Consumer medicine information

Jene-35 ED

Cyproterone acetate + Ethinylestradiol

BRAND INFORMATION

Brand name

Jene-35 ED

Active ingredient

Cyproterone acetate + Ethinylestradiol

Schedule

What is in this leaflet

This leaflet answers some common questions about Jene-35 ED™. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Jene-35 ED™ against the benefits this medicine is expected to have for you.

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

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

What Jene-35 ED™ is used for

Jene-35 ED is used for the treatment of signs of androgenisation in women, such as severe acne where other treatments have not been successful, or for excessive growth of facial or body hair (known as hirsutism) of a mild to moderate degree, where no underlying cause has been found.

Jene-35 ED can also be used as a contraceptive to prevent pregnancy in women who are taking it for the treatment of signs of androgenisation as described above. Jene-35 ED contains a progestogen and an oestrogen hormone, and therefore works similarly to the combined oral contraceptive birth control pill. It should not be used in combination with another hormonal contraceptive.

While taking Jene-35 ED you may also experience the following benefits:

more regular and lighter periods – potentially resulting in a decrease in anaemia (iron deficiency)
a decrease in period pain
reduction of greasiness in skin and hair.

Some conditions such as pelvic inflammatory disease, ovarian cysts, ectopic pregnancy, fibrocystic breast changes and cancer of the uterus (womb) and ovaries may be less common in women taking Jene-35 ED.

Your doctor, however may have prescribed Jene-35 ED for another purpose.

Ask your doctor if you have any questions about why it has been prescribed for you.

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

Before you take Jene-35 ED™

When you must not take it

Do not take Jene-35 ED if you are allergic to it or any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

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

Do not take Jene-35 ED if you have, or have had, a blood clot in:

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

Studies have suggested an association between the use of combined hormonal contraceptives (CHCs) containing ethinylestradiol and an increased risk of cardiovascular diseases such as heart attack, stroke, blood clots or blockage of blood vessels by clots. These events have shown to occur rarely in women with average risk.

If you think you may have symptoms of any of the above cardiovascular diseases seek urgent medical attention.

Do not take Jene-35 ED if you are concerned about an increased risk of blood clots. Blood clots are rare. Very occasionally blood clots may cause serious permanent disability and may even be fatal.

All combined oral contraceptive pills, including Jene-35 ED, increase the risk of having a blood clot. However, the risk of having a blood clot when taking the contraceptive pill is less than the risk of having a blood clot during pregnancy.

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

Do not take Jene-35 ED if you have or have had:

angina (chest pain)
a mini-stroke (also known as transient ischaemic attack (TIA)
migraine, accompanied by visual symptoms, speech disability, or weakness or numbness in any part of your body
diabetes mellitus with blood vessel damage
pancreatitis (an inflammation of the pancreas) associated with high levels of fatty substances in your blood
severe liver disease and your liver function has not returned to normal
cancer that may grow under the influence of sex hormones (e.g. of the breast or the genital organs)
a benign or malignant liver tumour
unexplained vaginal bleeding.

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

Do not take Jene-35 ED™ if you are using another hormonal contraceptive.

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

Do not breast-feed if you are taking this medicine.

Do not give this medicine to a child.

Do not take this medicine after the expiry date printed on the pack and blister. If you take it after the expiry date has passed, it may not work as well. If it has expired return it to your pharmacist for disposal.

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

If you are not sure whether you should start taking Jene-35 ED, talk to your doctor.

Before you start to take it

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

Tell your doctor if:

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

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

diabetes
high blood pressure
heart valve disorders or certain heart rhythm disorders
inflammation of your veins (superficial phlebitis)
varicose veins
migraine
epilepsy.

Ask your doctor to check if you:

are overweight
have high cholesterol or triglycerides
have liver disease
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 the above conditions appear for the first time, recur, or worsen while taking Jene-35 ED, you should contact your doctor.

If you have either recently developed hirsutism or you have had a considerable increase in symptoms, tell your doctor, as the cause of the changes must be determined.

Jene-35 ED contains lactose. If you have an intolerance to some sugars, contact your doctor before you start taking Jene-35 ED.

If you have not told your doctor about any of the above, tell them before you use Jene-35 ED.

Taking other medicines

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

Some medicines and Jene-35 ED may interfere with each other. These include:

medicines used to treat tuberculosis such as rifampicin or rifabutin
medicines used to treat epilepsy such as phenytoin, primidone, barbiturates (e.g. phenobarbitone), carbamazepine, oxcarbazepine, topiramate, felbamate or lamotrigine
medicines used to treat HIV, such as ritonavir or nevirapine
some medicines used to treat Hepatitis C Virus (HCV) such as boceprevir, telapravir
antibiotics such as penicillin, ampicillin, erythromycin or tetracycline
medicines used to treat fungal infections, such as ketoconazole or griseofulvin
cyclosporine, an immunosuppressant medicine
herbal medicines containing St John’s Wort.

These medicines may be affected by Jene-35 ED, or may affect how well it works. Your doctor may need to alter the dose of your medicine or prescribe a different medicine.

You may need to use additional barrier methods of contraception (such as condoms or a diaphragm) while you are taking any of these medicines with Jene-35 ED and for some time after stopping them. Your doctor will be able to advise you about how long you will need to use additional contraceptive methods.

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

How to take it

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

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

How much to take

Take one tablet daily at about the same time every day. You must take Jene-35 ED every day regardless of how often you have sex. This will also help you remember when to take it.

How and when to take it

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

Each blister pack is marked with the day of the week. Take your first tablet from the red 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.

Always start a new blister pack on the same day of the week as your previous pack.

Taking it for the first time

If you are starting Jene-35 ED 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 must also use additional barrier contraceptive precautions (e.g. condoms or a cap or diaphragm plus spermicide) for the first 14 days of tablet-taking when having intercourse.

Your doctor will advise you when to start if you:

are taking Jene-35 ED™ after having a baby
have had a miscarriage or an abortion.

Changing from another contraceptive

Changing from a combined oral contraceptive:
Start taking Jene-35 ED on the day after taking the last active tablet in your previous contraceptive pill pack. Bleeding may not occur until the end of the first pack of Jene-35 ED.

If you are not sure which were the active/inactive tablets in your previous contraceptive pill pack, ask your doctor or pharmacist.

Your previous contraceptive pill pack may have different colour tablets to those of Jene-35 ED.

Changing from a vaginal ring:
Start taking Jene-35 ED on the day of removal of the last vaginal ring.

Changing from a progestogen only pill (‘minipill’):
Stop taking the minipill on any day and start taking Jene-35 ED™ at the same time the next day.

You must also use additional barrier contraceptive precautions (e.g. condoms or a diaphragm) for the first 14 days of tablet-taking when having intercourse.

Changing from a progestogen only injection, implant or intrauterine system (IUS):
Start taking Jene-35 ED when your next injection is due, or on the day that your implant or IUS is removed.

You must also use additional barrier contraceptive precautions (e.g. condoms or a diaphragm) for the first 14 days of tablet-taking when having intercourse.

How long to take it

You may have to take Jene-35 ED for at least 6 months before you see an improvement in your condition. The length of treatment depends on the severity of the condition and how well it responds to treatment.

You may be advised by your doctor to stop Jene-35 ED 3 to 4 months after your symptoms have completely resolved. You should have regular check-ups with your doctor to determine how long to keep taking Jene-35 ED.

Stopping it

You can stop taking Jene-35 ED at any time.

It is possible that the original condition may recur one Jene-35 ED is stopped.

Do not start taking Jene-35 ED again without seeing your doctor first.

If you do not wish to fall pregnant, you should use additional barrier contraceptive precautions (e.g. condoms or a diaphragm) when you stop taking Jene-35 ED.

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 Jene-35 ED and not stop until your doctor advises this. Seek advice from your doctor or pharmacist about suitable supplements. It is both safe and recommended that you take folic acid during pregnancy.

If you forget to take it

If you miss a tablet and take the missing tablet within 12 hours of missing it, contraceptive efficacy is not reduced.

If you are more than 12 hours late follow these detailed instructions:

For Jene-35 ED to be most effective, the yellow active tablets need to be taken uninterrupted for 7 days.

If you have been taking the yellow active tablets for 7 uninterrupted days and miss a yellow 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 at the same time. You will not need to use additional barrier contraceptive precautions.

The chance of pregnancy after missing a yellow active tablet depends on when you missed the tablet.

There is a higher risk of becoming pregnant if you miss a yellow tablet at the beginning or end of a pack.

If after taking your missed tablet you have less than 7 days of yellow 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 with the yellow active tablets corresponding to the correct day of the week. This is the best way to maintain contraceptive protection. However, you may not have a period until the end of the yellow active tablets of the second pack. You may have spotting or breakthrough bleeding on tablet taking days.

If you have been taking the yellow active tablets for less than 7 days and miss a yellow 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 at the same time. 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 in the preceding 7 days, there is a possibility of pregnancy and you may need emergency contraception. You should discuss this with your doctor or pharmacist.

If you forget to take more than one yellow 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. You should discuss this with your doctor or pharmacist.

If you forget to take a white inactive tablet, take it as soon as you remember and take the next tablet at the usual time. The contraceptive efficacy against pregnancy is not reduced because the white tablets do not contain any active ingredients.

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

If you take too much (Overdose)

Immediately telephone your doctor or the Poisons Information Centre (Australia: 13 11 26) for advice, or go to the Accident and Emergency Department at your nearest hospital, if you think that you or anyone else may have taken too much Jene-35 ED. Do this even if there are no signs of discomfort or poisoning. You may need medical attention.

While you are taking it

Things you must do

Tell any other 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 results of some tests.

Have regular check-ups with your doctor. When you are taking the contraceptive pill, your doctor will tell you to return for regular check-ups, including getting a Pap (cervical) smear test. Your doctor will advise how often you need a Pap (cervical) smear test. A Pap (cervical) smear test can detect abnormal cells lining the cervix. Sometimes abnormal cells can progress to cancer.

If you are about to start on any new medicine, remind your doctor and pharmacist that you are taking Jene-35 ED.

Stop taking Jene-35 ED and immediately see your doctor if you notice possible signs of thrombosis (blood clot). Possible symptoms of a blood clot include:

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

Common symptoms associated with the use of oral contraceptive pill are:

acne
breast tenderness
nausea.

Other symptoms which may/may not be due to the oral contraceptive pill but may be concerning you and need review by your doctor are:

weight gain
excessive hairiness (hirsutism)
unusual hair loss or thinning (alopecia).

If you are going to have surgery, tell the surgeon or anaesthetist beforehand that you are taking Jene-35 ED. The risk of having deep venous thrombosis is temporarily increased as a result of an operation or immobilisation (for example, when you have your leg(s) in plaster of splints). In women who take the contraceptive pill, the risk may be higher.

Your doctor may tell you to stop taking Jene-35 ED several weeks before surgery, or at the time of immobilisation, and when you can start taking it again. If you notice possible signs of a thrombosis, stop taking Jene-35 ED and consult your doctor immediately.

Consult your doctor if you develop high blood pressure while taking Jene-35 ED – you may be told to stop taking it.

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

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

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

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

you have taken the yellow active tablets at the right time
you have not been taking medicine(s) that may interfere with Jene-35 ED
you have not vomited or had severe diarrhea during this cycle.

If this is so, continue to take Jene-35 ED 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 contraceptive pill correctly. Stop taking Jene-35 ED 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.

Jene-35 ED will not protect you from HIV-AIDS or any other sexually transmitted infections (STIs), such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, human papilloma virus and syphilis.

To protect yourself from STIs, you will need to use additional barrier contraceptives (e.g. condoms).

Things you must not do

Do not take Jene-35 ED to treat any other conditions, unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

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 Jene-35 ED, or do not take a tablet every day.

Side Effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Jene-35 ED.

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

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

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

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

The following list includes the more common side effects of Jene-35 ED. These are usually mild and lessen with time.

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

Nausea
abdominal pain
changes in weight
headache, including migraines
mood changes, including depression
breast tenderness or pain.

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

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

pain in the chest, arm, or below the breastbone
discomfort radiating to the 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 abdominal pains
a fainting attack or you collapse
unusual headaches or migraines that are worse than usual
sudden problems with speech, understanding or eyesight.

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

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

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

Thrombosis and the contraceptive pill

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

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

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

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

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

If you notice possible signs of a thrombosis, stop taking Jene-35 ED and consult your doctor immediately.

If you are concerned about an increased risk of blood clots while on Jene-35 ED, speak to your doctor.

Cancer and the contraceptive 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 contraceptive 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 contraceptive pill.

It is not known whether the difference is caused by the contraceptive 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 lump.

In rare cases benign liver tumours and, even more rarely, malignant liver tumours have been reported in users of the contraceptive 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 contraceptive pill for a long time. This finding may not be caused by the contraceptive pill, but may be related to sexual behaviour and other factors.

After taking it

Storage

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

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

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

Keep Jene-35 ED where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

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

Product description

What Jene-35 ED™ looks like

Jene-35 ED™ is a calendar pack containing 21 small yellow active tablets and 7 larger white non-active (placebo) tablets per blister strip.

Available as packs of 28 and 84 tablets (not all pack sizes may be marketed).

Ingredients

Each yellow active tablet contains:

35 micrograms of ethinylestradiol
2 mg of cyproterone acetate

Inactive ingredients:

lactose monohydrate
microcrystalline cellulose
povidone
croscarmellose sodium
magnesium stearate
Opadry white
Opadry buff
Opaglos white
Quinoline yellow
sucrose.

Each white inactive tablet contains:

lactose monohydrate
microcrystalline cellulose
magnesium stearate

Tablets do not contain gluten.

Sponsor

Strides Pharma Science Pty Ltd
Sydney, Australia
www.stridespharma.com.au

Australian Registration Number:

AUST R 144128

This leaflet was prepared in January 2021.

Published by MIMS June 2021

BRAND INFORMATION

Brand name

Jene-35 ED

Active ingredient

Cyproterone acetate + Ethinylestradiol

Schedule

1 Name of Medicine

Cyproterone acetate and ethinylestradiol.

2 Qualitative and Quantitative Composition

Each yellow active tablet contains cyproterone acetate 2 mg and ethinylestradiol 35 microgram.
Cyproterone acetate is a white or almost white, crystalline powder, practically insoluble in water, very soluble in methylene chloride, freely soluble in acetone, soluble in methanol, sparingly soluble in ethanol. It melts at about 210°C.
Ethinylestradiol is a white or slightly yellowish-white, crystalline powder, practically insoluble in water, freely soluble in alcohol. It dissolves in dilute alkaline solutions. It shows polymorphism.
Excipients with known effect: lactose monohydrate. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablet, film coated (active): A yellowish buff, round, biconvex tablet, plain on both faces.
Tablet (placebo): White, round, biconvex tablet, plain on both surfaces.

4 Clinical Particulars

4.1 Therapeutic Indications

For the treatment of signs of androgenisation in women such as severe acne (involving inflammation or nodularity or risk of scarring) where prolonged oral antibiotics or local treatment alone has not been successful, or idiopathic hirsutism of mild to moderate degree.
Jene-35 ED will also provide effective oral contraception in this patient group. It should not be used in combination with other hormonal contraceptives (see Section 4.3 Contraindications).
If the hirsutism has only recently appeared or has lately intensified to a considerable extent the cause (androgen producing tumour or an adrenal enzyme defect) must be clarified by differential diagnosis.

4.2 Dose and Method of Administration

Combined oral contraceptives, when taken correctly have a failure rate of approximately 1% per year.
Jene-35 ED is to be taken regularly in order to achieve therapeutic efficacy and the required contraceptive protection. Previously used hormonal contraception should be discontinued. The dose regimen of Jene-35 ED is similar to the usual regimen of most of the combined oral contraceptives. Thus, the same administration rules must be considered. The irregular intake of Jene-35 ED can lead to intermenstrual bleeding and could deteriorate the therapeutic and contraceptive reliability. Therapy should not be initiated unless pregnancy has been excluded.

Duration of treatment.

Treatment will probably need to be continued for about 6 months and probably much longer to gain an acceptable therapeutic effect, especially if Jene-35 ED is being used for the treatment of excessive hair. The length of use depends on the severity of the symptoms of androgenisation and their response to treatment. Acne and seborrhoea usually respond sooner than hirsutism. The need to continue treatment should be evaluated periodically by the treating doctor. It is possible that the original condition will recur once treatment with Jene-35 ED is stopped.
Jene-35 ED should be withdrawn 3 to 4 cycles after the treated condition has completely resolved. Repeat course of Jene-35 ED may be given if the androgen-dependent condition(s) recur. In case of a restart with Jene-35 ED (following a 4 week or greater tablet-free interval), the increased risk of VTE should be considered (see Section 4.4 Special Warnings and Precautions for Use).

How to take Jene-35 ED.

One tablet is to be taken daily. The tablets must be taken in the order directed on the pack at about the same time every day, with some liquid as needed. Tablet taking should be continuous for 28 consecutive days, starting with a tablet corresponding to that day of the week from the red section of the Jene-35 ED pack.
If a woman starts on a Monday, Tuesday, Wednesday, Thursday or Friday, her first tablet is a white placebo tablet, while if she starts on a Saturday or Sunday her first tablet will be yellow active tablet. Thereafter, one tablet is taken daily, following the arrows marked on the pack, until all tablets have been taken. Each subsequent pack is started the day after the last tablet of the previous pack.
Withdrawal bleeding should usually occur on day 2 to 3 after the last yellow active tablet is taken and may not have finished before the next pack is started.

How to start Jene-35 ED.

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). Additional non-hormonal contraceptive methods must be used for the next 14 days.

Changing from a combined hormonal contraceptive (combined oral contraceptive/ COC), vaginal ring.

The woman should start with Jene-35 ED on the day after the last active tablet (the last tablet containing the active substances) of her previous COC. In case of a vaginal ring has been used the woman should start taking Jene-35 ED on the day of removal.

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

The woman may switch any day from the minipill (from an implant, or the IUS on the day of its removal, from an injectable when the next injection would be due) but in all of these cases should be advised to additionally use an additional non-hormonal method of contraception for the first 14 days of tablet-taking.

Following first trimester abortion.

The woman may start immediately. Additional non-hormonal contraceptive methods are necessary for the next 14 days.

After childbirth or a second trimester abortion.

Women should be advised to start 21 to 28 days after delivery or second-trimester abortion. Additional non-hormonal contraceptive methods are necessary for the next 14 days. 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. Jene-35 ED should not be used in breastfeeding women (see Section 4.6 Fertility, Pregnancy and Lactation).

Additional contraceptive precautions.

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

How to manage reduced reliability.

When Jene-35 ED is taken according to the directions for use, the occurrence of pregnancy is highly unlikely. However, the reliability of contraceptive protection may be reduced under the following circumstances.

Management of missed tablets.

Missed pills from the red section 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 following advice only refers to missed yellow active tablets (rows 1-3 of the blister):
If the user is less than 12 hours late in taking any yellow 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 user is more than 12 hours late in taking any yellow active tablet, contraceptive protection may be reduced. The management of missed tablets can be guided by the following two basic rules:
1. 'Active tablet' taking must never be discontinued for longer than 7 days.
2. Seven days of uninterrupted 'active tablet' taking are required to attain adequate suppression of the hypothalamic-pituitary-ovarian-axis.
Accordingly, the following advice can be given in daily practice.

Week 1.

The user should take the last missed yellow active tablet as soon as she remembers, even if this means taking two yellow active tablets in one day at the same time, and then continue to take tablets at the normal time. Additional contraceptive precautions should be taken for the next 7 days.
If intercourse took place in the preceding 7 days, the possibility of a pregnancy should be considered. The more tablets are missed and the closer they are to the regular placebo tablet interval, the higher the risk of a pregnancy.

Week 2.

The user should take the last missed yellow active tablet as soon as she remembers, even if this means taking two yellow active tablets at the same time. She then continues to take tablets at her usual time. Provided that the user has taken her tablets correctly in the 7 days preceding the first missed yellow 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 yellow active tablet, the user should be advised to use extra precautions for 7 days.

Week 3.

The risk of reduced reliability is imminent because of the forthcoming white placebo tablet interval. 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 yellow active tablet the user has taken all tablets correctly. If this is not the case, the user 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 user should take the last yellow active missed tablet as soon as she remembers, even if this means taking two yellow active tablets at the same time. She then continues to take tablets at her usual time until the yellow active tablets are taken. The 7 white placebo tablets must be discarded. The next pack must be started right away. The user 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 user may also be advised to discontinue tablet taking from the current pack. She should then have a tablet-free interval of up to 7 days, including the days she missed tablets, and subsequently continue with the next pack.
If the user missed tablets and subsequently has no withdrawal bleed in the placebo tablet interval, the possibility of a pregnancy should be considered.

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 taking an active tablet, the advice concerning management of missed tablets 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

Preparations containing oestrogen/progestogen combinations 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 their 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; or
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; or severe dyslipoproteinaemia.
Pancreatitis or a history thereof if associated with severe hypertriglyceridemia.
Presence or history of severe hepatic disease as long as liver function values have not returned to normal.
Presence or history of liver tumours (benign or malignant).
Known or suspected sex-steroid influenced malignancies (e.g. of the genital organs or the breasts).
Concomitant use with another hormonal contraceptive.
Undiagnosed vaginal bleeding.
Known or suspected pregnancy.
Lactation.
Hypersensitivity to any of the ingredients contained in Jene-35 ED.
A history of otosclerosis with deterioration during pregnancy.
A history of herpes gestationis.
Sickle-cell anaemia.
Abnormal lipid metabolism.
Jene-35 ED is not for use in men.
Jene-35 ED is composed of the progestogen cyproterone acetate and the oestrogen ethinylestradiol and is administered for 21 days of a monthly cycle. It has a similar composition to that of COC. The clinical and epidemiological experience with oestrogen/progestogen combinations like Jene-35 ED is predominantly based on COCs. Therefore, the following precautions related to the use of COCs apply also for Jene-35 ED.

4.4 Special Warnings and Precautions for Use

If any of the conditions/ risk factors mentioned below are present, the benefits of Jene-35 ED 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 Jene-35 ED should be discontinued.

Identified precautions.

Circulatory disorders.

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

Risk of venous thromboembolism (VTE).

The use of any combined hormonal contraceptive (CHC) increases the risk of VTE compared with no use. The woman should be advised that her VTE risk is highest in the first ever year of use and that there is some evidence that the risk is increased when a CHC is re-started after a break in use of 4 weeks or more.
It is important that women understand that VTE associated with CHC 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 CHC use.
Combined hormonal contraceptive (CHC) in the table below refers to oral contraceptives with a low oestrogen dose (< 50 microgram ethinylestradiol). An additional increase in VTE risk for CHCs containing ≥ 50 microgram ethinylestradiol cannot be excluded.
The decision to use any product other than one with the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with CHCs, and how her current risk factors influence this risk.
Products that contain the progestagens levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. Products containing cyproterone such as Jene-35 ED may have up to twice this level of risk.

The increased risk of VTE during the postpartum period must be considered. 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 CHC users in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral or retinal veins and arteries.
The risk for venous thromboembolic complications in CHC users may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see list below).
Jene-35 ED is contraindicated if a woman has multiple risk factors that put her at high risk of venous thrombosis. If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors - in this case her total risk of VTE should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed.
When considering risk/benefit, the doctor should take into account that the adequate treatment of a condition may reduce the associated risk of thrombosis.

Risk factors for VTE.

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

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

Women should be informed of the symptoms of VTE and be advised to seek urgent medical attention if VTE symptoms develop and to inform the healthcare professional that she is taking a CHC.
Symptoms of deep vein thrombosis (DVT) can include:
unilateral swelling of the leg and/or foot or along a vein in the leg;
pain or tenderness in the leg which may be felt only when standing or walking; or
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; or
rapid or irregular heartbeat.
Some of these symptoms (e.g. "shortness of breath", "coughing") are non-specific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections).
Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of an extremity.
If the occlusion occurs in the eye symptoms can range from painless blurring of vision which can progress to loss of vision. Sometimes loss of vision can occur almost immediately.

Risk of arterial thromboembolism (ATE).

Epidemiological studies have associated the use of CHCs with an increased risk for arterial thromboembolism (e.g. myocardial infarction, angina pectoris, stroke or TIA). Arterial thromboembolic events may be fatal.
The risk of arterial thromboembolic complications in CHC users increases in women with risk factors. Jene-35 ED is contraindicated if a woman has one serious or multiple risk factors for ATE that puts her at high risk of arterial thrombosis. If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors - in this case her total risk should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed.

Risk factors for ATE.

Increasing age, particularly above 35 years;
smoking;
hypertension;
obesity;
positive family history (arterial thromboembolism ever in a sibling or parent especially at relatively early age e.g. below 50);
biochemical factors that may be indicative of hereditary or acquired predisposition for ATE include: hyperhomocysteinaemia and antiphospholipid antibodies (e.g. anticardiolipin antibodies, and lupus anticoagulant);
migraine;
other medical conditions associated with adverse vascular events: diabetes mellitus; polycystic ovary syndrome; hyperhomocysteinaemia; valvular heart disease; atrial fibrillation; dyslipoproteinaemia; or systemic lupus erythematosus.
Women should be advised not to smoke if they wish to use a CHC. Women over 35 years who continue to smoke should be strongly advised to use a different method of contraception. If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use.
An increase in frequency or severity of migraine during CHC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation.
The user group of Jene-35 ED is likely to include patients that may have an inherently increased cardiovascular risk.

Symptoms of ATE.

Women should be informed of the symptoms of ATE and be advised to seek urgent medical attention if ATE symptoms develop and to inform the healthcare professional that she is taking a CHC.
Symptoms of a stroke can include:
sudden numbness or weakness of the face, arm or leg, especially on one side of the body;
sudden trouble walking, dizziness, loss of balance or coordination;
sudden confusion, slurred speech or aphasia; sudden partial or complete loss of vision; diplopia;
sudden, severe or prolonged headache with no known cause; or
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; or
rapid or irregular heartbeats.

Tumours.

The most important risk factor for cervical cancer is persistent 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 have a fatal outcome.

Other conditions.

Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when taking COCs.
Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. A relationship between COC use and clinical hypertension has not been established. However, if a sustained clinically significant hypertension develops during the use of a COC then it is prudent for the 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, and otosclerosis-related hearing loss.
In women with hereditary angio-oedema exogenous oestrogens may induce or exacerbate symptoms of angio-oedema.
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.
If in women suffering from hirsutism, symptoms have recently developed or increased substantially, the causes (androgen-producing tumour, adrenal enzyme defect) must be clarified by differential diagnosis.
Each yellow active tablet contains 41.19 mg of lactose and each white placebo tablet contains 67 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.
Each yellow active film-coated tablet contains 10.358 mg of sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose, malabsorption or sucrose-isomaltase insufficiency should take this amount into consideration.

Medical examination/consultation.

A complete medical history and physical examination should be taken prior to the initiation or reinstitution of Jene-35 ED, see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, and should be repeated periodically. In general, an annual examination is recommended. Periodic medical assessment is also of importance because contraindications (e.g. a transient ischaemic attack, etc.) or risk factors (e.g. a family history of venous or arterial thrombosis) may appear for the first time during the use of a COC. The frequency and nature of these assessments should be 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 HIV infections and AIDS.

Jene-35 ED does not protect against sexually transmitted infections (STIs), including HIV infections (AIDS). The woman should be advised that additional barrier contraceptive measures are needed to prevent transmission of STIs.

Reduced efficacy.

The contraceptive efficacy of Jene-35 ED may be reduced in the event of missed yellow active tablets, vomiting, or diarrhoea during yellow active tablet taking (see Section 4.2 Dose and Method of Administration) or concomitant medication (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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 indicated to exclude malignancy or pregnancy. These may include curettage.
In some women, withdrawal bleeding may not occur during the placebo tablet interval. If the COC has been taken according to the directions, it is unlikely that the woman is pregnant. However, if the COC has not been taken according to these directions prior to the first missed withdrawal bleed or if two withdrawal bleeds are missed, pregnancy must be ruled out before COC use is continued.

Use in hepatic impairment.

Jene-35 ED is contraindicated in women with severe hepatic diseases as long as liver function values have not returned to normal (see Section 4.3 Contraindications).

Use in renal impairment.

Jene-35 ED has not been specifically studied in renally impaired patients.

Use in the elderly.

Jene-35 ED is not indicated after menopause.

Paediatric use.

Jene-35 ED is only indicated after menarche.

Effects on laboratory tests.

The use of preparations like Jene-35 ED may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of carrier proteins, e.g. corticosteroid binding globulin and lipid/ lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Interactions between oestrogen/ progestogen combinations like Jene-35 ED and other medicines may lead to breakthrough bleeding and/or oral contraceptive failure. The following interactions have been reported in the literature.

Effects of other medicines on Jene-35 ED.

Interactions can occur with medicines that induce microsomal enzymes which can result in increased clearance of sex hormones and which may lead to breakthrough bleeding and/or contraceptive failure.
Women prescribed any of these medicines should temporarily use a barrier method in addition to Jene-35 ED 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 during which the barrier method is used runs beyond the end of the yellow active tablets in the Jene-35 ED pack, the larger white placebo tablets should be omitted, and the next pack be started.

Substances increasing the clearance of Jene-35 ED (diminished efficacy of Jene-35 ED by enzyme induction).

Phenytoin, barbiturates, primidone, carbamazepine, rifampicin and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and products containing St. John's Wort (Hypericum perforatum).

Substances with variable effects on the clearance of Jene-35 ED.

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

Antibiotics (interference with enterohepatic circulation).

Some clinical reports suggest that enterohepatic circulation of oestrogens may decrease when certain antibiotic agents (e.g. penicillins, tetracyclines) are given which may reduce ethinylestradiol concentrations.
Women prescribed antibiotics (except rifampicin and griseofulvin) should use the barrier method until 7 days after completing a course of antibiotics. 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.

Influence of Jene-35 ED on other medication.

Oestrogen/ progestogen preparations like Jene-35 ED may affect the metabolism of certain other medicines. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporin) or decrease (e.g. lamotrigine).

Note.

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

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category B3¹)
Animal studies showed that the drug combination of ethinylestradiol and cyproterone acetate or cyproterone acetate alone (given at high doses) can cause signs of feminisation in male foetuses if given during the phase of differentiation of the foetal male genital organs. The relevance of these findings to man is not known.
Isolated cases of inadvertent use of Jene-35 ED during pregnancy have so far given no indications of a corresponding risk in humans. Despite this, the possibility must be considered that the use of Jene-35 ED during the hormone sensitive phase of differentiation of the genital organs in male foetuses (from about the 45^th day of pregnancy) might cause signs of feminisation. For this reason, Jene-35 ED is contraindicated during pregnancy.
If pregnancy occurs during treatment with Jene-35 ED, further intake must be stopped.
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 foetus having been observed. Studies in animals have shown evidence of an increased occurrence of foetal damage, the significance of which is considered uncertain in humans.
The use of Jene-35 ED is contraindicated during lactation as small amounts of cyproterone acetate are excreted in breast milk. Oestrogen containing oral contraceptives may decrease the quantity and quality of breast milk.

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)

Various adverse reactions have been associated with oral contraceptive use. The most serious reactions associated with the use of oral contraceptives are discussed (see Section 4.4 Special Warnings and Precautions for Use).
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 its use should be discontinued. See Table 2.

Other adverse reactions.

Eyes disorders.

Cataract.

Reporting suspected adverse effects.

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

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Jene-35 ED is a progestogen-oestrogen combination for the treatment of signs of androgenisation in the woman. At the same time, it is a reliable contraceptive for women who suffer primarily from these signs or in whom acne and similar conditions occur or deteriorate under the use of other ovulation inhibitors.
The substance cyproterone acetate contained in Jene-35 ED blocks the effect of endogenously produced and exogenously administered androgens at the target organs by means of competitive inhibition. As a result there is a gradual regression of signs of androgenisation, irrespective of whether increased androgen values or increased peripheral sensitivity are the cause of the disorder. The decrease in androgen concentration at the target organs has an additional therapeutic effect.
While Jene-35 ED is being taken, the increased sebaceous gland function, which plays an important role in the development of acne and seborrhoea, is reduced. This leads - usually after 3 to 4 months of therapy - to the healing of existing acne efflorescences. The excessive greasiness of the hair and skin generally disappears earlier. The loss of hair which frequently accompanies seborrhoea likewise diminishes. Treatment with Jene-35 ED is indicated in women of child-bearing age who exhibit mild forms of hirsutism, and in particular in slightly increased facial hair; results do not, however, become apparent until after several months of use.
Apart from the described anti-androgen effect, cyproterone acetate has also a pronounced progestational action. The combination of ethinylestradiol and cyproterone acetate prevents a possible pregnancy by the inhibition of ovulation, the inspissation of cervical mucus so as to constitute a barrier to sperm, and the rendering of the endometrium unreceptive to implantation.
As well as protection against pregnancy, combined oral contraceptives (COCs) have several positive properties which, next to negative properties (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)), can be useful in deciding on the method of birth control. For the majority of users, the cycle is more regular, the menstruation is often less painful and bleeding is lighter. The latter may result in a decrease in the occurrence of iron deficiency. In addition, with the higher dosed COCs (> 35 microgram ethinylestradiol), there is evidence of a reduced risk of fibrocystic tumours of the breasts, ovarian cysts, pelvic inflammatory disease, ectopic pregnancy, endometrial and ovarian cancer. These additional benefits have only been established in case control and cohort studies. Results from randomised controlled trials are not available.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

In a bioequivalence study, Jene-35 ED was compared to a tablet containing cyproterone acetate and ethinylestradiol. Orally both substances are completely absorbed from the Jene-35 ED tablet, ethinylestradiol being slightly faster. Maximum plasma levels can be expected within 1 hour to 4 hours. The mean C_max and median T_max values were 12.8 nanogram/mL and 1.51 hours respectively for cyproterone and 406 picogram/mL and 1.46 hours respectively for ethinylestradiol. The course of the post-maximum concentration is characterised by a two-phase decrease with half-lives of 3-4 hours and 2 days for cyproterone acetate and 1-3 hours and approximately 1 day for ethinylestradiol.

Distribution.

Because the plasma half-life of cyproterone acetate is twice as long as that of other progestogens, a stable substance level that is scarcely influenced by the individual dose is reached with daily administration.

Metabolism.

Approximately 0.2% of the maternal progestogen (cyproterone acetate) dose and approximately 0.02% of the oestrogen dose can be passed on to the infant with the maternal milk.
After oral administration cyproterone acetate is completely bioavailable, while ethinylestradiol is approximately 40-60% bioavailable.

Carbohydrate metabolism.

Depending on the nature and amount of their active substances, ovulation inhibitors may lead to an excessive glucose and plasma insulin reaction (reduced glucose tolerance), especially on oral glucose loading. The changes are generally reversible after discontinuation of medication.

Lipometabolism.

Studies of serum lipids and lipoproteins conducted by various groups have produced somewhat inconsistent results. Whereas, for example, the majority of workers found normal or even reduced cholesterol levels, others reported an increase. The results on the behaviour of the phospholipids, which generally increased slightly, show greater consistency - as do also the results for the plasma triglyceride values, which all study groups agree are increased. This appears to correlate with the oestrogen content of oral ovulation inhibitors.

Other metabolic functions.

A few authors have observed isolated disturbances of folic acid metabolism. The resultant megaloblastic anaemia proved responsive to the administration of folic acid and vitamin B₁₂ even without withdrawal of the oral ovulation inhibitors.
An effect was also observed on tryptophan and vitamin B₆ metabolism (increased xanthurenic acid elimination after tryptophan loading). Some authors see an association between this and the occurrence of depressive states.

Excretion.

The two steroids are eliminated mainly as metabolites: cyproterone acetate is eliminated by the kidneys (30%) and with the bile (70%) with a half-life of 2 days, and ethinylestradiol is eliminated by the kidneys (40%) and with the bile (60%) with a half-life of 1 day.

5.3 Preclinical Safety Data

Genotoxicity.

There is limited evidence available in the literature suggesting that oestrogens 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 (clastogenic effects were not consistently seen and occurred at high doses).
Cyproterone acetate was negative in a standard battery of genotoxicity studies. However, further tests showed that CPA was capable of producing DNA adducts in hepatocytes in rats, dogs and monkeys in vivo and also in freshly isolated rat and human liver cells in vitro following metabolism by hydroxysteroid sulfotransferases. This DNA adduct formation occurred at exposures that might be expected to occur with the recommended dose regimen for Jene-35 ED.
CPA increased DNA repair activity in rat and human hepatocytes in vitro. CPA was clastogenic in a female rat liver micronucleus test. Other in vivo consequences of CPA treatment were an increased incidence of focal, possibly pre-neoplastic, liver lesions in which cellular enzymes were altered in female rats, and an increase of mutation frequency in transgenic rats carrying a bacterial gene as a target for mutations. In all of these positive in vivo tests, hepatocyte proliferation is likely to have contributed to the results being positive. CPA had mitogenic activity towards rat hepatocytes in vitro, but not human hepatocytes.

Carcinogenicity.

Long-term continuous administration of natural and synthetic oestrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis and liver.
In a long-term carcinogenicity study of CPA in rats, an increased incidence of hepatomas was reported at oral dose levels of 50 mg/kg CPA and above. In mouse (and a second rat) carcinogenicity studies, increases in benign proliferative changes (nodular hyperplasia) in liver cells of female mice and male and female rats were reported at oral doses of 2 mg/kg. Because of shortcomings in these studies (inadequate pharmacokinetic data and the need to reassess the liver pathology), the carcinogenic potential of CPA in animals could not be determined.
The clinical relevance of these findings is presently uncertain. Clinical experience and limited epidemiological data available to date do not appear to have supported an increased incidence of hepatic tumours in humans at the recommended clinical dose of 2 mg/day cyproterone acetate. It should also be borne in mind that sexual steroids can promote the growth of certain hormone-dependent tissues and tumours.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each yellow active tablet contains the following core excipients: lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, magnesium stearate and ethanol. The following excipients are used in the tablet coating: Opadry white Y-IR-7000B, Opadry buff OY-3690, Eurolake quinoline yellow, Opaglos 6000 white, and sucrose (hypromellose, titanium dioxide, macrogol 400, indigo carmine aluminium lake, iron oxide yellow, iron oxide red, iron oxide black, ethanol, shellac, carnauba wax yellow and beeswax white.
Each white placebo tablet contains lactose monohydrate, microcrystalline cellulose and magnesium stearate.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 30°C. Protect from light and moisture.

6.5 Nature and Contents of Container

Jene-35 ED tablets are available in PVC/PVDC/Al blister packs consisting of 21 yellow tablets containing cyproterone acetate 2.0 mg and ethinylestradiol 35 microgram and 7 white inactive placebo tablets (AUST R 144128).
The calendar-pack consists of a foil backed blister platform containing twenty-eight tablets. On the foil reverse side of the platform, the tablets are allocated to days of the week in calendar format. The starting sector is coloured red.
Jene-35 ED is available in pack sizes* of 28 (one month) and 84 tablets (3 months).
*Not all pack sizes are 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

Ethinylestradiol.

19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol.
Chemical Formula: C₂₀H₂₄O₂.
Molecular Weight: 296.4.

Chemical structure.

CAS number.

57-63-6.

Cyproterone acetate.

6-chloro-17-hydroxy-1α,2α-methylene-pregna-4,6-diene-3,20-dione-acetate.
Chemical Formula: C₂₄H₂₉ClO₄.
Molecular Weight: 416.9.

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Jene-35 ED

Cyproterone acetate + Ethinylestradiol

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