Zoely - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf Life and Storage

Active ingredients: Nomegestrol (Nomegestrol acetate), Estradiol

Zoely 2.5 mg / 1.5 mg film-coated tablets

Indications Why is Zoely used? What is it for?

Zoely is a birth control pill that is used to prevent pregnancy.

• The 24 white film-coated tablets are active tablets that contain a small amount of two different female hormones. These hormones are nomegestrol acetate (a progestin) and estradiol (an estrogen).
• The 4 yellow tablets are inactive tablets that do not contain hormones and are called placebo tablets.
• Birth control pills that contain two different hormones, such as Zoely, are called "combination pills".
• Estradiol, the estrogen contained in Zoely, is identical to the hormone produced by the ovaries during the menstrual cycle.
• Nomegestrol acetate, the progestin contained in Zoely, is derived from the hormone progesterone. Progesterone is produced by the ovaries during the menstrual cycle.

Important things to know about combined hormonal contraceptives (COCs):

• When used correctly, they are one of the most reliable reversible methods of contraception.
• COCs slightly increase the risk of a blood clot forming in the veins and arteries, particularly in the first year of use or if you resume use of a combined hormonal contraceptive after a break of 4 or more weeks.
• Be careful and see your doctor if you think you may have symptoms due to a blood clot (see section "Blood clots").

Contraindications When Zoely should not be used

General consideration

Before you start using Zoely you should read the information on blood clots (thrombosis). It is especially important to read the text on symptoms related to a blood clot - see section "Blood clots").

Before you can start taking Zoely, your doctor will ask you a few questions about your medical history and the medical history of your close relatives. Your doctor will also measure your blood pressure and, depending on your personal situation, may also carry out other tests.

This leaflet describes several situations in which you will have to stop taking the pill, or in which the reliability of the pill may be reduced. In these situations you will have to give up having sexual intercourse or take additional non-hormonal contraceptive measures, eg. a condom or other barrier method. Do not use methods based on biological rhythms or temperature. These methods may be ineffective, because the pill changes the changes in body temperature and cervical mucus that normally occur during the menstrual cycle.

Zoely, like other hormonal contraceptives, does not protect against HIV infection (AIDS) or other sexually transmitted diseases.

You should not use Zoely if any of the conditions listed below apply to you. If any of the conditions listed below apply to you, you should tell your doctor. Your doctor will discuss other more suitable birth control methods with you.

• if you have (or have ever had) a blood clot in a blood vessel of the legs (deep vein thrombosis, DVT), lungs (pulmonary embolus, PE) or other organs;
• if you know that you have a bleeding disorder such as protein C deficiency, protein S deficiency, antithrombin III, factor V Leiden or antiphospholipid antibodies deficiency;
• if you need to have surgery or lie down for a long time (see section "Blood clots");
• if you have had a heart attack or stroke in the past;
• if you have (or have had in the past) angina pectoris (a condition that causes severe chest pain and may be a first sign of a heart attack) or a transient ischemic attack (TIA - temporary stroke symptoms) ;
• if you have any of the following diseases which may increase the risk of blood clots in the arteries:

- severe diabetes with vascular damage

- very high blood pressure

- very high levels of fat in the blood (cholesterol or triglycerides);

- a condition called hyperhomocysteinemia

• if you have (or have ever had) a type of migraine called "migraine with aura";
• if you have (have ever had) "inflammation of the pancreas (pancreatitis) associated with high levels of fat in the blood;
• if you have (have had) severe liver disease and your liver is still not functioning as it should;
• if you have (have ever had) a benign or malignant tumor of the liver;
• if you have (have had), or may have, breast or genital cancer;
• if you have vaginal bleeding of unknown origin.
• if you are allergic to estradiol or nomegestrol acetate or any of the other ingredients of this medicine.

If any of these conditions appear for the first time while using Zoely, stop taking it immediately and tell your doctor. In the meantime, use a non-hormonal contraceptive. See also "General considerations"

Precautions for use What you need to know before taking Zoely

When should you contact your doctor? Contact your doctor urgently

• if you notice possible signs of a blood clot which may indicate that you have a clot in the leg (ie deep vein thrombosis), a clot in the lung (ie a "pulmonary embolism), a heart attack or a stroke (see section" Blood clots "below).

For a description of the characteristic symptoms of these serious side effects, see "How to recognize a blood clot".

• if you notice any change in your state of health, especially as regards the aspects mentioned in this leaflet (see also section "When you should not use Zoely"; do not forget the changes in the state of health of your close relatives);
• if you notice a lump in your breast;
• if you experience symptoms of angioedema such as swelling of the face, tongue and / or throat and / or difficulty in swallowing or hives with difficulty in breathing;
• if you need to use other medicines (see also section "Other medicines and Zoely");
• if you need to lie down for a long time or have surgery (tell your doctor at least four weeks in advance);
• if you have unusual and intense vaginal bleeding;
• if you have forgotten two or more tablets in the first week of the strip and have had sex in the previous seven days (see also section "If you forget to take Zoely");
• in case of severe diarrhea;
• if you are not menstruating and suspect pregnancy (do not start the next strip without consulting your doctor, see also section "If you have not had your period once or more").

Tell your doctor if any of the following apply to you.

You should also tell your doctor if any of these conditions appear or worsen while using Zoely.

• if you have hereditary angioedema. Consult your doctor immediately if you experience symptoms of angioedema such as swelling of the face, tongue and / or throat and / or difficulty in swallowing or hives with difficulty in breathing. Preparations containing estrogen may induce or worsen the symptoms of " angioedema;
• if a close relative has or had breast cancer;
• if you have epilepsy (see section "Other medicines and Zoely");
• if you have liver disease (e.g. jaundice) or gallbladder disease (e.g. gallstones);
• if you are diabetic;
• if you suffer from depression;
• if you have Crohn's disease or ulcerative colitis (chronic inflammatory bowel disease);
• if you have systemic lupus erythematosus (SLE, a disease that affects the body's defense system);
• if you have haemolytic uraemic syndrome (HUS, a bleeding disorder causing kidney failure);
• if you have sickle cell anemia (an inherited disease of the red blood cells);
• if you have high levels of fat in the blood (hypertriglyceridaemia) or a positive family history for this disease. Hypertriglyceridaemia has been associated with an increased risk of developing pancreatitis (inflammation of the pancreas);
• if you need to have surgery or lie down for a long time (see under "Blood clots").
• if you have just given birth, the risk of blood clots is higher. Ask your doctor how long after having a baby you can start taking Zoely.
• if you have "inflammation of the veins under the skin (superficial thrombophlebitis);
• if you have varicose veins.
• if you have a condition that first appeared or got worse during pregnancy or with previous use of sex hormones (eg hearing loss, porphyria [a blood disorder], gestational herpes [rash with blisters during pregnancy ], Sydenham's chorea [a nerve disease in which sudden body movements occur], (see "When to contact your doctor" section);
• if you have (or have had in the past) chloasma [yellow-brown pigmented spots, so-called 'pregnancy spots', especially on the face]. If so, avoid excessive exposure to sunlight or ultraviolet light

BLOOD CLOTS

Using a hormonal contraceptive such as Zoely increases your risk of developing a clot compared to the risk you would have if you didn't use it. In rare cases, a blood clot can block blood vessels and cause serious problems.

Clots can develop

• in veins (referred to as "venous thrombosis", "venous thromboembolism" or VTE)
• in the arteries (referred to as "arterial thrombosis", "arterial thromboembolism" or ATE).

Recovery after a blood clot isn't always complete. Rarely, severe effects may persist or, very rarely, they may be fatal.

It is important to remember that the overall risk of a harmful blood clot from Zoely is low.

HOW TO RECOGNIZE A BLOOD CLOT

See your doctor urgently if you notice any of the following signs or symptoms.

Notice any of these signs? What do you possibly suffer from? swelling of one leg or along a vein in the leg or foot, especially when accompanied by:

• pain or excessive tenderness in the leg, which may occur only when standing or walking
• excessive heat in the affected leg
• change in color of the skin on the leg, for example turning pale, red or blue

Deep vein thrombosis

• wheezing or unexplained rapid breathing of sudden onset;
• sudden cough with no obvious cause, including bleeding;
• stinging pain in the chest, which may increase with deep breathing;
• severe lightheadedness or dizziness;
• rapid or irregular heartbeat;
• severe stomach pain;

If in doubt, consult your doctor, as some of these symptoms, such as coughing or wheezing, may be mistaken for a less serious illness, such as a "respiratory infection (such as a common cold). Pulmonary embolism Most commonly, symptoms affect only one eye:

• immediate loss of vision or
• painless blurring of vision, which may progress to loss of vision

Retinal vein thrombosis (blood clot in the eye)

• chest pain, discomfort, pressure, heaviness
• sensation of constriction or tightness in the chest, arm or below the breastbone;
• feeling of fullness, indigestion or choking;
• upper body discomfort radiating to the back, jaw, throat, arm, stomach;
• sweating, nausea, vomiting or dizziness;
• extreme weakness, anxiety, or wheezing;
• rapid or irregular heartbeat

Heart attack

• sudden weakness or numbness in the face, arm or leg, especially on one side of the body;
• sudden confusion, difficulty speaking or understanding;
• sudden visual difficulty affecting one or both eyes;
• sudden difficulty walking, dizziness, loss of balance or coordination;
• sudden, severe, or prolonged headache with no known cause;
• loss of consciousness or fainting with or without seizure.

Sometimes, stroke symptoms may be short-lived and recovery may be almost complete and immediate, but you still need to see a doctor urgently as there may be a risk of another stroke. Stroke

• swelling and slight bluish discoloration in one extremity;
• severe stomach pain (acute abdomen);

Clots that block other blood vessels

BLOOD CLOTS IN A VEIN

What can happen if a blood clot forms in a vein?

• The use of combined hormonal contraceptives has been associated with an increased risk of blood clots (venous thrombosis). However, these side effects are rare. They most frequently occur in the first year of using a combined hormonal contraceptive.
• If a blood clot forms in a vein in the leg or foot, it can cause a deep vein thrombosis (DVT).
• If a blood clot travels from the leg and lodges in the lung it can cause a "pulmonary embolism."
• Very rarely, a clot may form in a vein in another organ, such as the eye (retinal vein thrombosis).

When is the risk of a blood clot in a vein highest?

The risk of a blood clot forming in a vein is highest in the first year of taking a combined hormonal contraceptive for the first time. The risk may also be higher if you resume taking a combined hormonal contraceptive (the same product or a different preparation) after a break of 4 weeks or more. After the first year the risk decreases, but is always slightly higher than the risk of not using a combined hormonal contraceptive.

When you stop taking Zoely, the risk of blood clots returns to normal levels within a few weeks.

What is the risk of a blood clot forming?

The risk depends on your natural risk of VTE and the type of combined hormonal contraceptive you are taking. The overall risk of developing a blood clot in the leg or lung (DVT or PE) with Zoely is low.

• Out of 10,000 women who are not using any combined hormonal contraceptive and are not pregnant, about 2 will develop a clot in a year.
• Out of 10,000 women who are using a combined hormonal contraceptive that contains levonorgestrel, norethisterone, or norgestimate, about 5-7 will develop a clot in a year.
• The risk of blood clots associated with Zoely compared to the risk associated with a combined hormonal contraceptive containing levonorgestrel is not yet known.
• The risk of developing a blood clot varies according to your personal medical history (see "Factors that increase the risk of a blood clot" below).

There is a risk of a blood clot forming in one year

Women who are not using a combined hormone pill and who are not pregnant About 2 out of 10,000 women Women using a combined hormonal contraceptive pill containing levonorgestrel, norethisterone or norgestimate About 5-7 out of 10,000 women Women who use Zoely Not yet known

Factors that increase the risk of a blood clot in a vein

The risk of a blood clot forming with Zoely is low, but it increases under certain conditions. The risk is greater:

• if you are overweight (body mass index or BMI over 30 kg / m 2);
• if a member of your immediate family has had a blood clot in the leg, lung or other organ at a young age (for example, before around 50 years of age). If so, you may have a hereditary bleeding disorder;
• if you need to have surgery or stay in bed for a long time due to an accident or illness, or if you have a leg in a cast. Zoely may need to be stopped several weeks before surgery or while you are less mobile. If you need to stop taking Zoely, ask your doctor when you can start using it again.
• with increasing age (especially after about 35 years);
• if she gave birth less than a few weeks ago

The risk of a blood clot forming increases the more of these conditions affect you. Air travel (longer than 4 hours) can temporarily increase the risk of a blood clot, particularly if you have any of the other risk factors listed.

It is important to tell your doctor if any of these apply to you, even if it is not safe. Your doctor may decide that the use of Zoely should be discontinued.

If any of the conditions reported change while using Zoely, for example if a close relative has a thrombosis without a known cause or if you gain considerable weight, please tell your doctor.

BLOOD CLOTS IN AN ARTERY

What can happen if a blood clot forms in an "artery? Like a blood clot in a vein, a clot in an artery" can cause serious problems. For example, it can cause a heart attack or stroke.

Factors that increase the risk of a blood clot in an artery

It is important to note that the risk of heart attack or stroke from using Zoely is very low, but it can increase:

• with increasing age (after about 35 years);
• if you smoke. When using a combined hormonal contraceptive such as Zoely you should stop smoking. If you are unable to stop smoking and are over the age of 35, your doctor may advise you to use a different type of contraceptive.
• if you are overweight;
• if you have high blood pressure;
• if a member of your immediate family has had a heart attack or stroke at a young age (before approximately 50 years of age).If so, you too may have a higher risk of having a heart attack or stroke;
• if you or a close relative have high levels of fat in the blood (cholesterol or triglycerides);
• if you suffer from migraines, especially migraines with aura;
• if you have a heart problem (a disease of the heart valves, a rhythm disorder called atrial fibrillation)
• if you have diabetes.

If more than one of these conditions applies to you or if one of them is particularly severe, the risk of a clot forming may be even greater.

If any of the conditions you report change while using Zoely, for example if you start smoking, if a close relative has a thrombosis without a known cause or if you gain considerable weight, please tell your doctor.

Cancer

Breast cancer has been observed slightly more frequently in combination pill users, but it is not known whether this is caused by combination pills. For example, more cancers may be diagnosed in women using combination pills because these women are seen by their doctor more often. After stopping the combined pill, the increased risk is gradually reduced.

It is important to check your breasts regularly and to contact your doctor if you have any lumps. Also tell your doctor if a close relative has or has had breast cancer in the past (see "When to take special care with Zoely"). In rare cases, benign (non-cancerous) liver tumors and, even more rarely, malignant (cancerous) liver tumors have been reported in birth control pill users. Contact your doctor if you have particularly severe unusual pain in the abdomen.

Cervical cancer is caused by an infection with the human papilloma virus (HPV). This cancer is more common in women who use the pill for a long time. It is not known whether this is due to the use of hormonal contraceptives or to hormonal contraceptives. other factors, such as differences in sexual behavior.

Diagnostic tests

If you need to have any blood or urine tests, tell your doctor that you are using Zoely, as it may change the results of some tests.

Children and adolescents

No efficacy and safety data are available in adolescents under 18 years of age

Interactions Which drugs or foods can change the effect of Zoely

Tell your doctor or pharmacist if you are taking, or have recently taken or might take any other medicines, including non-prescription and herbal preparations. Also tell other doctors or dentists who prescribe other medicines (or the pharmacist who provides them) about your use of Zoely. They will tell you if you need to take additional contraceptive measures (barrier methods) and, if so, for how long.

Some medicines can make Zoely less effective in preventing pregnancy, or cause unexpected blood loss.

These include medicines used to treat:

• l "epilepsy (eg primidone, phenytoin, phenobarbital, carbamazepine, oxcarbazepine, topiramate, felbamate);
• tuberculosis (eg rifampicin);
• HIV infections (eg ritonavir, nevirapine, nelfinavir, efavirenz);
• other infectious diseases (eg griseofulvin);
• high pressure in the blood vessels of the lungs (bosentan).
• The herbal product St. John's wort can also prevent Zoely from working properly. If you wish to use herbal products containing St. John's wort while you are already using Zoely, you should consult your doctor first.
• Some medicines can increase the levels of the active substances of Zoely in the blood. The effectiveness of the pill is preserved, but tell your doctor if you are using antifungal medicines containing ketoconazole.
• Zoely can also interfere with the action of other medicines, such as the antiepileptic lamotrigine.

Warnings It is important to know that:

Pregnancy and breastfeeding

Zoely should not be used by women who are pregnant or who think they may be pregnant. If you become pregnant while using Zoely you should stop using Zoely and contact your doctor.

If you want to stop taking Zoely because you want to become pregnant, see section "If you stop taking Zoely".

The use of Zoely is generally not recommended while breastfeeding. If you want to use the pill while breastfeeding, ask your doctor for advice.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Zoely is unlikely to affect the ability to drive or use machines.

Zoely contains lactose Zoely contains lactose.

If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking this medicinal product.

Dose, Method and Time of Administration How to use Zoely: Posology

When and how to take the tablets

The Zoely blister contains 28 tablets: 24 white tablets with active ingredients (numbers 1-24) and 4 yellow tablets without active ingredients (numbers 25-28).

Each time you start a new strip of Zoely, take the white active tablet number 1 in the upper left corner (see "Start"). In the gray column, choose the adhesive label that begins with your starting day between 7 am. adhesive labels available. For example, if it starts on a Wednesday, you use the adhesive label starting with "WED". You stick it on the blister, immediately above the row of white active tablets, where it says "Paste the label of the day of the week here". This way you can check if you have taken the tablet every day.

Take one tablet every day, at approximately the same time, with a little water if needed.

Follow the direction of the arrows on the blister, i.e. use the white active tablets first and then the yellow placebo tablets.

Your period will start in the 4 days you use the yellow placebo tablets (so-called withdrawal bleeding). Withdrawal bleeding usually starts 2-3 days after taking the last white active tablet and may not have finished yet at the start of the new strip.

Start the new strip immediately after the last yellow tablet, even if your period has not yet finished. This means that you must always start a new strip on the same day of the week, and that your period should occur every month, on approximately the same days.

In some women, your period may not occur every month while taking the yellow tablets. If you have taken Zoely every day as directed, it is unlikely that you are pregnant (see also section "If you have not had a period on one or two occasions). many times").

How to start the first pack of Zoely

If you have not used hormonal contraceptives in the previous month

Start taking Zoely on the first day of your period (i.e. the first day of your period). Zoely acts immediately. He does not need an additional birth control method.

If you have previously used another combined hormonal contraceptive (combination pill, vaginal ring, or transdermal patch)

You can start taking Zoely the day after taking the last contraceptive tablet you are currently taking (ie without observing any interval). If the contraceptive pack you are currently taking also contains inactive tablets (placebo), you can start with Zoely the day after taking the last active tablet (if you don't know which one, ask your doctor or pharmacist). It can also start later, but never after the next day after the tablet-free interval of the contraceptive you are currently taking (or the day after the last inactive tablet). If you are using a vaginal ring or transdermal patch, you should preferably start Zoely on the day you remove the ring or patch. You can also start on the day at the latest. which one would use the next ring or patch. If you follow these instructions, you don't need an additional birth control method.

If you have previously used a progestogen-only pill (minipill)

You can stop taking the minipill on any day and start taking Zoely the next day. If you have sex, remember to use a barrier method of birth control for the first 7 days of taking Zoely.

If you have previously used an injectable progestogen, implant or hormonal intrauterine device (IUS)

Start using Zoely on the day your next injection is due or the day the implant or intrauterine device is removed. If you have sex, remember to use a barrier method of birth control for the first 7 days of taking Zoely.

After giving birth

You can start Zoely between 21 and 28 days after having a baby. If you start after day 28, you should also use a barrier method of birth control in the first 7 days of Zoely use. If, after having a baby, you have had sex before starting Zoely, make sure you are not pregnant or wait until your next period. If you want to start Zoely after giving birth and while breastfeeding, please also read the section on "Pregnancy and breastfeeding". Ask your doctor for advice if you are not sure when to start.

After a "termination of pregnancy or abortion

Follow your doctor's instructions

If you forget to take Zoely

The following recommendations refer exclusively to forgetting the white active tablets.

• If you are less than 12 hours late in taking a tablet, the reliability of the pill is preserved. Take the tablet as soon as you remember and take the following tablets at the usual time.
• If you are more than 12 hours late in taking a tablet, the reliability of the pill may be reduced. The more consecutive tablets you have forgotten, the greater the risk that contraceptive efficacy will be reduced. The risk of pregnancy is particularly high if you forget white active tablets at the beginning or at the end of the strip. You must then follow the instructions below.

Day 1-7 of taking the white active tablets

Take the last missed white active tablet as soon as you remember (even if that means taking two tablets at the same time) and take the next tablet at the usual time. However, use a barrier method as an extra precaution for the next 7 days.

If you have had sexual intercourse in the week prior to forgetting the tablets, there is a possibility that you may become pregnant. Contact your doctor immediately.

Day 8-17 of taking the white active tablets

Take the last missed tablet as soon as you remember (even if that means taking two tablets at the same time) and take the following tablets at the usual time. The protection against pregnancy is not reduced and you do not need to take additional precautionary measures. However, if you have forgotten more than one tablet, you should take additional precautionary measures for 7 days.

Day 18-24 of taking the white active tablets

The risk of becoming pregnant is particularly high if you miss the white active tablets when the yellow placebo tablet range approaches. By changing the intake schedule you can prevent this risk.

It has two options:

Option 1) Take the last missed white active tablet as soon as you remember (even if that means taking two tablets at the same time) and take the next tablets at the usual time. Start the next blister as soon as the white active tablets in the current blister are used up and do not take the yellow placebo tablets. Your period may not appear until you have taken the yellow placebo tablets at the end of the second strip, but you may have mild discharge (drops or bloodstains) or bleeding while taking the white active tablets.

Option 2) Stop taking the white active tablets immediately and switch directly to the yellow placebo tablets in the interval. When the yellow placebo tablets in the interval are finished, start with the next strip.

If you do not remember how many white active tablets you have forgotten, follow the first option, use a barrier method as a precaution within the next 7 days and contact your doctor.

If you have forgotten any white active tablets from a strip and do not have your expected period while taking the yellow placebo tablets from the same strip, you may be pregnant. Contact your doctor before starting a new strip.

Forgotten yellow placebo tablets

The last 4 yellow tablets of the fourth row are placebo tablets which do not contain active ingredients. If you have forgotten one of these tablets, the reliability of Zoely is preserved. Throw away the forgotten yellow placebo tablet (s) and take the next tablets at the usual time.

In case of vomiting or severe diarrhea

If you vomit within 3-4 hours after taking a white active tablet or have severe diarrhea, it is possible that the active ingredients in the Zoely tablet have not been fully absorbed by the body. The situation is similar to forgetting a white active tablet. After vomiting or diarrhea, you must take another white active tablet from a reserve strip as soon as possible. If possible, take it within 12 hours of the usual time. If this is not possible or if 12 hours have already passed, follow the instructions given in the section "If you forget to take Zoely". If you have severe diarrhea, please tell your doctor.

The latest yellow tablets are placebo tablets that do not contain active ingredients. If vomiting or severe diarrhea occurs within 3-4 hours after taking a yellow tablet, the reliability of Zoely is preserved.

If you want to delay your period

You can delay your period by not taking the yellow placebo tablets and switching directly to a new strip of Zoely. You may experience mild or menstruation-like bleeding while using this second strip. If you want your period to start while you are using the second strip, stop taking the white active tablets and start taking the yellow placebo tablets. Once you have finished the 4 yellow placebo tablets from the second strip, start with the next (third) strip.

If you want to change the start day of your period

If you take the tablets according to the instructions, your period will start on the days of taking the placebo. If you want to change the start day of your cycle, reduce the number of placebo days, i.e. the days you take the yellow placebo tablets (but never increase the number, 4 days is the maximum). For example, if you start taking the placebo tablets on Friday and want to start on Tuesday instead (3 days earlier), you should start a new strip 3 days earlier than usual. You may not have any bleeding during this shortened phase of taking yellow placebo tablets. During the use of the next strip, you may experience light discharge (drops or blood spots) or heavy bleeding while taking the white active tablets.

If you are unsure of what to do, consult your doctor.

If you have unexpected bleeding

With all combination pills, irregular vaginal bleeding (mild or heavy discharge) between menstruation may occur in the first few months. You may need to use a sanitary napkin, but keep taking your tablets as normal. Irregular vaginal bleeding usually stops once your body gets used to the pill (usually after 3 months). If bleeding continues, increases in intensity or starts again, contact your doctor.

If you have not had your period one or more times

Clinical studies conducted with Zoely have shown that menstruation occasionally does not appear after day 24.

• If you have taken all the tablets correctly, have not had severe vomiting or diarrhea and have not taken any other medicines, it is highly unlikely that you are pregnant. Continue to take Zoely as normal. See also in the section "If you have severe vomiting or diarrhea" or in the section "Other medicines and Zoely".
• If you have not taken all the tablets correctly or if your period does not occur twice in a row, you may have become pregnant. Contact your doctor immediately. Do not start the next Zoely strip until your doctor has determined that you are not pregnant.

If you stop taking Zoely

You can stop taking Zoely at any time. If you don't want to become pregnant, consult your doctor about other birth control methods.

If you stop taking Zoely because you want to become pregnant, it is recommended that you wait until a natural period occurs before attempting to conceive. This will make it easier to determine the expected date of delivery.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

Overdose What to do if you have taken too much Zoely

If you take more Zoely than you should

There have been no reports of serious harmful effects of taking too many Zoely tablets at one time. If you have taken several tablets at the same time, nausea, vomiting or vaginal bleeding may occur. If you notice that a child has taken Zoely, ask your doctor for advice.

Side Effects What are the side effects of Zoely

Like all medicines, Zoely can cause side effects, although not everybody gets them.

If you experience any side effects, especially if they are severe or persistent, or if you notice any change in your health condition and believe that this may be due to Zoely, please consult your doctor.

There is an increased risk of blood clots in the veins (venous thromboembolism (VTE)) or arteries (arterial thromboembolism (ATE)) in all women taking combined hormonal contraceptives. For more detailed information on the different risks associated with taking combined hormonal contraceptives, see section "What you need to know before you use Zoely".

The following side effects have been associated with the use of Zoely:

Very common (may affect more than 1 in 10 people):

• acne
• menstruation abnormalities (e.g. absent or irregular menstruation)

Common (may affect up to 1 in 10 people):

• reduced interest in sexual activities, depression / depressed mood, mood swings
• headache or migraine
• nausea
• abundant menstruation; breast pain; pelvic (belly) pain
• weight gain

Uncommon (may affect up to 1 in 100 people):

• increased appetite; water retention (edema)
• hot flashes
• swollen abdomen
• increased sweating; hair loss; itch; dry skin; greasy skin
• heaviness in the limbs
• regular, but scanty menstruation; breast enlargement; breast lump; milk production in the absence of pregnancy; premenstrual syndrome; pain during sexual intercourse; dryness of the vagina or vulva; spasm of the uterus
• irritability
• increased liver enzymes

Rare (may affect up to 1 in 1,000 people):

• harmful clots in a vein or an "artery, for example: o in a leg or foot (ie DVT) or in a lung (ie PE) or heart attack or stroke or mini-stroke or temporary symptoms similar to" stroke, called transient ischaemic attack (TIA) or blood clots in the liver, stomach / intestines, kidneys or eye.

The likelihood of a blood clot forming may be higher if you have any other conditions that increase your risk (see section for more information on conditions that increase the risk of clots and symptoms of a clot.)

• decreased appetite
• increased interest in sexual activities
• attention disorders
• dry eyes; intolerance to contact lenses
• dry mouth
• yellow-brown pigmented spots, especially on the face; excessive hair growth
• vaginal odor; discomfort in the vagina or vulva
• hunger
• gallbladder disease

Allergic (hypersensitivity) reactions have been reported in users of Zoely, but the frequency cannot be estimated from the available data.

Further information on possible side effects related to your period (eg absent or irregular periods) while using Zoely can be found in the sections "When and how to take the tablets", "If you have unexpected bleeding" and "If you do not has had your period one or more times ".

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the blister and carton after EXP. The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Combination pills (including Zoely tablets) that are no longer needed should not be disposed of via wastewater or household waste. The hormonally active excipients contained in the tablet may have harmful effects if they reach the aquatic environment. Return the tablets to the pharmacy or dispose of them otherwise safely in accordance with local regulations. This will help protect the environment.

What Zoely contains

• The active ingredients are:

in the white active film-coated tablets: each tablet contains 2.5 mg of nomegestrol acetate and 1.5 mg of estradiol (as hemihydrate); in the yellow placebo film-coated tablets: the tablet does not contain active substances.

• The other ingredients are:

Tablet core (white active film-coated tablets and yellow placebo film-coated tablets):

Lactose monohydrate (see section "Zoely contains lactose"), microcrystalline cellulose (E460), crospovidone (E1201), talc (E553b), magnesium stearate (E572) and colloidal anhydrous silica

Tablet coating (white active film-coated tablets):

Poly (vinyl alcohol) (E1203), titanium dioxide (E171), macrogol 3350 and talc (E553b)

Tablet coating (yellow placebo film-coated tablets):

Poly (vinyl alcohol) (E1203), titanium dioxide (E171), macrogol 3350, talc (E553b), yellow iron oxide (E172) and black iron oxide (E172)

Description of Zoely's appearance and contents of the pack

Active film-coated tablets (tablets) are white and round. On both sides there is the inscription "ne".

Placebo film-coated tablets are yellow and round. On both sides there is the inscription "p".

Zoely is available in 1, 3, 6 or 13 blisters of 28 film-coated tablets (24 active white film-coated tablets and 4 yellow film-coated placebo tablets) packed in a carton.

Not all pack sizes may be marketed

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

More information about Zoely can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, ADDITIONAL DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

ZOELY 2.5 MG / 1.5 MG TABLETS COATED WITH FILM

▼ Medicinal product subject to additional monitoring. This will allow the rapid identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for information on how to report adverse reactions.

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

White active film-coated tablets: Each film-coated tablet contains 2.5 mg of nomegestrol acetate and 1.5 mg of estradiol (as hemihydrate).

Yellow placebo film-coated tablets: the tablet does not contain active ingredients.

Excipients with known effects:

Each white active film-coated tablet contains 57.71 mg of lactose monohydrate

Each yellow film-coated placebo tablet contains 61.76 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Film-coated tablet (tablet).

Active film-coated tablets: white, round, with "ne" debossed on both sides.

Placebo film-coated tablets: yellow, round, with "p" debossed on both sides.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Oral contraception.

The decision to prescribe Zoely should take into account the woman's current individual risk factors, particularly those related to venous thromboembolism (VTE), and the risk of VTE associated with Zoely compared to other CHCs (see sections 4.3 and 4.4).

04.2 Posology and method of administration

Dosage

One tablet should be taken every day for 28 consecutive days. Each pack starts with 24 white active tablets, followed by 4 yellow placebo tablets. Once a pack is finished, the next pack is started immediately, without interrupting the daily intake of the tablets and regardless of the presence or absence of withdrawal bleeding. Withdrawal bleeding generally begins 2-3 days after taking the last white tablet. and may not be finished yet at the start of the new pack. See "Cycle Control" in section 4.4.

Special populations

Renal impairment

Although no data are available in patients with renal impairment, renal impairment is unlikely to affect the elimination of nomegestrol acetate and estradiol.

Hepatic impairment

No clinical studies have been conducted in patients with hepatic insufficiency. Since the metabolism of steroid hormones may be impaired in patients with severe liver disease, Zoely is not indicated for use in these women until liver function values ​​have returned to normal (see section 4.3).

Method of administration

Oral use.

How to take Zoely

The tablets should be taken at approximately the same time each day, regardless of meals. The tablets should be taken with some liquid, as needed, in the order indicated on the blister. Adhesive labels are attached to the package indicating the 7 days of the week. The woman must choose the label that begins with the day she starts taking the tablets and apply it to the blister.

How to start taking Zoely

In the absence of previous hormonal contraception (in the past month)

The first tablet should be taken on the first day of the natural cycle (i.e. the first day of menstruation). In this case it is not necessary to take additional contraceptive measures.

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

The woman should preferably take Zoely on the day following the last active tablet (the last tablet containing the active substances) of her previous combined oral contraceptive, at the latest on the day following the tablet-free interval or taking placebo tablets. of her previous combined oral contraceptive. In case of vaginal ring or transdermal patch, the woman should start taking Zoely preferably on the day of removal of the device, at the latest on the day scheduled for the next application.

Changing from a progestogen-only method (minipill, implant, injectable) or a hormonal intrauterine device (Intra Uterine System, IUS)

Switching from the minipill can occur on any day and Zoely should be taken the next day. An implant or IUS can be removed on any day and Zoely should be taken on the day of removal. In the case of an injectable contraceptive, Zoely should be taken on the day the next injection would have been scheduled. In all these cases, the woman should be advised to use an additional barrier method until 7 days of uninterrupted intake have elapsed. of white active tablets.

After an abortion in the first trimester of pregnancy

The intake can be started immediately. In this case it is not necessary to use additional contraceptive measures.

After a birth or abortion in the second trimester of pregnancy

The woman should be advised to take between days 21 and 28 after delivery or after an abortion in the second trimester of pregnancy. In case of a later onset, the woman should be advised to use an additional barrier method up to 7 days of uninterrupted intake of the white active tablets have not elapsed. However, if intercourse has already taken place, pregnancy must be ruled out before starting COC use, or the woman must wait for the onset of her first menstrual cycle.

For use during lactation see section 4.6.

What to do if you forget one or more tablets

The following recommendations refer exclusively to forgetting the white active tablets:

In case of delay less than 24 hours when taking any active tablet, contraceptive protection is not reduced. The woman should take the forgotten tablet as soon as she remembers and then take the following tablets at the usual time.

In case of delay more than 24 hours when taking any active tablet, contraceptive protection can be reduced. The behavior to be followed in case of forgetting is based on two fundamental rules:

• 7 days of uninterrupted intake of white active tablets are required for adequate suppression of the hypothalamic-pituitary-ovarian axis.

• the more white active tablets you have forgotten and the closer they are to the 4 yellow placebo tablets, the higher the risk of pregnancy.

Day 1-7

The woman should take the last missed tablet as soon as she remembers, even if that means taking two tablets at the same time. She then continues to take the tablets at the usual time. Also, a barrier method, such as a condom, should be used for the next 7 days. In case of sexual intercourse in the previous 7 days, the possibility of pregnancy should be considered.

Day 8-17

The woman should take the last missed tablet as soon as she remembers, even if that means taking two tablets at the same time. She then continues to take the tablets at the usual time. Provided that the woman has taken the tablets correctly in the 7 days preceding the first missed tablet, there is no need to use additional contraceptive measures. However, if more than 1 tablet has been forgotten, the woman should be instructed to take additional precautionary measures for 7 days.

Day 18-24

The risk of reduced reliability is imminent due to the proximity to the placebo tablet phase. However, by changing the tablet-taking schedule, a reduction in contraceptive protection can still be prevented. Adhering to either of the following two options is therefore not necessary to use additional contraceptive measures, provided that the woman has taken all tablets correctly in the 7 days preceding the first missed tablet. If not, you should stick to the first of the two options and take additional precautionary measures over the next 7 days.

1. The woman should take the last missed tablet as soon as she remembers, even if that means taking two tablets at the same time. She then continues to take the tablets at the usual time, until the active tablets are finished. The 4 placebo tablets from the last row should be discarded. The next blister pack should be started immediately. Withdrawal bleeding is unlikely until the active tablets in the second pack are finished, but spotting may occur while taking the tablets. or metrorrhagia.

2. The woman may also be instructed to stop taking the active tablets from the current blister pack. In this case, she should take the placebo tablets from the last row for up to 4 days, including the days when she forgot the tablets. , and then continue with the next blister pack.

If the woman has forgotten to take a few tablets and consequently no withdrawal bleeding in the placebo tablet phase, the possibility of pregnancy should be considered.

Forgotten yellow placebo tablets

Contraceptive protection is not reduced. The yellow tablets from the last (4th) row of the blister can be skipped. However, missed tablets should be discarded to avoid inadvertently prolonging the placebo phase.

Warnings in case of gastrointestinal disorders

In case of severe gastrointestinal disturbances (eg vomiting or diarrhea), the absorption of the active substances may be incomplete and additional contraceptive measures must be used.

If vomiting occurs within 3-4 hours after taking a white tablet, the tablet should be considered lost and a new tablet should be taken as soon as possible. If possible, the new tablet should be taken within 24 hours of the time of intake. habitual. The next tablet should then be taken at the usual time.If more than 24 hours have elapsed since the last taking of a tablet, the instructions on forgetting the tablets in section 4.2 "What to do in case of forgotten one or more tablets" apply. If the woman does not want to change the schedule you usually take the tablet or additional white tablets from another pack.

How to shift or delay menstruation

To delay menstruation, the woman should continue with another blister pack of Zoely without taking the yellow placebo tablets from the current pack. The cycle can be extended as desired, until the white active tablets from the second pack are finished. Zoely regular will resume after the yellow placebo tablets from the second pack have been taken. The woman in the prolongation phase of the cycle may experience breakthrough bleeding or spotting.

In order to shift her period to a different day of the week than in the current dosing schedule, the woman can shorten the phase of the yellow placebo tablets by up to 4 days. The shorter the interval, the greater the risk that withdrawal bleeding will not occur and that bleeding and spotting will occur during the next pack (such as when you delay your period).

04.3 Contraindications

Combined hormonal contraceptives (COCs) should not be used in the following conditions. As epidemiological data regarding COCs containing 17β-estradiol are not yet available, the contraindications of COCs containing ethinylestradiol are also considered valid for Zoely. If any of the following conditions occur for the first time while using Zoely, taking the medicine should be stopped immediately.

• presence or risk of venous thromboembolism (VTE)

- Venous thromboembolism "." Current VTE (under anticoagulant therapy) or history (eg deep vein thrombosis [DVT] or pulmonary embolism [PE]).

- Known hereditary or acquired predisposition to venous thromboembolism, such as resistance to APC (including factor V Leiden), antithrombin III deficiency, protein C deficiency, protein S deficiency.

- Major surgery with prolonged immobilization (see section 4.4).

- High risk of venous thromboembolism due to the presence of multiple risk factors (see section 4.4).

• presence or risk of arterial thromboembolism (ATE)

- Arterial thromboembolism "." Current arterial thromboembolism, history of arterial thromboembolism (e.g. myocardial infarction) or prodromal condition (e.g. angina pectoris).

- Cerebrovascular disease "." current stroke, history of stroke or prodromal condition (e.g. transient ischemic attack [transient ischaemic attack, TIA]).

- Known hereditary or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinemia and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).

- History of migraine with focal neurological symptoms.

- High risk of arterial thromboembolism due to multiple risk factors (see section 4.4) or the presence of a single serious risk factor such as:

• diabetes mellitus with vascular symptoms

• severe hypertension

• severe dyslipoproteinemia.

• pancreatitis or a history of pancreatitis if associated with severe hypertriglyceridaemia.

• presence or history of severe liver disease until liver function values ​​return to normal.

• presence or history of liver tumors (benign or malignant).

• Known or suspected sex steroid-dependent malignancies (eg cancers of the genital organs or breast).

• undiagnosed vaginal bleeding.

• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

04.4 Special warnings and appropriate precautions for use

Warnings

In the presence of any of the conditions or risk factors mentioned below, the suitability of Zoely should be discussed with the woman.

In the event of worsening or first appearance of any of the conditions or risk factors mentioned, the woman should be advised to contact her physician to determine whether the use of Zoely should be discontinued. All the data below are based on Epidemiological data obtained with COCs containing ethinylestradiol Zoely contains 17β-estradiol As epidemiological data are not yet available regarding COCs containing estradiol, the warnings are also considered valid for Zoely.

Risk of venous thromboembolism (VTE)

• The use of any combined hormonal contraceptive (CHC) increases the risk of venous thromboembolism (VTE) compared with no use. Preparations containing levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. It is not yet known. magnitude of risk associated with Zoely compared to these lower risk preparations. The decision to use any preparation other than those known to be associated with the lowest risk of VTE should only be made after an interview with the woman, to ensure that she understands the risk of VTE associated with CHCs, as well as her current risk factors. influence this risk and that the risk of VTE is highest in the first year of first use. In addition, there is some evidence to suggest that the risk is greater if the use of a COC is resumed after a break of 4 weeks or more.

• Among women who do not use a CHC and who are not pregnant, about 2 in 10,000 develop a VTE within a year. However, each individual woman may be at a much higher risk depending on their pre-existing risk factors (see below).

• Epidemiological studies in women using low-dose combined hormonal contraceptives (

• Out of 10,000 women who use a levonorgestrel-containing CHC, about 6 are thought to develop a VTE within a year.

• The extent of the risk of VTE associated with COCs containing nomegestrol acetate in combination with estradiol compared to the risk associated with low-dose levonorgestrel-containing COCs is not yet known.

• The number of VTEs per year with low-dose CHCs is less than the number expected in pregnant or postpartum women.

• VTE can be fatal in 1-2% of cases.

• In extremely rare cases, thrombosis affecting other blood vessels, eg. hepatic, mesenteric, renal or retinal veins or arteries.

Risk factors for VTE

The risk of venous thromboembolic complications in COC users may increase considerably in a woman who has additional risk factors, particularly if the risk factors are multiple (see table).

Zoely is contraindicated if the woman has multiple risk factors leading to a high risk of venous thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increased risk is greater than the sum of the individual factors, in which case her overall risk of VTE should be considered. If the balance of benefits and risks is considered negative no CHC should be prescribed (see section 4.3).

Table: Risk factors for VTE

Risk factor Comment Obesity (body mass index greater than 30 kg / m2) The risk increases considerably as the BMI increases. This is particularly important in the presence of other risk factors. Prolonged immobilization, major surgery, any leg or pelvic surgery, neurosurgery or major trauma Note: Even temporary immobilization, such as air travel> 4 hours, can be a risk factor for VTE, particularly in women which have other risk factors. In such situations it is advisable to discontinue use of the pill (in the case of elective surgery, at least four weeks in advance) and not to resume it before two weeks have elapsed after complete mobilization. To avoid unwanted pregnancy, a other contraceptive method. If Zoely has not been previously discontinued, antithrombotic treatment should be considered. Positive family history (previous venous thromboembolism in a brother / sister or parent at a relatively young age, e.g. before age 50). In case of suspected hereditary predisposition, the woman must consult a specialist before a decision is made on the use of any COC. Other medical conditions associated with VTE. Malignant neoplasm, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell anemia Older age Especially over the age of 35

• There is no consensus on the possible role of varicose veins and superficial thrombophlebitis in the onset or progression of venous thrombosis.

• The increased risk of thromboembolism in pregnancy and especially in the 6 weeks of the puerperium must be taken into account (for information on "Pregnancy and lactation" see section 4.6).

Symptoms of VTE (deep vein thrombosis and pulmonary embolism)

If symptoms occur, women should be instructed to seek urgent medical attention and inform the health care practitioner of the use of 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;

• excessive pain or tenderness in the leg, which may occur only when standing or walking;

• excessive heat in the affected leg; redness or discolouration of the skin of the leg.

Symptoms of pulmonary embolism (PE) can include:

• unexplained wheezing or rapid breathing of sudden onset;

• sudden cough, which may be associated with hemoptysis;

• stinging chest pain;

• severe feeling of lightheadedness or dizziness;

• rapid or irregular heartbeat.

Some symptoms (eg "wheezing", "cough") are not specific and may be misinterpreted as more common or less serious events (eg respiratory tract infections).

Other signs of vascular occlusion may include: sudden pain, swelling and a slight bluish discoloration of one "extremity.

If the occlusion affects the eye, symptoms may include painless blurring of vision, which can progress to loss of vision. Sometimes, vision loss can occur almost immediately.

Risk of arterial thromboembolism (ATE)

Epidemiological studies have associated the use of CHCs with an increased risk of arterial thromboembolism (myocardial infarction) or cerebrovascular accident (eg transient ischemic attack, stroke). Arterial thromboembolic events can be fatal.

Risk factors of ATE

The risk of arterial thromboembolic complications or a cerebrovascular accident in COC users increases in women with risk factors (see table). Zoely is contraindicated if a woman has a single serious risk factor or multiple risk factors for ATEs that carry a high risk of arterial thrombosis (see section 4.3). 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 which case her overall risk must be considered. If the balance of benefits and risks is considered negative no CHC should be prescribed (see section 4.3).

Table: Risk factors of ATE

Risk factor Comment Older age Especially over the age of 35 Smoking habit Women should be advised not to smoke if they wish to use a COC. Women over the age of 35 who continue to smoke should be strongly advised to use a different method of contraception. Hypertension Obesity (body mass index greater than 30 kg / m2) The risk increases considerably as the BMI increases. Particularly important in women with additional risk factors Positive family history (prior arterial thromboembolism in a sibling or parent, especially at a relatively young age, e.g. before age 50) In case of suspected hereditary predisposition, the woman must consult a specialist before a decision is made on the use of any COC. Migraine An increase in the frequency or severity of migraine during COC use (which may be prodromal to a cerebrovascular event) may be a reason to discontinue COC use immediately. Other medical conditions associated with adverse vascular events Diabetes mellitus, hyperhomocysteinemia, cardiac valvulopathy and atrial fibrillation, dyslipoproteinemia and systemic lupus erythematosus

Symptoms of ATE

If symptoms occur, women should be instructed to seek urgent medical attention and inform the health care practitioner of the use of a COC.

Symptoms of a cerebrovascular accident can include:

• sudden numbness or weakness in the face, arm or leg, especially on one side of the body;

• sudden difficulty walking, dizziness, loss of balance or coordination;

• sudden confusion or difficulty speaking or understanding;

• sudden visual difficulty affecting one or both eyes;

• sudden, severe or prolonged headache with no known cause;

• loss of consciousness or fainting with or without a seizure.

Temporary symptoms suggest that the event is a transient ischemic attack (transient ischaemic attack, TIA).

Symptoms of myocardial infarction (MI) can include:

• pain, discomfort, pressure, heaviness, sensation of constriction or tightness in the chest, arm or below the breastbone;

• discomfort radiating to the back, jaw, throat, arm, stomach;

• feeling of fullness, indigestion or choking;

- sweating, nausea, vomiting or dizziness;

• extreme weakness, anxiety or shortness of breath;

• rapid or irregular heartbeat.

Tumors

• An increased risk of cervical cancer in women using COCs for prolonged periods (> 5 years) has been reported in some epidemiological studies, but it is still controversial to what extent these data are attributable to other factors, such as. sexual behavior and the human papilloma virus (HPV). There are no epidemiological data on the risk of cervical cancer in users of Zoely.

• With the use of higher-dosed COCs (50 mcg ethinylestradiol), the risk of endometrial and ovarian cancer is reduced. It must be confirmed whether this also applies to COCs containing 17β-estradiol.

• A meta-analysis of 54 epidemiological studies showed that there is a slightly increased relative risk (RR = 1.24) of breast cancer diagnosis in women currently using COCs. The additional risk gradually disappears over 10 years after stopping the use of COCs. Because breast cancer is rare in women under 40 years of age, the higher number of breast cancer diagnoses in current and recent COC users is low in relation to the overall risk of breast cancer. in women who use or have used COCs tends to be generally in a clinically less advanced stage of the cancer diagnosed in women who have never used COCs. The observed increase in risk may be due to an earlier diagnosis of the cancer. in COC users, the biological effects of COCs or a combination of these two factors.

• In rare cases, benign liver tumors and, even more rarely, malignant liver tumors have been reported in COC users. In isolated cases, these tumors have caused life-threatening intra-abdominal haemorrhages. Hepatic cancer should therefore be considered in the differential diagnosis in the presence of severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage in COC users.

Other conditions

• Women with hypertriglyceridaemia or a family history of hypertriglyceridaemia may have an increased risk of pancreatitis when using COCs.

• Although small increases in blood pressure have been observed in many COC users, clinically relevant increases are rare. A correlation between COC use and clinical hypertension has not been established. However, if you develop clinically significant and lasting hypertension while using a COC, it is prudent for your doctor to stop taking the tablets and treat the hypertension. If appropriate, COC use can be resumed if normal blood pressure values ​​can be achieved with antihypertensive therapy.

• The onset or worsening of the following conditions has been reported both during pregnancy and during the use of COCs, but the evidence of a correlation with COC use is not conclusive: jaundice and / or itching related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; uremic-haemolytic syndrome; Sydenham's chorea; gestational herpes; hearing loss related to otosclerosis.

• In women with hereditary angioedema, exogenous estrogens can induce or exacerbate the symptoms of angioedema.

• The presence of acute or chronic liver dysfunction may make it necessary to discontinue use of COCs until markers of liver function return to normal. A recurrence of cholestatic jaundice that occurred for the first time during pregnancy or previous use of sex steroids makes it necessary to discontinue use of combined oral contraceptives.

• Although COCs may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to change the treatment regimen in diabetic women using low-dose combined oral contraceptives (containing

• Worsening of depression, Crohn's disease and ulcerative colitis have been associated with the use of COCs.

• Chloasma may occasionally occur, particularly in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while using COCs.

• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Medical examination / consultation

Before initiating or resuming use of Zoely, a full medical history (including family history) should be taken and a pregnancy excluded. Blood pressure should be measured and a physical examination taking into account contraindications ( see section 4.3) and warnings (see section 4.4). It is important to draw a woman's attention to information regarding venous and arterial thrombosis, including the risk associated with Zoely compared to the risk associated with other CHCs, symptoms of VTE and ATE. , the known risk factors and the measures to be taken in case of suspected thrombosis.

The woman should also be instructed to read the package leaflet carefully and to follow the instructions. The frequency and nature of examinations should be based on standard guidelines and tailored to the individual needs of each woman.

Women should be advised that hormonal contraceptives do not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Reduced effectiveness

The efficacy of COCs may be reduced, for example, in case of forgotten tablets (see section 4.2), gastrointestinal disturbances while taking active ingredients (see section 4.2) or concomitant treatments with other medicinal products (see section 4.5). ).

Control of the cycle

With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, particularly in the first months of use. Therefore, the assessment of any irregular blood loss is only meaningful after an adaptation interval of approximately 3 cycles. The percentage of Zoely users who experienced menstrual bleeding after this adaptation period was 15-20%.

If irregularities persist or occur after previously regular cycles, non-hormonal causes must be considered and adequate diagnostic procedures are indicated to rule out the presence of malignancy or pregnancy. A curettage may be required.

In Zoely users, the duration of withdrawal bleeds averages 3-4 days. In users of Zoely it is also possible that withdrawal bleeding may not occur, even though they are not pregnant. In clinical studies, withdrawal bleeding was absent in cycles 1-12 in 18-32% of cases. In such cases, the absence of withdrawal bleeding was not associated with an increased frequency of breakthrough bleeding / spotting in subsequent cycles. 4.6% of women did not experience withdrawal bleeding in the first three cycles of use, and in this subgroup absence of withdrawal bleeding in subsequent cycles was frequent, ranging from 76% to 87% of women. 28% of women did not experience withdrawal bleeding in at least one of cycles 2, 3 and 4, associated with a more frequent "absence of withdrawal bleeding in subsequent cycles, ranging from 51% to 62%."

If withdrawal bleeding is absent and Zoely has been taken according to the instructions described in section 4.2, it is unlikely that the woman is pregnant. However, pregnancy must be ruled out before continuing Zoely use if Zoely has not been taken as prescribed or if there are no two consecutive withdrawal bleeds.

Pediatric population

It is not known whether the amount of estradiol contained in Zoely is sufficient to maintain adequate estradiol levels in adolescents, particularly with regard to bone mass acquisition (see section 5.2).

04.5 Interactions with other medicinal products and other forms of interaction

Interactions

Interactions of other medicines with Zoely

Interactions between oral contraceptives and enzyme-inducing medicinal products can lead to bleeding and even contraceptive failure.

Examples of active substances that induce liver enzymes and thereby increase the clearance of sex hormones include: phenytoin, phenobarbital, primidone, bosentan, carbamazepine, rifampicin and medicinal or herbal preparations containing St. John's wort and, to a lesser extent, oxcarbazepine , topiramate, felbamato and griseofulvin. HIV protease inhibitors that have induction potential (e.g. ritonavir and nelfinavir) and non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine and efavirenz) may also affect hepatic metabolism.

With liver enzyme-inducing substances, a barrier method should be used during co-administration of medicinal products and for 28 days following their discontinuation. In case of prolonged treatment with liver enzyme inducing substances, an alternative method of contraception should be considered.

No interaction studies have been performed with Zoely, but two studies with rifampicin and ketoconazole, respectively, were performed with a high-dose combination of nomegestrol acetate-estradiol (nomegestrol acetate 3.75 mg + 1.5 mg estradiol) in women in post-menopause. Concomitant use of rifampicin reduces the AUC0-∞ of nomegestrol acetate by 95% and increases the AUC0-tlast of estradiol by 25%. Concomitant use of ketoconazole (200 mg single dose) does not alter the metabolism of estradiol, but increases of no clinical relevance in peak concentration (85%) and AUC0-∞ (115%) of nomegestrol acetate were observed. Similar conclusions are expected in women of childbearing potential.

Effects of Zoely on other medicinal products

Oral contraceptives can alter the metabolism of other medicines. Particular attention should be paid to the interaction with lamotrigine.

Diagnostic tests

The use of contraceptive steroids may affect the results of certain diagnostic tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins, eg. Of globulin that binds corticosteroids and fractions lipid / lipoprotein parameters, carbohydrate metabolism parameters, and coagulation and fibrinolysis parameters Variations are generally within normal laboratory ranges.

04.6 Pregnancy and breastfeeding

Pregnancy

Zoely is not indicated during pregnancy.

If pregnancy occurs while taking Zoely, further intake should be stopped. Most epidemiological studies have revealed neither an increased risk of birth defects in children of women who used combined oral contraceptives containing ethinylestradiol before pregnancy, nor a teratogenic effect in case of accidental intake of combined oral contraceptives containing ethinyl estradiol in early pregnancy.

Clinical data on a limited number of exposed pregnancies indicate no adverse effects of Zoely on the fetus or neonate.

In animal studies, reproductive toxicity was observed with the combination nomegestrol acetate / estradiol (see preclinical safety data in section 5.3).

The increased risk of VTE in the postpartum period should be considered when resuming Zoely use (see sections 4.2 and 4.4).

Feeding time

Small amounts of the contraceptive steroids and / or their metabolites may be excreted in breast milk, but there is no evidence of adverse effects on the baby's health.

Breastfeeding can be influenced by COCs, because they can reduce the quantity and change the composition of breast milk. Therefore, the use of COCs should not be recommended until complete weaning and for women wishing to breastfeed it should be proposed an alternative method of contraception.

Fertility

Zoely is indicated for the prevention of pregnancy. For information on restoring fertility, see section 5.1.

04.7 Effects on ability to drive and use machines

No studies on the ability to drive or use machines have been performed with Zoely. However, no effects on ability to drive and use machines have been observed in COC users.

04.8 Undesirable effects

Summary of the safety profile

Six multicenter clinical trials of up to one year duration were conducted to evaluate the safety of Zoely. A total of 3,434 women between the ages of 18 and 50 were enrolled and completed 33,828 cycles.

Description of selected adverse reactions

An increased risk of arterial and venous thrombotic and thromboembolic events, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis and pulmonary embolism, has been observed in COC users; such events are discussed in more detail in section 4.4.

Summary table of adverse reactions

Possibly related adverse reactions that have been observed with Zoely in clinical studies or during use post-marketing are listed in the following table.

All adverse reactions are listed by system organ class and frequency; very common (≥ 1/10), common (≥ 1/100,

System and organ classification Adverse reaction according to MedDRA terminology1 Very common common Uncommon Rare Metabolism and nutrition disorders increased appetite, water retention decreased appetite Psychiatric disorders decreased libido, depression / depressed mood, mood changes increased libido Nervous system disorders headache, migraine cerebrovascular accident, transient ischemic attack, attention disturbance Eye disorders contact lens intolerance / dry eye Vascular pathologies hot flashes venous thromboembolism Gastrointestinal disorders nausea abdominal distension dry mouth Hepatobiliary disorders cholelithiasis, cholecystitis Skin and subcutaneous tissue disorders acne hyperhidrosis, alopecia, itching, dry skin, seborrhea chloasma, hypertrichosis Musculoskeletal and connective tissue disorders feeling of heaviness Diseases of the reproductive system and breast Abnormal withdrawal bleeding metrorrhagia, menorrhagia, breast pain, pelvic pain hypomenorrhea, breast swelling, galactorrhea, uterine spasm, premenstrual syndrome, breast mass, dyspareunia, vulvovaginal dryness vaginal odor, vulvovaginal discomfort General disorders and administration site conditions irritability, edema hunger Diagnostic tests weight gain increased liver enzymes

1 The MedDRA term that best describes a given adverse reaction is listed in the "list. Synonyms or related conditions do not appear in the" list, but must be considered.

In addition to the adverse reactions listed above, hypersensitivity reactions have been reported in users of Zoely (frequency not known).

Reporting of suspected adverse reactions

The reporting of suspected adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any adverse reactions via the Italian Medicines Agency

Website:

http://www.agenziafarmaco.gov.it/it/responsabili

04.9 Overdose

Multiple maximum doses of five times the daily dose of Zoely and maximum single doses of 40 times the daily dose of nomegestrol acetate alone have been used in women with no safety concerns. Based on the overall experience with COCs, symptoms that may occur are nausea, vomiting and, in girls, mild vaginal blood loss. There is no antidote and treatment should be symptomatic.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: sex hormones and modulators of the genital system, progestogens and estrogens, fixed combinations, ATC code: G03AA14.

Nomegestrol acetate is a highly selective progestin, derived from progesterone, a naturally occurring steroid hormone. Nomegestrol acetate exhibits "high affinity for the human progesterone receptor and possesses" anti-gonadotropic activity, "progesterone receptor-mediated anti-estrogenic activity, moderate anti-androgenic activity, and is devoid of any estrogenic activity," androgenic, glucocorticoid or mineralocorticoid.

The estrogen contained in Zoely is 17β-estradiol, a natural estrogen identical to the endogenous human 17β-estradiol.

The contraceptive effect of Zoely is based on the interaction of various factors, the most important of which are considered the inhibition of ovulation and changes in cervical secretion.

In two randomized, open-label, comparative efficacy-safety studies, over 3,200 women were treated for up to 13 consecutive cycles with Zoely and over 1,000 women with drospirenone 3 mg "." ethinyl estradiol 30 mcg (regimen 21/7).

Acne in the Zoely group was reported in 15.4% of women (vs.7.9% in the comparison group), weight gain in 8.6% of women (vs.5.7% in the comparison group) and abnormal withdrawal bleeding (mainly absence of withdrawal bleeding) in 10.5% of women (versus 0.5% in the comparator group).

In the clinical study conducted with Zoely in the European Union, the following Pearl indices were determined for the age group between 18 and 35 years:

Method Failure: 0.40 (upper limit 95% confidence interval 1.03)

Failure of the method and user error: 0.38 (upper limit 95% confidence interval 0.97)

In the clinical study conducted with Zoely in the United States, the following Pearl indices were determined for the age group between 18 and 35 years:

Method failure: 1.22 (upper limit 95% confidence interval 2.18)

Method failure and user error: 1.16 (upper limit 95% confidence interval 2.08)

In a randomized, open-label study, 32 women were treated for 6 cycles with Zoely.

After stopping Zoely, a resumption of ovulation was observed in 79% of women in the first 28 days following the last tablet taken.

In a clinical study, endometrial histology was evaluated in a subgroup of women (n = 32) after 13 cycles of treatment. No abnormal results were found.

Pediatric population

No efficacy and safety data are available in adolescents under 18 years of age. Available pharmacokinetic data are described in section 5.2.

05.2 Pharmacokinetic properties

Nomegestrol acetate

Absorption

Orally administered nomegestrol acetate is rapidly absorbed.

Maximum plasma concentrations of nomegestrol acetate, approximately 7 ng / ml, are reached 2 hours after single administration. The absolute bioavailability of nomegestrol acetate after a single dose is 63%. No clinically relevant effects were observed with food intake on the bioavailability of nomegestrol acetate.

Distribution

Nomegestrol acetate is extensively bound to albumin (97-98%), but does not bind to sex hormone binding globulin (Sex Hormone Binding Globulin, SHBG) or corticoid-binding globulin (Corticoid Binding Globulin, CBG). The apparent volume of distribution of nomegestrol acetate at steady state is 1,645 ± 576 l.

Biotransformation

Nomegestrol acetate is metabolised to many inactive hydroxylated metabolites by hepatic cytochrome P450 enzymes, mainly CYP3A4 and CYP3A5, with possible contributions from CYP2C19 and CYP2C8. Nomegestrol acetate and its hydroxylated metabolites undergo extensive phase 2 metabolism, with the formation of glucurone and sulfate conjugates. The apparent steady-state clearance is 26 l / h.

Elimination

The elimination half-life (t & 1frac12;) is 46 h (range 28-83 h) at steady state. The elimination half-life of the metabolites has not been determined.

Nomegestrol acetate is excreted in the urine and faeces. Approximately 80% of the dose is excreted in the urine and faeces within 4 days.The excretion of nomegestrol acetate was almost complete after 10 days and the quantities excreted were higher in the faeces than in the urine.

Linearity

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

Steady state conditions

The pharmacokinetics of nomegestrol acetate are not affected by SHBG.

Steady state is reached after 5 days. Maximum plasma concentrations of nomegestrol acetate, approximately 12 ng / ml, are reached 1.5 h after administration. Mean steady-state plasma concentrations are 4 ng / mL.

Drug interactions

In vitro, nomegestrol acetate does not cause significant induction or inhibition of cytochrome P450 enzymes and has no clinically relevant interactions with the P-gp transport protein.

Estradiol

Absorption

Estradiol is subject to a marked first pass effect after oral administration. Absolute bioavailability is approximately 1%. No clinically relevant effects were observed with food intake on the bioavailability of estradiol.

Distribution

The distribution of exogenous and endogenous estradiol is similar. Estrogens are widely distributed in the body and generally present in higher concentrations in the target organs of sex hormones. Estradiol circulates in the blood bound to SHBG (37%) and albumin (61%), while only about 1-2% is free.

Biotransformation

Orally administered exogenous estradiol is extensively metabolised. The metabolism of exogenous and endogenous estradiol is similar. Estradiol is rapidly transformed in the intestine and liver into many metabolites, mainly estrone, which are subsequently conjugated and enter the enterohepatic circulation. There is a dynamic equilibrium between estradiol, estrone and estrone-sulfate due to different enzymatic activities including estradiol-dehydrogenase, sulfotransferase and aryl sulfatase. The oxidation of estrone and estradiol is due to cytochrome P450 enzymes, mainly CYP1A2, CYP1A2 (extrahepatic), CYP3A4, CYP3A5, CYP1B1 and CYP2C9.

Elimination

Estradiol is rapidly cleared from the circulation. Due to metabolism and enterohepatic circulation there is a large circulating pool of estrogen sulfates and glucuronides. This results in a highly variable elimination half-life of estradiol corrected at baseline, which is equal to 3, 6 ± 1.5 h following intravenous administration.

Steady state conditions

The maximum serum concentrations of estradiol amount to approximately 90 pg / ml and are reached 6 hours after administration. The mean serum concentrations are 50 pg / ml and these estradiol levels correspond to the early and late phase of the menstrual cycle.

Special populations

Pediatric population

The pharmacokinetics of nomegestrol acetate (primary endpoint) following a single oral dose of Zoely were similar in healthy post-menarche adolescents and adult subjects. However, after a single oral dose, exposure for the estradiol component (secondary objective) was 36% less in adolescents compared to adults. The clinical relevance of this finding is unknown.

Effects of renal impairment

No studies have been performed to determine the effects of kidney disease on Zoely pharmacokinetics.

Effects of hepatic impairment

No studies have been performed to determine the effects of liver disease on Zoely pharmacokinetics. However, steroid hormones may be poorly metabolised in women with hepatic impairment.

Ethnic groups

No formal studies have been performed to determine pharmacokinetics in ethnic groups.

05.3 Preclinical safety data

Repeat dose toxicity studies with estradiol, nomegestrol acetate or the combination showed the expected effects of estrogen and progestogen.

Reproductive toxicity studies performed with the combination have shown fetal toxicity compatible with exposure to estradiol.

Genotoxicity and carcinogenicity studies have not been conducted with the combination. Nomegestrol acetate is not genotoxic.

However, it must be remembered that sex steroids can promote the proliferation of certain hormone-dependent tissues and tumors.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Tablet core (white active film-coated tablets and yellow placebo film-coated tablets)

Lactose monohydrate

Microcrystalline cellulose (E460)

Crospovidone (E1201)

Talc (E553b)

Magnesium stearate (E572)

Anhydrous colloidal silica

Tablet coating (white active film-coated tablets)

Poly (vinyl alcohol) (E1203)

Titanium dioxide (E171)

Macrogol 3350

Talc (E553b)

Tablet coating (yellow placebo film-coated tablets)

Poly (vinyl alcohol) (E1203)

Titanium dioxide (E171)

Macrogol 3350

Talc (E553b)

Yellow iron oxide (E172)

Black iron oxide (E172)

06.2 Incompatibility

Not relevant.

06.3 Period of validity

3 years

06.4 Special precautions for storage

This medicine does not require any special storage conditions.

06.5 Nature of the immediate packaging and contents of the package

PVC / aluminum blister containing 28 film-coated tablets (24 white film-coated tablets and 4 yellow film-coated tablets).

Pack sizes: 28, 84, 168 and 364 film-coated tablets.

Not all pack sizes may be marketed.

06.6 Instructions for use and handling

COC tablets (including Zoely tablets) that are no longer needed should not be disposed of via wastewater or household waste. The hormonally active substances contained in the tablet may have harmful effects if they reach the aquatic environment. The tablets must be returned to the pharmacy or disposed of otherwise safely in accordance with local regulations. This will help protect the environment.

07.0 MARKETING AUTHORIZATION HOLDER

Teva B.V.

Swensweg 5

2031 GA Haarlem

Netherlands

08.0 MARKETING AUTHORIZATION NUMBER

EU / 1/11/690/001

EU / 1/11/690/002

EU / 1/11/690/003

EU / 1/11/690/004

041400019

041400021

041400033

041400045

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

Date of first authorization: 27 July 2011

10.0 DATE OF REVISION OF THE TEXT

May 2015

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL