk in the post-partum period (45-65 per 10,000 women over 12 weeks) is higher than that as associated with CHC use.
An additional increase in VTE risk for CHCs containing ≥ 50 microgram ethinylestradiol cannot be excluded.
The decision to use any product other than one with the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with CHCs, and how her current risk factors influence this risk.
The increased risk of VTE during the postpartum period must be considered if re-starting Qlaira. See Section 4.2 Dose and Method of Administration; Section 4.6 Fertility, Pregnancy and Lactation.
VTE may be life threatening or may have a fatal outcome (in 1-2% of cases).
Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral or retinal veins and arteries.
The risk for venous thromboembolic complications in CHC users may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see list below).
Qlaira is contraindicated if a woman has multiple risk factors that put her at high risk of venous thrombosis. If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors - in this case her total risk of VTE should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed.
When considering risk/benefit, the doctor should take into account that the adequate treatment of a condition may reduce the associated risk of thrombosis.

Risk factors for VTE.

Obesity (body mass index over 30 kg/m2). Risk increases substantially as BMI rises.
Prolonged immobilisation, major surgery, any surgery to the legs or pelvis, neurosurgery, or major trauma.
Temporary immobilisation including air travel > 4 hours can also be a risk factor for VTE, particularly in women with other risk factors.
Positive family history (venous thromboembolism ever in a sibling or parent especially at a relatively early age e.g. before 50).
Biochemical factors that may be indicative of hereditary or acquired predisposition for VTE include Activated Protein C (APC) resistance (including Factor V Leiden), antithrombin-III deficiency, protein C deficiency, protein S deficiency.
Other medical conditions associated with VTE include: cancer, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis), sickle cell disease.
Increasing age, particularly above 35 years.
Smoking.
In women at risk of prolonged immobilisation (including major surgery, any surgery to the legs or pelvis, neurosurgery, or major trauma), it is advisable to discontinue use of Qlaira (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 Qlaira has not been discontinued in advance.
If a hereditary predisposition to VTE is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use.
There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism.

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

Women should be informed of the symptoms of VTE and be advised to seek urgent medical attention if VTE symptoms develop and to inform the healthcare professional that she is taking a CHC.
Symptoms of deep vein thrombosis (DVT) can include:
unilateral swelling of the leg and/or foot or along a vein in the leg;
pain or tenderness in the leg which may be felt only when standing or walking;
increased warmth in the affected leg; red or discoloured skin on the leg.
Symptoms of pulmonary embolism (PE) can include:
sudden onset of unexplained shortness of breath or rapid breathing;
sudden coughing which may be associated with haemoptysis;
sharp chest pain or sudden severe pain in the chest which may increase with deep breathing;
severe light headedness or dizziness;
rapid or irregular heartbeat.
Some of these symptoms (e.g. shortness of breath, coughing) are 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 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. Qlaira is contraindicated if a woman has one serious or multiple risk factors for ATE that puts her at high risk of arterial thrombosis. If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors - in this case her total risk should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed.

Risk factors for ATE.

Increasing age, particularly above 35 years.
Smoking.
Hypertension.
Obesity.
Positive family history (arterial thromboembolism ever in a sibling or parent especially at relatively early age e.g. below 50).
Biochemical factors that may be indicative of hereditary or acquired predisposition for ATE include: hyperhomocysteinaemia and antiphospholipid antibodies (e.g. anticardiolipin antibodies, and lupus anticoagulant).
Migraine.
Other medical conditions associated with adverse vascular events: diabetes mellitus, hyperhomocysteinaemia, valvular heart disease, atrial fibrillation, dyslipoproteinaemia, systemic lupus erythematosus.
Women should be advised not to smoke if they wish to use a CHC. Women over 35 years who continue to smoke should be strongly advised to use a different method of contraception.
If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use.
An increase in frequency or severity of migraine during CHC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation.

Symptoms of ATE.

Women should be informed of the symptoms of ATE and be advised to seek urgent medical attention if ATE symptoms develop and to inform the healthcare professional that she is taking a CHC.
Symptoms of a stroke can include:
sudden numbness or weakness of the face, arm or leg, especially on one side of the body;
sudden trouble walking, dizziness, loss of balance or coordination;
sudden confusion, slurred speech or aphasia;
sudden partial or complete loss of vision; diplopia;
sudden, severe or prolonged headache with no known cause;
loss of consciousness or fainting with or without seizure.
Temporary symptoms suggest the event is a transient ischaemic attack (TIA).
Symptoms of myocardial infarction (MI) can include:
pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone;
discomfort radiating to the back, jaw, throat, arm, stomach;
feeling of being full, having indigestion or choking;
sweating, nausea, vomiting or dizziness;
extreme weakness, anxiety, or shortness of breath;
rapid or irregular heartbeats.

Other conditions.

Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when taking COCs.
Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. However, if a sustained clinically significant hypertension develops during the use of a COC then it is prudent for the doctor to withdraw the COC and treat the hypertension. Where considered appropriate, COC use may be resumed if normotensive values can be achieved with antihypertensive therapy.
The following conditions have been reported to occur or deteriorate with both pregnancy and COC use, but the evidence of an association with COC use is inconclusive: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uremic syndrome; Sydenham's chorea; herpes gestationis; otosclerosis related hearing loss.
In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.
Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. Recurrence of cholestatic jaundice which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of COCs.
Although COCs may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence of a need to alter the therapeutic regimen in women with diabetes taking low dose COCs (containing < 0.05 mg ethinylestradiol). However, women with diabetes should be carefully observed while taking COCs.
Crohn's disease and ulcerative colitis have been associated with COC use.
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking COCs.
Each dark yellow, medium red, light yellow or dark red active film coated tablet contains 46 mg, 45 mg, 48 mg or 44 mg of lactose per tablet, respectively. Each placebo white, film coated tablet contains 50 mg of 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 this amount into consideration.

Medical examination/ consultation.

A complete medical history and physical examination should be taken prior to the initiation or reinstitution of COC use, guided by the contraindications and precautions, and should be repeated periodically. Periodic medical assessment is also of importance because contraindications (e.g. a transient ischaemic attack) 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 practice 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 should be advised that oral contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted infections.

Reduced efficacy.

The efficacy of COCs may be reduced for example in the following events: missed active tablets (see Section 4.2 Dose and Method of Administration, Management of missed tablets), gastrointestinal disturbances during active tablet taking (see Section 4.2 Dose and Method of Administration, Advice in case of gastrointestinal disturbances) or concomitant medication (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Cycle control.

Analyses of bleeding patterns and cycle control demonstrated that bleeding patterns were comparable to those of low dose COCs, whereas the cycle control was characterised by absence of withdrawal bleeding in more cases (range: 16.8% to 22.3%) than observed with the comparator (range: 6.2% to 10.5%).
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 3 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 phase. If the COC has been taken according to the directions described in dosage and administration, it is unlikely that the woman is pregnant. However, if the COC has not been taken according to these directions prior to the first missed withdrawal bleed or if two withdrawal bleeds are missed, pregnancy must be ruled out before COC use is continued.

Paediatric use.

Qlaira is only indicated after menarche.

Use in the elderly.

Not applicable. Qlaira is not indicated after menopause.

Patients with hepatic impairment.

Qlaira is contraindicated in women with severe hepatic diseases whilst liver function values have not returned to normal (see Section 4.3 Contraindications).

Patients with renal impairment.

Qlaira has not been specifically studied in renally impaired patients.

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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effects of other medicinal products on Qlaira.

Interactions can occur with medicines that induce microsomal enzymes which can result in increased clearance of sex hormones and which may lead to breakthrough bleeding and/or contraceptive failure.
Women on treatment with any of these medicines should temporarily use a barrier method in addition to the COC or choose another method of contraception. The barrier method should be used during the time of concomitant drug administration and for 28 days after their discontinuation.

Substances increasing the clearance of COCs (diminished efficacy of COCs by enzyme induction), e.g.

Phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and products containing St. John's wort (Hypericum perforatum).
The effect of the CYP3A4 inducer rifampicin was studied in healthy postmenopausal women. Coadministration of rifampicin with estradiol valerate/ dienogest tablets led to significant decreases in steady-state concentrations and systemic exposures of dienogest and estradiol. The systemic exposure of dienogest and estradiol at steady state, measured by AUC (0-24 h), were decreased by 83% and 44%, respectively.

Substances with variable effects on the clearance of COCs.

When coadministered with COCs, many human immunodeficiency virus(HIV)/ hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors can increase or decrease plasma concentrations of estrogen or progestogen. These changes may be clinically relevant in some cases.

Substances decreasing the clearance of COCs (enzyme inhibitors).

Dienogest is a substrate of cytochrome P450 (CYP) 3A4.
Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g. ketoconazole, itraconazole, voriconazole, fluconazole), cimetidine, verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem, antidepressants and grapefruit juice can increase plasma levels of the estrogen or the progestogen or both.
In a study investigating the effect of CYP3A4 inhibitors (ketoconazole, erythromycin), steady-state dienogest and estradiol plasma levels were increased. Coadministration with the strong inhibitor ketoconazole resulted in a 186% increase of AUC (0-24 h) at steady state for dienogest and a 57% increase for estradiol. When coadministered with the moderate inhibitor erythromycin, the AUC (0-24 h) of dienogest and estradiol at steady state were increased by 62% and 33%, respectively.

Effects of Qlaira on other medicinal products.

Oral contraceptives may affect the metabolism of certain other medicines. Accordingly, plasma and tissue concentrations may either increase or decrease (e.g. lamotrigine). However, based on the in vitro data, inhibition of CYP enzymes by Qlaira is unlikely at the therapeutic dose.

Note.

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

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Qlaira is indicated for prevention of pregnancy.
(Category B3)
Category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.
Qlaira is contraindicated in pregnancy. If pregnancy occurs during use of Qlaira, further intake must be stopped. However, extensive epidemiological studies with ethinylestradiol containing COCs 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 reproductive toxicity of Qlaira has not been assessed in animals. However, studies have been performed for 17β-estradiol and dienogest, the active components of Qlaira.
Oral treatment of rats and rabbits with dienogest during organogenesis caused an increase in postimplantation loss at systemic exposure levels (based on AUC) less than that anticipated clinically. No teratogenicity was evident in either species at systemic exposure levels up to around 8 (rat) or 15 (rabbit) fold higher than that expected at the clinical dose. Oral treatment of rats with dienogest during late pregnancy and lactation was shown to impair fertility in the offspring at maternal systemic exposure levels (based on AUC) considerably less than that anticipated clinically.
Lactation may be influenced by COCs as they may reduce the quantity and change the composition of breast milk. Small amounts of the contraceptive steroids and/or their metabolites may be excreted with the milk. Therefore, the use of COCs should generally not be recommended until the nursing mother has completely weaned her child.

4.8 Adverse Effects (Undesirable Effects)

The most serious undesirable effects associated with the use of COCs are described, see Section 4.4 Special Warnings and Precautions for Use.

Oral contraception.

Table 2 reports adverse drug reactions (ADRs) by MedDRA system organ classes (MedDRA SOCs). The most appropriate MedDRA term (version 10.0) to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed, but should be taken into account as well. The frequencies are based on clinical trial data. The adverse drug reactions were recorded in 3 phase III clinical studies (N = 2266 women at risk for pregnancy) and considered at least possibly causally related to Qlaira use. All ADRs listed in the category 'rare' occurred in 1 to 2 patients resulting in < 0.1%.
The comparative rates for adverse reactions for treatment (N = 399) in comparison to the reference COC containing 0.02 mg EE and 0.10 mg levonorgestrel (N = 399) in study 304004/A35644 were: breast pain (3.3% vs. 1.0%), headache (1.8% vs. 1.8%), acne (1.3% vs. 2.3%), alopecia (0.8% vs. 1.0%), migraine (0.5% vs. 1.3%) and weight increased (0.5% vs. 1.0%).

Treatment of heavy and/or prolonged menstrual bleeding in women without organic pathology who desire oral contraception.

Table 3 reports adverse drug reactions (ADRs) by MedDRA system organ classes (MedDRA SOCs). The frequencies are based on clinical trial data. The adverse drug reactions were recorded in 2 phase III clinical studies (N = 264 women suffering from heavy and/or prolonged bleeding without organic pathology who desire oral contraception) and considered at least possibly causally related to Qlaira use.
In addition to the above mentioned adverse reactions, erythema nodosum, erythema multiforme, breast discharge and hypersensitivity have occurred under treatment with ethinylestradiol containing COCs. Although these symptoms were not reported during the clinical studies performed with Qlaira, the possibility that they also occur under treatment cannot be ruled out. In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.

Reporting suspected adverse effects.

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

4.2 Dose and Method of Administration

Combined oral contraceptives (COCs), when taken correctly, have a failure rate of approximately 1% per year. The failure rate may increase when pills are missed or taken incorrectly.
Treatment of heavy and/or prolonged menstrual bleeding with Qlaira has been shown to result in a rapid normalisation of excessive menstrual blood losses. If Qlaira has been taken according to the directions provided (see Section 4.2 Dose and Method of Administration, How to take Qlaira) and the patient does not experience a reduction of her menstrual bleeding after 3 treatment cycles then treatment with Qlaira should be ceased and other treatment options should be considered.

How to take Qlaira.

Tablets must be taken in the order directed on the wallet pack every day at about the same time with some liquid as needed. Tablet taking is continuous. One tablet is to be taken daily for 28 consecutive days. Each subsequent pack is started the day after the last tablet of the previous wallet. Withdrawal bleeding usually starts during the intake of the last tablets of a wallet and may not have finished before the next wallet is started. In some women, the bleeding starts after the first tablets of the new wallet are taken.

How to start Qlaira.

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 Qlaira is taken in this manner, the woman is protected against pregnancy immediately.

Changing from a combined hormonal contraceptive or vaginal ring.

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

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

The woman may switch from the minipill on any day, from an implant or the IUS on the day of its removal, or from an injectable when the next injection would be due, but should in all of these cases she should be advised to additionally use a barrier method for the first 9 days of tablet taking.

Following first trimester abortion.

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

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 at day 21 to 28 after delivery or second trimester abortion. When starting later, the woman should be advised to additionally use a barrier method for the first 9 days of tablet taking. However, if intercourse has already occurred, pregnancy should be excluded before the actual start of COC use or the woman has to wait for her first menstrual period.

Management of missed tablets.

Missed (white) placebo tablets can be disregarded. However, they should be discarded to avoid unintentionally prolonging the interval between active tablet taking.
The following advice only refers to missed active tablets.
If the woman is less than 12 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 more than 12 hours late in taking any active tablet, contraceptive protection may be reduced. The woman 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.
Depending on the day of the cycle on which the tablet has been missed (see Table 1 for details), back up contraceptive measures (e.g. a barrier method such as a condom) have to be used according to the principles in Table 1.
Not more than two tablets are to be taken on a given day.
If a woman has forgotten to start a new wallet, or if she has missed one or more tablets during days 3-9 of the wallet, she may already be pregnant (provided she has had intercourse in the 7 days before the oversight). The more tablets (of those with the two combined active ingredients on days 3-24) that are missed and the closer they are to the placebo tablet phase, the higher the risk of a pregnancy.
If the woman missed tablets and subsequently has no withdrawal bleed at the end of the wallet/ beginning of new wallet, the possibility of a pregnancy should be considered.

Paediatric population.

There is no relevant indication for use of Qlaira (in children) before menarche.

Advice in case of gastrointestinal disturbances.

In case of severe gastrointestinal disturbances, absorption may not be complete and additional contraceptive measures should be taken.
If vomiting occurs within 3-4 hours after active tablet taking, the advice concerning missed tablets is applicable (see Section 4.2 Dose and Method of Administration, Management of missed tablets). 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.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration. However, adverse effects of Qlaira include dizziness and fatigue that could affect the ability to drive or use machines (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.9 Overdose

There have been no reports of serious deleterious effects from overdose. Symptoms that may occur in case of taking an overdose of active tablets 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 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

References

1 Dinger JC, Heinemann LAJ, Kuhl-Habich D. The safety of a drospirenone-containing oral contraceptive: final results from the European Active Surveillance study on Oral Contraceptives based on 142,475 women-years of observation. Contraception 2007;75:344-354.
2 Long-term Active Surveillance Study for Oral Contraceptives (LASS), 2nd update report based on study status of May 2009.
3 Heit J A et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30 year population-based study. Annals of Internal Medicine:2005;143/10:697-708.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each active tablet contains: lactose monohydrate, maize starch, pregelatinised maize starch, povidone, magnesium stearate, hypromellose, macrogol 6000, purified talc, titanium dioxide, and iron oxide yellow or iron oxide red.
Each placebo tablet contains: lactose monohydrate, maize starch, povidone, magnesium stearate, hypromellose, purified talc and titanium dioxide.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Blister packs consisting of transparent films made of polyvinyl chloride and metallic foils made of hard tempered aluminium (mat side hot sealable). The blister is glued into a cardboard wallet.
Each wallet containing 28 tablets.
Pack sizes: 1 x 28 film-coated tablets; 3 x 28 film-coated tablets.

6.6 Special Precautions for Disposal

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

Summary Table of Changes