Consumer medicine information

Yana

Drospirenone; Ethinylestradiol

BRAND INFORMATION

Brand name

Yana

Active ingredient

Drospirenone; Ethinylestradiol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Yana.

SUMMARY CMI

YANA®

Consumer Medicine Information (CMI) summary

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

1. Why am I using YANA®?

YANA® contains the active ingredients drospirenone and ethinylestradiol. YANA® is a combined oral contraceptive used to prevent pregnancy, treat moderate acne and treat symptoms of premenstrual dysphoric disorder (PMDD) in women seeking oral contraception. For more information, see Section 1. Why am I using YANA®? in the full CMI.

2. What should I know before I use YANA®?

Do not use if you have ever had an allergic reaction to YANA® or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, especially if it increases your risk of blood clots, if you have or had blood clots, certain cancers or migraines. Tell your doctor if you take any other medicines, are pregnant or plan to become pregnant or are breastfeeding.

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

3. What if I am taking other medicines?

Some medicines may interfere with YANA® and affect how it works. The main types of medicines that affect how well YANA® works include certain antibiotics, antifungal medicines, HIV treatments, hepatitis C virus treatments, epilepsy medicines, medicines for high blood pressure and the heart.

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

4. How do I use YANA®?

  • Take one tablet daily at about the same time each day. Swallow the tablet whole with a full glass of water.
  • If you vomit within 3-4 hours or have severe diarrhoea after taking a pink active tablet, the active ingredients may not have been completely absorbed. This is like missing a tablet. Follow the advice for missed tablets.

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

5. What should I know while using YANA®?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using YANA®.
  • Use additional barrier contraceptives (e.g. condoms) to protect yourself from STIs.
  • Tell your doctor if you are going to have surgery or if you plan to travel by air for greater than 4 hours.
  • Stop taking YANA® and call your doctor immediately if you notice signs of a possible blood clot e.g. chest pains, breathlessness or difficulty breathing, swelling, pain or tenderness of one leg, sudden dizziness, loss of balance, trouble speaking or seeing.
Things you should not doDo 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 YANA®, or do not take a tablet every day.
Looking after your medicineStore it in a cool dry place away from moisture, heat or sunlight where the temperature says below 25°C.

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

6. Are there any side effects?

Less serious side effects can include irregular periods or bleeding between periods, breast pain, mood changes, nausea, headaches (including migraines). Serious side effects include signs of a blood clot (e.g. breathlessness, sudden weakness/pins and needles, sudden stomach pains, fainting, unusual headaches or migraines that are worse than usual, sudden problems speaking, sudden trouble walking, pain in chest, arms or below breast bone), jaundice (yellowing skin or eyes), coughing up blood, unexplained vaginal bleeding, breast lumps.

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



FULL CMI

YANA®

Active ingredients: drospirenone and ethinylestradiol

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I using YANA®?

YANA® contains the active ingredients drospirenone and ethinylestradiol. YANA® is a combined oral contraceptive, commonly known as a ‘birth control pill’ or ‘the Pill’.

YANA® has 24 active (hormone) tablets and 4 inactive tablets, rather than the traditional 21 active tablets and 7 inactive tablets. This means that with YANA®, you take the active (hormone) tablets for 3 more days. This helps your hormone levels to stay even.

YANA® is used to:

  • prevent pregnancy
  • treat moderate acne
  • treat symptoms of premenstrual dysphoric disorder (PMDD) in women seeking oral contraception.

While taking YANA® you may also experience more regular and lighter periods – which may also help to improve iron deficiency (anaemia). YANA® can also help to decrease period pain as well as improve symptoms such as bloating, swelling or weight gain related to fluid retention.

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

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

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

2. What should I know before I use YANA®?

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

Warnings

Do not use YANA® if:

  • you have allergy to drospirenone, ethinylestradiol, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • you have intolerance or allergy to lactose. This medicine contain lactose.
  • you are taking antiviral medicines which contain: glecaprevir, pibrentasvir, sofosbuvir, velpatasvir, voxilaprevir, ombitasvir, paritaprevir or dasabuvir and combinations of these. These antiviral medicines are used to treat long-term hepatitis C (an infectious disease that affects the liver, caused by the hepatitis C virus).
  • 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) or other parts of the body
    - 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 miscarriages.
    - major surgery after which you have not been able to move around for a period of time.
    - angina (chest pain)
    - mini stroke (also known as TIA or transient ischaemic attack)
    - severe kidney insufficiency or an acute failure of your kidney
    - migraines, 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.
  • you have or are concerned about an increased risk of blood clots.
    You are more at risk of having a blood clot when you take the Pill. But the risk of having a blood clot when taking the Pill is less than the risk during pregnancy.

Check with your doctor if you:

  • smoke
  • 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
  • have, or have had any of the following medical conditions:
    - diabetes
    - high blood pressure
    - heart valve disorders or certain heart rhythm disorders
    - an increased potassium blood level (e.g. due to problems with your kidney/s) and also use diuretics or other drugs that may increase the potassium in your blood
    - cancer
    - hyperhomocysteinaemia, a condition characterised by high levels of the amino acid homocysteine in the blood
  • are overweight
  • have any hereditary or acquired conditions that may make it more likely for you to get blood clots
  • have high cholesterol or triglycerides
  • have liver disease
  • have kidney disease
  • have jaundice (yellowing of the skin) and/or pruritus (itching of the skin) related to cholestasis (condition in which the flow of bile from the liver stops or slows)
  • have gall bladder disease
  • have Crohn's disease or ulcerative colitis (chronic inflammatory bowel disease)
  • have systemic lupus erythematosus (SLE - a disease affecting the skin all over the body)
  • have haemolytic uraemic syndrome (HUS - a disorder of blood coagulation causing failure of the kidneys)
  • have sickle cell disease
  • have a condition that occurred for the first time, or worsened during pregnancy or previous use of sex hormones (e.g. hearing loss, a metabolic disease called porphyria, a skin disease called herpes gestationis, a neurological disease called Sydenham's chorea)
  • have chloasma (yellowish-brown pigmentation patches on the skin, particularly of the face) - if so, avoid exposure to the sun or ultraviolet radiation
  • have hereditary angio-oedema – you should see your doctor immediately if you experience symptoms of angio-oedema, such as swollen face, tongue and/or pharynx and/or difficulty swallowing, or hives together with difficulty in breathing.

If any of these conditions appear for the first time, recur or worsen while taking this medicine, 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).

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them.

See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

  • Check with your doctor if you are pregnant or intend to become pregnant. Do not take this medicine if you are pregnant or think you might be pregnant.
  • Tell your doctor immediately if you think you are pregnant.
  • Talk to your doctor if you are breastfeeding or intend to breastfeed. YANA® is generally not recommended if you are breastfeeding.

3. What if I am taking other medicines?

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

Some medicines and YANA® may interfere with each other. These include:

Medicine classExamples
Antibioticsrifampicin, rifabutin, macrolide antibiotics (e.g. Clarithromycin, erythromycin)
Antifungal medicinesgriseofluvin, ketoconazole
HIV medicinesritonavir, nevirapine
Hepatitis C Virus (HCV) medicinesboceprevir, telaprevir, glecaprevir, pibrentasvir, ombitasvir, paritaprevir, or dasabuvir, and combinations of these
Epilepsy medicinesphenytoin, primidone, barbiturates (e.g. phenobarbitone), carbamazepine, oxcarbazepine, topiramate, felbamate, lamotrigine
Immunosuppressantscyclosporin
Medicines for high blood pressure, chest pain and or irregular heart beatsdiltiazem, verapamil, spironolactone, eplerenone
ACE inhibitors (e.g. lisinopril, perindopril), angiotensin II receptor blockers (e.g. candesartan, irbesartan), diuretics (e.g. hydrochlorothiazide, furosemide), aldosterone antagonists (e.g. spironolactone, eplerenone)
Anti-inflammatory medicinesetoricoxib, indomethacin
Othertizanidine, melatonin, midazolam, theophylline, St John's Wort, grapefruit juice

These medicines may be affected by YANA® or may affect how well it works. They can:

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

Your doctor may need to alter the dose of these medicines, or prescribe a different medicine.

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

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

4. How do I use YANA®?

How much to take

Take one tablet daily at about the same time every day. You must take YANA® every day even if you do not have sex very often. This will also help you remember when to take it.

How to take YANA®

  • Swallow the tablet whole with water. It does not matter if you take it before or after food.
  • If you vomit within 3-4 hours or have severe diarrhoea after taking a pink active tablet, the active ingredients may not have been completely absorbed. This is like missing a tablet. Follow the advice for missed tablets.
  • Each blister pack is marked with the day of the week.
  • Take your first pink (active) tablet from the green area on the blister pack corresponding to the day of the week.
  • Follow the direction of the arrows on the blister pack until all the tablets have been taken.
  • Your period should begin 2-3 days after starting to take the white inactive tablets and may not have finished before the next pack is started.
  • Always start a new blister pack on the same day of the week as your previous pack.

Taking YANA® for the first time

If you are starting YANA® after a natural cycle, and you have not used a hormonal contraceptive in the past month, start on the first day of your period, i.e. on the first day of your menstrual bleeding.

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

Your doctor will advise you when to start if you:

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

Changing from another contraceptive

Type of contraceptiveHow do I change over to YANA®?Will I need additional contraception?
Combined oral contraceptiveStart taking YANA® on the day after taking the last active tablet in your previous pill pack. Bleeding may not occur until the end of the first pack of YANA®.
You can also switch to YANA® after taking one or more inactive tablets in your previous pack, but no later than the day after taking the last inactive tablet.		No
Vaginal ringStart YANA® on the day of removal of the vaginal ring or, at the latest, when the next application would have been due.No
Progesterone only pill (minipill)Stop taking the minipill on any day and start taking YANA® at the same time the day after you took your last minipill.You must also use additional barrier contraceptive precautions (e.g. condoms or a diaphragm) for the first 7 days of tablet-taking when having intercourse.
Progestogen-only injection, implant or intrauterine system (IUS)Start taking YANA® when your next injection is due, or on the day that your implant or IUS is removed.

If you want to delay a period

To delay your period:

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

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

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

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

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

If you forget to take YANA®

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

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

  • If you have been taking the pink active tablets for 7 uninterrupted days and miss a pink active tablet, take the missed tablet as soon as you remember, then go back to taking your medicine as you would normally, even if this means taking two tablets in one day. You will not need to use additional barrier contraceptive precautions.
  • The chance of pregnancy after missing a pink active tablet depends on when you missed the tablet. There is a higher risk of becoming pregnant if you miss a tablet at the beginning or end of a pack.
    - If after taking your missed tablet you have less than 7 days of pink active tablets left in a row, you should finish the active tablets in your pack but skip the white inactive tablets and start a new pack.
    - This is the best way to maintain contraceptive protection. However, you may not have a period until the end of the pink active tablets of the second pack. You may have spotting or breakthrough bleeding on tablet-taking days.
  • If you have been taking the pink active tablets for less than 7 days and miss a pink active tablet, take the missed tablet as soon as you remember, then go back to taking your medicine as you would normally, even if this means taking two tablets in one day. In addition, you must also use additional barrier contraceptive precautions (e.g. condoms or a diaphragm) for the next 7 days.
    - If you have had sexual intercourse during that time, there is a possibility of pregnancy and you may need emergency contraception.
  • If you forget to take more than one pink active tablet, seek advice from your doctor or pharmacist about what to do.
    - If you have had sexual intercourse in the week before missing your tablets, there is a possibility of becoming pregnant.
  • If you miss a white inactive tablet, you do not need to take them later because they do not contain any active ingredients. However, it is important that you discard the missed white tablet(s) to make sure that the number of days between taking active tablets is not increased as this would increase the risk of pregnancy. Continue with the next tablet at the usual time.

Please see the diagram at the end of this leaflet for “Summary of advice if you missed a pink active tablet more than 24 hours ago”.

How long to take it for

You can stop taking YANA® at any time. If you are considering becoming pregnant, it is recommended that you begin taking a vitamin supplement containing folic acid. It is best that you start taking folic acid tablets before you stop taking YANA® 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 take too much YANA®

If you think that you have used too much YANA®, you may need urgent medical attention.

You should immediately:

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

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

If you take several pink active tablets at once, you may feel sick or vomit or may bleed from the vagina. Even girls who have not yet started to menstruate but have accidentally taken this medicine may experience such bleeding.

5. What should I know while using YANA®?

Things you should 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.
  • Use additional barrier contraceptives (e.g. condoms) to protect yourself from STIs. YANA® 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.
  • If you are going to have surgery, tell your doctor beforehand that you are taking YANA®. 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 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 YANA® has not been discontinued in advance.
  • Tell your doctor if you plan to air travel for greater than 4 hours. There may be an increased risk of blood clots due to lack of movement, particularly in women with other risk factors.
  • Have regular check-ups with your doctor. When you are taking the Pill, your doctor will tell you to return for regular check-ups, including getting a Cervical Screening Test. Your doctor will advise how often you need a Cervical Screening Test. A Cervical Screening Test can detect abnormal cells lining the cervix. Sometimes abnormal cells can progress to cancer.
  • Tell your doctor if you develop high blood pressure while taking YANA®. You may be told to stop taking it.
  • If you are about to start on any new medicine, remind your doctor and pharmacist that you are taking YANA®.

Call your doctor straight away 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
  • unexpected bleeding and it continues, becomes heavy, or occurs again
  • pregnancy.

Things you should not do

  • Do not take YANA® 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 YANA®, or do not take a tablet every day.

Bleeding and Missed Periods

When taking these tablets for the first few months, you can have irregular vaginal bleeding (spotting or breakthrough bleeding) between your periods. You may need to use sanitary products, but continue to take your tablets as normal. Irregular vaginal bleeding usually stops once your body has adjusted to the Pill, usually after about 3 months.

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

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

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

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

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

Driving or using machines

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

Looking after your medicine

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

Store it in a cool dry place away from moisture, heat or sunlight where the temperature stays below 25°C.

Do NOT store it in the bathroom or near a sink, or in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

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

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

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

Less serious side effects

Less serious side effectsWhat to do
Reproductive system-related
  • unscheduled vaginal bleeding
  • abnormal periods
  • irregular bleeding between periods
  • breast tenderness or pain
Mood related
  • mood changes, including depression
General
  • nausea
  • headache, including migraines
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Signs of blood clot, such as:
  • pain in the chest, arm or below the breastbone
  • pain or discomfort that goes to your back
  • breathlessness and/or difficulty breathing
  • swelling, pain or tenderness of one leg
  • sudden weakness, numbness or bad ‘pins and needles’ of the face, arm or leg, especially on one side of the body
  • sudden trouble walking, dizziness, loss of balance or coordination
  • severe, sudden stomach pains
  • a fainting attack, or you collapse
  • unusual headaches or migraines that are worse than usual
  • sudden problems with speech, understanding or eyesight
Liver-related
  • jaundice (yellowing skin or yellowing eyes)
Blood-related
  • coughing up blood
Reproductive system-related
  • breast lumps
  • unexplained vaginal bleeding
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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

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

Blood clots and the Pill

Blood clots are rare. Very occasionally blood clots may cause serious permanent disability and may even be fatal.

Blood clots can form, travel and block different blood vessels in the body. They can occur in the deep veins of the legs (causing deep vein thrombosis), the clot can travel and cause a blockage in the lungs (called pulmonary embolism). Blood clots can occur in the blood vessels of the heart (causing a heart attack) or the brain (causing a stroke).

All combined oral contraceptive pills, including YANA®, increase the risk of having a blood clot. However, blood clots can form whether or not you are taking the pill, including in pregnancy. The risk of having a blood clot when taking YANA® is less than the risk of having a blood clot 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.

Stop taking YANA® and call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice signs of a possible blood clot.

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

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.

Reporting side effects

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

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

7. Product details

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

What YANA® contains

Active ingredient
(main ingredient)		Each pink active tablet contains:
  • 3 milligram drospirenone
  • 20 microgram ethinylestradiol
Other ingredients
(inactive ingredients)		Each pink active tablet contains:
  • lactose monohydrate
  • pregelatinised maize starch
  • povidone
  • croscarmellose sodium
  • polysorbate 80
  • magnesium stearate
  • OPADRY II complete film coating system 85F34610 Pink
Each white inactive tablet contains:
  • lactose
  • povidone
  • magnesium stearate
  • OPADRY II complete film coating system 85F18422 White.
Potential allergenslactose monohydrate

This medicine contains lactose.

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

What YANA® looks like

YANA® is a calendar pack containing 24 pink active tablets and 4 white inactive tablets per blister strip.

Active tablet: Plain, round, pink, film coated tablet.

Inactive tablet: Plain, round, white, film coated tablet.

AUST R 200633

Available as packs of 1, 3 or 6* blister packs.

* Not all pack sizes may be available.

Who distributes YANA®

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

This leaflet was prepared in March 2025.

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

Published by MIMS July 2025

BRAND INFORMATION

Brand name

Yana

Active ingredient

Drospirenone; Ethinylestradiol

Schedule

S4

 

1 Name of Medicine

Drospirenone, ethinylestradiol (EE).

2 Qualitative and Quantitative Composition

Yana is a combined oral contraceptive (COC) tablet containing the synthetic progestogen, drospirenone and the synthetic estrogen, ethinylestradiol.
Each pink active tablet contains drospirenone 3 mg and ethinylestradiol 20 microgram.

Excipients with known effect.

Active tablet.

Lactose monohydrate.

Placebo tablet.

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

3 Pharmaceutical Form

Yana.

Active tablet.

Plain, round, pink, film coated tablet.

Placebo tablet.

Plain, round, white, film coated tablets.

4 Clinical Particulars

4.1 Therapeutic Indications

This medicine is indicated for use as:
An oral contraceptive.
Treatment of moderate acne vulgaris in women who seek oral contraception.
Treatment of symptoms of premenstrual dysphoric disorder (PMDD) in women who have chosen oral contraceptives as their method of birth control. The efficacy of drospirenone 3 mg/ethinylestradiol 20 microgram for PMDD was not assessed beyond 3 cycles. Drospirenone 3 mg/ethinylestradiol 20 microgram has not been evaluated for treatment of PMS (premenstrual syndrome), see Section 5.1 Pharmacodynamic Properties, Clinical trials.

4.2 Dose and Method of Administration

Yana is intended for oral administration.

Dosage.

Combined oral contraceptives, when taken correctly, have a failure rate of approximately 1% per year. The failure rate may increase when pills are missed or taken incorrectly.
Tablets must be taken in the order directed on the package every day at about the same time with some liquid as needed. Tablet taking is continuous. One tablet is taken daily for 28 consecutive days. Each subsequent pack is started the day after the last tablet of the previous pack. A withdrawal bleed usually starts on day 2 - 3 after starting the white placebo tablets (last row) and may not have finished before the next pack is started.

How to start this medicine.

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

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

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

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

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

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

Following first trimester abortion.

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

Following delivery or second trimester abortion.

Women should be advised to start on day 21 to 28 after delivery or second trimester abortion. When starting later, the woman should be advised to additionally use a barrier method for the first 7 days of tablet-taking. However, if intercourse has already occurred, pregnancy should be excluded before the actual start of COC use or the woman has to wait for her first menstrual period.
For breastfeeding women see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation.

Management of missed tablets.

Missed white pills from the last row of the blister are placebo tablets and thus can be disregarded. However they should be discarded to avoid unintentionally prolonging the placebo tablet phase.
The risk of pregnancy increases with each pink active tablet missed. The following advice only refers to missed pink active tablets.
If the woman is less than 24 hours late in taking any pink active tablet, contraceptive protection is not reduced. The woman should take the tablet as soon as she remembers and should take further tablets at the usual time.
If the woman is more than 24 hours late in taking any pink active tablet, contraceptive protection may be reduced.
The management of missed tablets can be guided by the following two basic rules:
1. The placebo tablet interval for this medicine is 4 days. Active tablet-taking must never be discontinued for longer than 7 days.

Please note.

This medicine is registered in Australia for use as a contraceptive using a continuous 28 day regimen consisting of 24 active tablets followed by 4 inactive tablets; the stated efficacy in preventing pregnancy is based on this regimen.
2. Seven days of uninterrupted active tablet-taking are required to attain adequate suppression of the hypothalamic pituitary ovarian axis.
Accordingly the following advice can be given in daily practice:

Day 1 - 7.

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

Day 8 - 14.

The woman should take the last missed pink active tablet as soon as she remembers, even if this means taking two pink active tablets at the same time. She then continues to take tablets at her usual time. Provided that the woman has taken her tablets correctly in the 7 days preceding the first missed pink active tablet, there is no need to use extra contraceptive precautions. However, if this is not the case, or if she missed more than one pink active tablet, the woman should be advised to use extra precautions for 7 days.

Day 15 - 24.

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

How to delay a period.

To delay a period the woman should continue with another pack of this medicine without taking the white placebo tablets from her current pack. The extension can be carried on for as long as wished until the end of the active tablets in the second pack. During the extension the woman may experience breakthrough-bleeding or spotting. Regular intake of this medicine is then resumed with the next pack (after the placebo tablet interval).
To shift her periods to another day of the week than the woman is used to with her current scheme, she can be advised to shorten her forthcoming placebo tablet phase 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).

Advice in case of gastro-intestinal disturbances.

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

4.3 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.
Severe renal insufficiency or acute renal failure.
Drospirenone 3 mg /ethinylestradiol 20 microgram tablet is contraindicated for concomitant use with the medicinal products glecaprevir, pibrentasvir, sofosbuvir, velpatasvir, voxilaprevir, ombitasvir, paritaprevir or dasabuvir and combinations of these (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Presence or history of liver tumours (benign or malignant).
Known or suspected sex steroid-influenced malignancies (e.g. of the genital organs or the breasts).
Undiagnosed vaginal bleeding.
Known or suspected pregnancy.
Hypersensitivity to any of the ingredients contained in this medicine.

4.4 Special Warnings and Precautions for Use

If any of the conditions/risk factors mentioned below are 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 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 on whether COC use should be discontinued.

Circulatory disorders.

Epidemiological studies have suggested an association between the use of COCs and an increased risk of arterial and venous thrombotic and thromboembolic diseases such as myocardial infarction, stroke, deep venous thrombosis, pulmonary embolism and of cerebrovascular accidents. These events occur rarely in average-risk women.
Risk of venous thromboembolism (VTE). The use of any combined oral contraceptive (COC) 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 COC is re-started after a break in use of 4 weeks or more.
Data from a large, prospective, multinational, cohort study (EURAS and LASS) on the safety of OC use, suggests that this increased risk is mainly present during the first 3 months.
Two prospective cohort studies (EURAS and Ingenix), each evaluating the risk of venous and arterial thromboembolism and death, were initiated separately at the time of ethinylestradiol/drospirenone 30 microgram/3 mg approval in Europe and the United States. The first (EURAS) showed the risk of thromboembolism (particularly venous thromboembolism) and death in ethinylestradiol/drospirenone 30 microgram/3 mg users to be comparable to that of other oral contraceptive preparations, including those containing levonorgestrel (a so-called second generation COC).
In the EURAS study, the VTE incidence rate for all OC users ranged from 8.0 to 9.9 per 10,000 WY. The overall incidence rate for past OC users was 4.7 VTE/10,000 WY, which was further specified to 19.4 VTE/10,000 WY for pregnant past OC users and 2.3 VTE/10,000 WY for non-pregnant past OC users. The second prospective cohort study (Ingenix) also showed a comparable risk of thromboembolism in ethinylestradiol/drospirenone 30 microgram/3 mg users compared to users of other COCs, including those containing levonorgestrel. In this second study, COC comparator groups were selected based on their having similar characteristics to those being prescribed ethinylestradiol/drospirenone 30 microgram/3 mg.
Another large population based study (Heit et al.) found an incidence rate of 20 VTE/10,000 WY in pregnant or postpartal women and 4.6 in non-pregnant women of reproductive age. All of these rates tend to be higher than those reported in the past.
Based on this data it can be assumed that the VTE risk in users of OC users is roughly twice as high for non-pregnant non OC users. The absolute attributable risk (approximately 4 VTEs per 10,000 WY of use) was found to be slightly higher in these studies than reported in the past. Nevertheless the risk in OC users remains lower than the VTE risk associated with pregnancy and the first weeks following delivery.
Two additional epidemiological studies, one case control study (van Hylckama Vlieg et al.) and one retrospective cohort study (Lidegaard et al., 2009) suggested that the risk of venous thromboembolism occurring in ethinylestradiol/drospirenone 30 microgram/3 mg users was higher than that for users of levonorgestrel-containing COCs and lower than that for users of desogestrel/gestodene-containing COCs (so called third generation COCs). In the case-control study however, the number of ethinylestradiol/drospirenone 30 microgram/3 mg cases was very small (1.2% of all cases making the risk estimates unreliable). The relative risk for ethinylestradiol/drospirenone 30 microgram/3 mg users in the retrospective cohort study was greater than that for users of other COC products when considering women who used the products for less than one year. However, these one-year estimates may not be reliable because the analysis may include women of varying risk levels. Among women who used the products for 1 to 4 years, the relative risk was similar for users of ethinylestradiol/drospirenone 30 microgram/3 mg to that of other COC products.
Two further retrospective database studies (Parkin et al., Jick and Hernandez) published in 2011, suggested a greater risk for VTE in users of drospirenone-containing COCs compared to levonorgestrel-containing COCs. However, the number of drospirenone cases in the Parkin et al. study was very small.
It is important that women understand that VTE associated with COC use is rare in average-risk women (see Table 1).
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 COC use.
Combined oral contraceptive (COC) in Table 1 refers to oral contraceptives with a low estrogen dose (< 50 microgram ethinylestradiol).
Drospirenone containing COCs may be associated with a higher risk of VTE than COCs containing the progestogen levonorgestrel or some other progestogens. Epidemiologic studies that compared the risk of VTE reported that the risk ranged from no increase to a three-fold increase.
An additional increase in VTE risk for COCs 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 COCs, and how her current risk factors influence this risk.
Products that contain the progestogens levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE.
Products containing drospirenone, may have up to twice this level of risk.
The increased risk of VTE during the postpartum period must be considered if re-starting a COC. See Section 4.2 Dose and Method of Administration; Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy, Use in lactation.
VTE may be life-threatening or may have a fatal outcome (in 1 - 2% of cases).
Extremely rarely, thrombosis has been reported to occur in COC users in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral or retinal veins and arteries.
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).
This medicine 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.
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 a COC (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 the COC 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 or sudden severe pain in the chest which may increase with deep breathing;
severe light headedness or dizziness;
rapid or irregular heartbeat.
Some of these symptoms (e.g. "shortness of breath", "coughing") are non-specific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections).
Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of an extremity.
If the occlusion occurs in the eye symptoms can range from painless blurring of vision which can progress to loss of vision. Sometimes loss of vision can occur almost immediately.
Risk of arterial thromboembolism (ATE). Epidemiological studies have associated the use of 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. This medicine 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.
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 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, slurred speech or aphasia;
sudden partial or complete loss of vision; diplopia;
sudden, severe or prolonged headache with no known cause;
loss of consciousness or fainting with or without seizure.
Temporary symptoms suggest the event is a transient ischaemic attack (TIA).
Symptoms of myocardial infarction (MI) can include:
pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone;
discomfort radiating to the back, jaw, throat, arm, stomach;
feeling of being full, having indigestion or choking;
sweating, nausea, vomiting or dizziness;
extreme weakness, anxiety, or shortness of breath;
rapid or irregular heartbeats.

Tumours.

The most important risk factor for cervical cancer is persistent human papillomavirus (HPV) infection. Some epidemiological studies have indicated that long term use of COCs may further contribute to this increased risk but there continues to be controversy about the extent to which this finding is attributable to confounding effects, e.g. cervical screening and sexual behaviour including use of barrier contraceptives.
A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently taking COCs. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. These studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.
In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been reported in users of COCs. In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhages. A liver tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage occur in women taking COCs.
Malignancies may be life-threatening or may have a fatal outcome.

Other conditions.

Potassium excretion capacity may be limited in patients with renal insufficiency. In a clinical study, drospirenone intake did not show an effect on the serum potassium concentration in patients with mild or moderate renal impairment. A theoretical risk for hyperkalaemia can be assumed only for patients whose pre-treatment serum potassium is in the upper reference range, and who are additionally using potassium sparing medicines.
Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when taking COCs.
Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. The antimineralocorticoid effect of drospirenone may counteract ethinylestradiol-induced increases in blood pressure observed in normotensive women taking other combined oral contraceptives. However, if a sustained clinically significant hypertension develops during the use of a COC 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 uraemic syndrome; Sydenham's chorea; herpes gestationis; otosclerosis-related hearing loss.
In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.
Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. Recurrence of cholestatic jaundice which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of COCs.
Although COCs may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics taking low-dose COCs (containing < 50 microgram ethinylestradiol). However, diabetic women should be carefully observed while taking COCs.
Crohn's disease and ulcerative colitis have been associated with COC use.
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking COCs.
Each pink active tablet contains 44 mg of lactose and each white placebo tablet contains 89.5 mg of lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption who are on a lactose free diet should take this amount into consideration.
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 the contraindications and precautions, and should be repeated at least annually during the use of COCs. Periodic medical assessment is also of importance because contraindications (e.g. a transient ischaemic attack, etc.) or risk factors (e.g. a family history of venous or arterial thrombosis) may appear for the first time during the use of a COC. The frequency and nature of these assessments should be adapted to the individual woman but should generally include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests.

Sexually transmitted infections including human immunodeficiency virus (HIV) infections and acquired immune deficiency syndrome (AIDS).

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

Reduced efficacy.

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

Reduced cycle control.

With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. Therefore, the evaluation of any irregular bleeding is only meaningful after an adaptation interval of about three cycles.
If bleeding irregularities persist or occur after previously regular cycles, then non-hormonal causes should be considered and adequate diagnostic measures are indicated to exclude malignancy or pregnancy. These may include curettage.
In some women withdrawal bleeding may not occur during the placebo tablet interval. If the COC has been taken according to the directions, it is unlikely that the woman is pregnant. However, if the COC has not been taken according to these directions prior to the first missed withdrawal bleed or if two withdrawal bleeds are missed, pregnancy must be ruled out before COC use is continued.
In women who choose to use drospirenone 3 mg/ethinylestradiol 20 microgram tablet with a continuous regimen, withdrawal bleeding is not expected to occur during the extension period when active tablet taking is uninterrupted. Therefore, the absence of withdrawal bleeding cannot be used as a sign of an unexpected pregnancy and as such, unexpected pregnancy may be difficult to recognise. This may be of particular importance to women using teratogenic drugs. Although pregnancy is unlikely if drospirenone 3 mg/ethinylestradiol 20 microgram tablet is taken as directed, if for any reason, pregnancy is suspected, a pregnancy test should be performed.

Alanine transaminase (ALT) elevations.

In patients treated with hepatitis C antiviral medications including glecaprevir, pibrentasvir ombitasvir, paritaprevir or dasabuvir, ALT elevations may occur in women using ethinylestradiol-containing medications such as CHCs. Prescribers should consult the relevant antiviral 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.

Use in hepatic impairment.

Drospirenone 3 mg/ethinylestradiol 20 microgram tablet is contraindicated in women with severe hepatic disease as long as liver function values have not returned to normal (see Section 4.3 Contraindications).

Use in renal impairment.

Drospirenone 3 mg/ethinylestradiol 20 microgram tablet is contraindicated in women with severe renal insufficiency or acute renal failure (see Section 4.3 Contraindications).

Use in the elderly.

Drospirenone 3 mg/ethinylestradiol 20 microgram tablet is not indicated after menopause.

Paediatric use.

Drospirenone 3 mg/ethinylestradiol 20 microgram tablet is only indicated after menarche.

Effects on laboratory tests.

The use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of carrier proteins, e.g. corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range. Drospirenone causes an increase in plasma renin activity and plasma aldosterone induced by its mild antimineralocorticoid activity.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effects of other medicines on drospirenone 3 mg/ethinylestradiol 30 microgram.

Interactions can occur with medicines that induce microsomal enzymes, which can result in increased clearance of sex hormones and may lead to break-through bleeding and/or contraceptive failure.
Enzyme induction can already be observed after a few days of treatment. Maximal enzyme induction is generally seen within a few weeks. After the cessation of drug therapy enzyme induction may be sustained for about 4 weeks. Women prescribed any of these medicines should temporarily use a barrier method in addition to the COC, or choose another method of contraception. The barrier method should be used during the time of concomitant medicine administration and for 28 days after their discontinuation. If the period in which the barrier method is used runs beyond the end of the active tablets in the COC pack, the white placebo tablets should be omitted and the next COC pack started.

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

For example, phenytoin, barbiturates, primidone, carbamazepine and rifampicin; and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and products containing St John's wort (Hypericum perforatum).

Substances with variable effects on the clearance of COCs.

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

Substances decreasing the clearance of COCs (enzyme inhibitors).

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

Effects of COCs on other medicines.

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

Pharmacodynamic interactions.

Co-administration of ethinylestradiol-containing medicinal products with direct-acting antiviral (DAA) medicinal products containing ombitasvir, paritaprevir, or dasabuvir, and combinations of these has been shown to be associated with increases in alanine aminotransferase (ALT) levels to greater than 20 times the upper limit of normal in healthy female subjects and HCV infected women (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use). ALT elevations have also been observed with HCV anti-viral medicinal products including glecaprevir/pibrentasvir. 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.

Other interactions.

There is a theoretical potential for an increase in serum potassium in women taking drospirenone 3 mg/ethinylestradiol 20 microgram tablets with other medicines that may increase serum potassium levels. Such medicines include angiotensin-II-receptor antagonists, potassium-sparing diuretics, and aldosterone antagonists. However, in studies evaluating the interaction of drospirenone (combined with estradiol) with an ACE inhibitor or indomethacin, no clinically or statistically significant differences in serum potassium concentrations were observed.

Note.

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

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category B31)
Drospirenone and/or its metabolites crossed the placenta and entered the foetus when administered orally to pregnant rats and rabbits. Treatment of pregnant rats with a combination of drospirenone and ethinylestradiol resulted in a dose-dependent increased incidence of embryolethality due to increased pre- and post-implantation losses. There was no indication of teratogenic effects of drospirenone in rats or rabbits.
Dose-dependent feminisation of male foetuses and virilisation of female foetuses were seen following administration of a combination of drospirenone and ethinylestradiol to female rats in the last third of pregnancy. Feminising effects in male foetuses were consistent with drospirenone's anti-androgenic activity and were observed at an estimated systemic exposure approximately 8 - 13 fold than that anticipated clinically (based on AUC). Virilisation of female foetuses was seen following systemic drospirenone exposure of approximately 2 to 5-fold than that anticipated clinically (based on AUC). This effect has previously been described for estrogens in rats. When pregnant monkeys received a combination of drospirenone and ethinylestradiol by daily oral administration during the major period of organogenesis and sexual organ differentiation, abortion rates were increased in a dose-dependent manner. However there were no indications of teratogenicity.
Extensive epidemiological studies have revealed neither an increased risk of birth defects in children born to women who take COCs prior to pregnancy, nor a teratogenic effect when COCs were taken inadvertently during early pregnancy. Drospirenone 3 mg/ethinylestradiol 20 microgram tablets are contraindicated during pregnancy. Pregnancy should be ruled out before the start of therapy. Should pregnancy occur during the use of drospirenone 3 mg/ethinylestradiol 20 microgram tablets, the preparation must be discontinued immediately (see Section 4.3 Contraindications).
1Category B3: drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.
 Lactation may be influenced by COCs as they may reduce the quantity and change the composition of breast milk. Small amounts of the contraceptive steroids and/or their metabolites may be excreted in the milk. Therefore the use of COCs should generally not be recommended until the nursing mother has completely weaned her child.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

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

Clinical trial data.

See Table 2.

Post marketing data.

In addition, the following undesirable effects have been reported in users of COCs and the association has been neither confirmed nor refuted:
Common: breast tenderness.
Uncommon: breast hypertrophy, fluid retention.
Rare: vaginal discharge, breast discharge, contact lens intolerance.
In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.
Erythema multiforme has been reported in post marketing surveillance. The frequency cannot be estimated from the available data and is therefore unknown.

Reporting suspected adverse effects.

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

4.9 Overdose

There has not yet been any clinical experience of overdose with drospirenone 3 mg/ethinylestradiol 20 microgram tablets. On the basis of general experience with COCs, symptoms that may occur in case of overdose of active tablets are: nausea, vomiting and withdrawal bleeding. The last may even occur in girls before their menarche, if they have accidentally taken the medicinal product. There are no antidotes and further treatment should be symptomatic.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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

Clinical trials.

In a study comparing Yana with the innovator, the two products were shown to be equivalent. Yana was found to be clinically equivalent to the innovator brand and more efficacious than placebo in the treatment of patients with the indication studied, and its safety profile was comparable to the innovator.

Contraception.

Study A12007 and Study A30713 were both large multi-centre open trials evaluating contraceptive efficacy of drospirenone 3 mg/ethinylestradiol 20 microgram in 1,027 and 1,101 women respectively over 13 cycles. The age range was 17 to 36 years. The BMI in these studies ranged from 17 to 37.6 kg/m2 with mean values of 22.4 (A12007) and 21.7 (A30713) respectively. The primary efficacy variable was the number of unintended pregnancies (Pearl Index). The Pearl Index (PI) is defined as the number of pregnancies divided by the exposure time in woman years (WY) multiplied by 100. Pregnancies attributed to non-compliant use of the contraceptive were considered patient failure; all other pregnancies were considered method failure. In Study A12007 the PI was 1.29 with an upper two-sided 95% confidence interval of 2.30. When corrected to exclude patient failure the PI was 0.72 with an upper two sided 95% confidence interval of 1.69. In Study A30713, the PI was 0.49 with an upper two-sided 95% confidence interval of 1.14. When corrected to exclude patient failure the PI was 0.22 with an upper two sided 95% confidence interval of 0.80.
Study A29551 was a multi-centre open randomised study to investigate the bleeding pattern, cycle control, contraceptive reliability and general safety of drospirenone 3 mg/ethinylestradiol 20 microgram tablets in 229 women compared to desogestrel 0.15 mg/ethinylestradiol 20 microgram in 220 women taken for 21 days followed by pill free interval of 7-days over 7 cycles. There were no pregnancies in the drospirenone 3 mg/ethinylestradiol 20 microgram group which lead to a Pearl Index of 0 with an upper two sided 95% confidence interval of 3.40 and 3.55 for the Pearl Index and corrected index respectively.
A small fourth study (A 09151) evaluated lipid and haemostatic and carbohydrate parameters in 29 women taking drospirenone 3 mg/ethinylestradiol 20 microgram tablets compared to desogestrel 0.15 mg/ ethinylestradiol 20 microgram in 30 women taken for 21 days followed by pill free interval of 7-days over 7 cycles. No significant differences in any of the lipid, haemostatic, or carbohydrate parameters were observed between the two treatments.
The Pearl Index from the integrated efficacy analysis from these 4 studies was 0.80 with an upper two-sided 95% confidence interval of 1.30. When corrected to exclude patient failure the Pearl Index, was 0.41 with an upper two-sided 95% confidence interval of 0.85.
The Pearl Index for drospirenone 3 mg/ethinylestradiol 20 microgram tablets was calculated from data from studies in which the protocol allowed up to 24 hours delay in pill taking without a requirement for additional contraception, and in which the regimen was 24 active pills and 4 inactive pills, taken sequentially over 28 days per cycle.
The parameters of bleeding pattern and cycle control demonstrated a well-controlled and regular bleeding sequence for drospirenone 3 mg/ethinylestradiol 20 microgram as compared to the comparator used. No clinically relevant changes in blood pressure or weight were observed. Irrespective of treatment duration, the mean absolute change in body weight at the final examination was -0.1 kg and the mean maximum increase in body weight versus baseline was 1.2 kg (n = 1,319). The mean maximum decrease was 1.6 kg. The majority of women treated with drospirenone 3 mg/ethinylestradiol 20 microgram were satisfied or very satisfied with the treatment and reported no change or improvement in their physical or emotional well-being. The overall subjective assessment of drospirenone 3 mg/ethinylestradiol 20 microgram treated women was equivalent to the comparator group.

Acne.

Drospirenone 3 mg/ethinylestradiol 20 microgram as an acne therapy was evaluated in two pivotal multi-centre, double blind, randomised placebo controlled studies of 6 month duration. A total of 451 drospirenone 3 mg/ethinylestradiol 20 microgram and 442 placebo subjects were included in the final integrated analysis. Patients had moderate acne defined in the protocol as a minimum of 40 lesions (i.e. at least 20 inflammatory lesions and at least 20 non-inflammatory lesions) and were between ages of 14 to 45. The primary efficacy endpoints were the percent change in total lesions, inflammatory lesions, non-inflammatory lesions, and the percentage of subjects with a "clear" or "almost clear" rating on the Investigator's Static Global Assessment (ISGA) on day 15 of cycle 6. The results for the primary efficacy variables are provided in Table 3.
In addition, there was a statistical difference (p = < 0.0001) in the percentage of patients considered improved at the final assessment by the investigator for drospirenone 3 mg/ethinylestradiol 20 microgram (87.6%) as compared to placebo (66.0%) [odds ratio; 3.83 95% CI 2.58, 5.80].

Premenstrual dysphoric disorder (PMDD).

The essential features of PMDD according to the Diagnostic and Statistical Manual-4th edition (DSM-IV) include markedly depressed mood, anxiety or tension, affective lability, and persistent anger or irritability. Other features include decreased interest in usual activities, difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control. Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle pain, bloating and weight gain. In this disorder, these symptoms occur regularly during the luteal phase and remit within a few days following onset of menses. The disturbance markedly interferes with work or school, or with usual social activities and relationships with others. Diagnosis is made by healthcare providers according to DSM-IV criteria, with symptomatology assessed prospectively over at least two menstrual cycles. In making the diagnosis, care should be taken to rule out other cyclical mood disorders.
Two multi-centre, double-blind, randomised, placebo-controlled studies were conducted to evaluate the effectiveness of drospirenone 3 mg/ethinylestradiol 20 microgram in treating the symptoms of PMDD. Women aged 18 - 42, > 1 year after menarche with no known contraindications for oral contraceptives and who met DSM-IV criteria for PMDD, confirmed by prospective daily ratings of their symptoms, were enrolled. Subjects with past or present psychiatric disorders other than PMDD were excluded. Both studies measured the treatment effect of drospirenone 3 mg/ethinylestradiol 20 microgram using the Daily Record of Severity of Problems scale, a patient-rated instrument that assesses the symptoms that constitute the DSM-IV diagnostic criteria. The primary study was a parallel group design that included 384 evaluable reproductive-aged women with PMDD who were randomly assigned to receive drospirenone 3 mg/ethinylestradiol 20 microgram or placebo treatment for 3 menstrual cycles. The supportive study, a crossover design, was terminated prematurely prior to achieving recruitment goals due to enrolment difficulties. In the supportive study, a total of 64 women of reproductive age with PMDD were treated initially with drospirenone 3 mg/ethinylestradiol 20 microgram or placebo for up to 3 cycles followed by a washout cycle and then crossed over to the alternate medication for 3 cycles.
Efficacy was assessed in both studies by the change from baseline during treatment using a scoring system based on the first 21 items of the Daily Record of Severity of Problems (DRSP). Each of the 21 items was rated on a scale from 1 (not at all) to 6 (extreme); thus a maximum score of 126 was possible. In both trials, women who received drospirenone 3 mg/ethinylestradiol 20 microgram had statistically significantly greater improvement in their Daily Record of Severity of Problems scores. In the primary study, the average decrease (improvement) from baseline was 37.5 points in women taking drospirenone 3 mg/ethinylestradiol 20 microgram tablets, compared to 30.0 points in women taking placebo in the full analysis set. The difference between treatment groups (-7.5) was statistically significant (p = 0.0001). In the supportive study, the average decrease from baseline for drospirenone 3 mg/ethinylestradiol 20 microgram (n = 42) was -22.9, compared to -10.5 in women (n = 41) taking placebo (p = 0.0001; difference -12.47; 95% CI: -18.28, -6.66).
A statistical comparison between the treatments for the efficacy variables (full analysis set) in the PMDD pivotal study are presented in Table 4.

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 AUC72 and Cmax for drospirenone were found to be 95.01 - 98.85% and 83.08 - 94.54%, and, AUCt and Cmax for ethinylestradiol were 93.39 - 106.32% and 89.28 - 100.39% respectively.

Drospirenone.

Absorption. Orally administered drospirenone is rapidly and almost completely absorbed. Maximum concentrations of the drug in serum of about 35 nanogram/mL are reached at approximately 1 - 2 h after single ingestion. Bioavailability is between 76 and 85%. The intake of food had no influence on the extent of absorption but the maximum concentration was reduced as compared to drug intake on an empty stomach.
Distribution. After oral administration, serum drospirenone levels decrease in two phases which are characterised by half-lives of 1.6 ± 0.7 h and 27.0 ± 7.5 h, respectively. Drospirenone is bound to serum albumin and does not bind to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG). Only 3 - 5% of the total serum drug concentrations are present as free steroid. The ethinylestradiol-induced increase in SHBG does not influence the serum protein binding of drospirenone. The mean apparent volume of distribution of drospirenone is 3.7 ± 1.2 L/kg.
Metabolism. Drospirenone is extensively metabolised after oral administration. The major metabolites in the plasma are the acid form of drospirenone, generated by opening of the lactone ring, and the 4,5-dihydro-drospirenone-3-sulfate, both of which are formed without involvement of the P450 system. Drospirenone is metabolised by cytochrome P450 3A4 and has demonstrated a capacity to inhibit this enzyme and cytochrome P450 1A1, cytochrome P450 2C9 and cytochrome P450 2C19 in vitro.
Excretion. The metabolic clearance rate of drospirenone in serum is 1.5 ± 0.2 mL/min/kg.
Drospirenone is excreted only in trace amounts in unchanged form. The metabolites of drospirenone are excreted with the faeces and urine at an excretion ratio of approximately 1.2 to 1.4. The half-life of metabolite excretion with the urine and faeces is approximately 40 h.
Steady-state conditions. During a treatment cycle, maximum steady-state concentrations of drospirenone in serum of about 60 nanogram/mL are reached between day 7 and day 14 of treatment. Serum drospirenone levels accumulated by a factor of about 2 to 3 as a consequence of the ratio of terminal half-life and dosing interval. Further accumulation of drospirenone levels beyond treatment cycles was observed between cycles 1 and 6 but thereafter, no further accumulation was observed.
Special populations.

Effect of renal impairment.

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

Effect of hepatic impairment.

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

Ethnic groups.

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

Ethinylestradiol.

Absorption.

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

Distribution.

Serum ethinylestradiol levels decrease in two phases, the terminal disposition phase is characterised by a half-life of approximately 24 hours. Ethinylestradiol is highly but non-specifically bound to serum albumin (approximately 98.5%), and induces an increase in the serum concentrations of SHBG. An apparent volume of distribution of approximately 5 L/kg was determined.

Metabolism.

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

Excretion.

Ethinylestradiol is not excreted in unchanged form to any significant extent. The metabolites of ethinylestradiol are excreted at a urinary to biliary ratio of 4:6. The half-life of metabolite excretion is approximately 1 day.

Steady-state conditions.

Steady-state conditions are reached during the second half of a treatment cycle and serum levels of ethinylestradiol accumulate by a factor of approximately 1.4 to 2.1.

5.3 Preclinical Safety Data

Genotoxicity.

There is limited evidence available in the literature suggesting that estrogens may be weakly genotoxic at high doses. Ethinylestradiol was negative in studies for DNA-adduct formation in cultured human liver slices and in assays for gene mutations (bacterial or mammalian cells in vitro) and gave equivocal results in assays for chromosomal damage in vitro (clastogenic effects were not consistently seen and occurred at high concentrations). In vivo studies did not confirm these results.
Drospirenone was found to induce chromosome aberrations in human peripheral lymphocytes. However, drospirenone was not mutagenic in bacterial and mammalian cell gene mutation assays in vitro, and was not clastogenic in mouse micronucleus assays in vivo. Interactions between drospirenone and the DNA of liver cells which indicate a genotoxic potential were found in in vitro and in vivo studies in rats. No such finding was observed in human liver cells in vitro.

Carcinogenicity.

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

6 Pharmaceutical Particulars

6.1 List of Excipients

Each pink active tablet contains: lactose monohydrate, pregelatinised maize starch, povidone, croscarmellose sodium, polysorbate 80, magnesium stearate, Opadry II complete film coating system 85F34610 Pink.
Each white placebo tablet contains: lactose, povidone, magnesium stearate, Opadry II complete film coating system 85F18422 White.

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

Yana.

Pack sizes (PVC/PVDC/Al blister packaging).

1 x 28's (24 active tablets + 4 placebo tablets).
3 x 28's (24 active tablets + 4 placebo tablets).
6 x 28's (24 active tablets + 4 placebo tablets).
AUST R number 200633.
Yana is a registered trade mark of Apotex Pty Ltd.
(Not all pack sizes may be marketed).

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Drospirenone is a white to off-white crystalline powder. It is freely soluble in methylene chloride, soluble in acetone, methanol, sparingly soluble in ethyl acetate and ethanol 96% (v/v) and practically insoluble in hexane and water.
Ethinylestradiol is a white to creamy white, odourless, crystalline powder. It is insoluble in water and soluble in alcohol, chloroform, ether, vegetable oils, and aqueous solutions of alkali hydroxides.

Chemical structure.

Drospirenone.


Chemical name: 6β,7β,15β,16β-Dimethylene-3-oxo-17α-pregn-4-ene-21,-17-carbolactone.
Molecular formula: C24H30O3.
Molecular weight: 366.50.

Ethinylestradiol (EE).


Chemical name: 19-Nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17β-diol.
Molecular formula: C20H24O2.
Molecular weight: 296.41.

CAS number.

Drospirenone.

67392-87-4.

Ethinylestradiol (EE).

57-63-6.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes