Miranova - Package Leaflet

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

Active ingredients: Levonorgestrel, Ethinylestradiol

Miranova 0.1 mg + 0.02 mg coated tablets

Why is Miranova used? What is it for?

Miranova is a combined hormonal contraceptive (COC) used to prevent pregnancy.

Each tablet contains a small amount of two different female hormones, levonorgestrel and ethinylestradiol (pharmacotherapeutic group of progestogens and estrogens).

Contraceptive pills that contain two hormones are called "combination pills".

Contraindications When Miranova should not be used

Do not take Miranova

• if you are allergic to levonorgestrel, ethinyl estradiol or any of the other ingredients of this medicine; Do not use Miranova if you have any of the conditions listed below. If you have any of the conditions listed below, talk to your doctor. Your doctor will discuss this with you. other birth control methods that may be more suitable for you.
• if you have (or have ever had) a blood clot in a blood vessel of the leg (deep vein thrombosis, DVT), lung (pulmonary embolism, PE) or other organs;
• if you know you have a disorder that affects blood clotting, such as protein C deficiency, protein S deficiency, antithrombin-III deficiency, factor V Leiden or antiphospholipid antibodies;
• if you are going to have an "operation or if you will lie down for a long time (see section" Blood clots ");
• if you have ever had a heart attack or stroke;
• if you have (or have ever had) angina pectoris (a condition that causes severe chest pain and may be a first sign of a heart attack) or transient ischemic attack (TIA - temporary stroke symptoms);
• if you have any of the following diseases, which could increase the risk of blood clots in the arteries: severe diabetes with damage to the blood vessels, very high blood pressure, very high level of fat (cholesterol or triglycerides) in the blood, a a disease known as hyperhomocysteinemia (high amount of homocysteine ​​in the blood);
• if you have (or have ever had) a type of migraine called 'migraine with aura';
• if you have vascular eye diseases;
• if you have or have ever had jaundice (yellowing of the skin) or severe liver disease; in this case, do not use Miranova until the liver function values ​​have returned to normal;
• if you have or have ever had breast or genital cancer
• if you have or have ever had benign or malignant liver cancer;
• if you have vaginal bleeding of unknown origin;
• if you are or suspect that you are pregnant;
• in combination with Ritonavir (antiviral medicine).

If any of these conditions appear for the first time while using the medicine, stop taking it immediately and consult your doctor. In the meantime, use non-hormonal methods of contraception. See also "General Notes".

Precautions for use What you need to know before taking Miranova

Talk to your doctor or pharmacist before taking Miranova.

General notes

Before you start taking Miranova you should read the information on blood clots in the section "Blood clots". It is especially important to read the symptoms of a blood clot (see section "Blood clots").

Before starting or restarting to take Miranova it is advisable to carry out a thorough medical examination and pregnancy must be excluded. It is also advisable to carry out periodic check-ups, at least once a year, during the use of the medicine. the type of visit, will be established by the doctor and aimed in particular at the control of blood pressure, a breast, abdomen and general gynecological examination including a Pap test and relative blood tests.

Like all contraceptive pills, Miranova does not protect against HIV infection (AIDS) or any other sexually transmitted disease.

Miranova is prescribed for personal use and must not be available to several people at the same time.

When to be especially careful with Miranova

When should you see a doctor?

Contact a doctor urgently

if you notice possible signs of a blood clot which may indicate that you are suffering from a blood clot in the leg (deep vein thrombosis), a blood clot in the lung (pulmonary embolism), a heart attack or stroke (see following paragraph "Blood clot (thrombosis)").

For a description of the symptoms of these serious side effects go to the section "How to recognize a blood clot".

In this leaflet, some situations are described in which it is necessary to stop taking the medicine or in which there may be a reduction in the effectiveness of the medicine. In such situations you should not have sex or you should take extra non-hormonal contraceptive precautions such as the use of condoms or other barrier methods. Do not use rhythm and basal temperature methods, which can be unreliable, as the pill alters the normal changes in temperature and cervical mucus that occur during the menstrual cycle.

If you have any of the conditions listed below, the use of the combined pill may require close supervision by your doctor. Warn your doctor of any of the conditions listed below before you start using Miranova. Your doctor may recommend a different (non-hormonal) method of contraception.

Tell your doctor if any of the following apply to you. If this condition appears or worsens while you are taking Miranova you should tell your doctor.

• smoke;
• diabetes;
• overweight;
• increased blood pressure (hypertension);
• heart valve defects or certain heart rhythm disturbances;
• superficial phlebitis (inflammation of the veins);
• varicose veins;
• history of thrombosis, heart attack or stroke (including in close family members);
• migraine (one-sided headache);
• depression;
• epilepsy (see "Other medicines and Miranova");
• a history of high levels of cholesterol and triglycerides (fats) in the blood (including in close family members);
• breast lumps;
• family history of breast cancer;
• liver or gallbladder disease;
• porphyria (metabolic blood abnormality);
• if you suffer or have suffered from current or previous chloasma (yellow-brown spots on the skin, especially on the face). If so, avoid prolonged exposure to the sun or ultraviolet rays;
• if you have suffered from herpes gestationis (autoimmune skin disease affecting women during pregnancy or in the immediate postpartum period);
• some pathological conditions characterized by resistance to Activated Protein C, hyperhomocysteinemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant), which predispose to the onset of venous or arterial thrombosis;
• Sydenham's chorea (central nervous system disorder);
• hearing loss from otosclerosis.
• if you have hereditary angioedema, estrogen-containing medicines can induce or aggravate the symptoms of angioedema. If you notice symptoms of angioedema such as swelling of the face, tongue and / or pharynx and / or difficulty in swallowing or hives with difficulty in breathing , tell your doctor immediately.
• 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 natural defense system);
• if you have haemolytic uremic syndrome (HUS, a blood clotting disorder that causes impaired kidney function);
• 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 of this condition." Hypertriglyceridaemia has been associated with an increased risk of developing pancreatitis (inflammation of the pancreas);
• if you are going to have an "operation or if you will lie down for a long time (see section" Blood clots ");
• if you have just given birth, your risk of developing blood clots is higher. Ask your doctor how long after having a baby you can start taking Miranova;
• if you have "inflammation of the veins under the skin (superficial thrombophlebitis);
• if you have varicose veins.

In case of first appearance, recurrence or worsening of any of the above conditions while using the pill, consult your doctor.

Do not take St. John's wort (Hypericum perforatum) preparations simultaneously with medicines containing oral contraceptives, digoxin, theophylline, carbamazepine, phenobarbital, phenytoin due to the risk of decreased blood levels and decreased therapeutic efficacy of oral contraceptives, digoxin, theophylline, carbamazepine, phenobarbital, phenytoin (see "Other medicines and Miranova").

BLOOD CLOTS

Using a combined hormonal contraceptive such as Miranova increases your risk of developing a blood clot compared with not using one. In rare cases, a blood clot can block blood vessels and cause serious problems. Blood clots can develop.

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

Healing from blood clots is not always complete. Rarely, long-lasting severe effects can occur or, very rarely, they can be fatal.

It is important to remember that the overall risk of a harmful blood clot associated with Miranova is low.

HOW TO RECOGNIZE A BLOOD CLOT

See a doctor immediately if you notice any of the following signs or symptoms.

Do you have any of these signs? What are you probably suffering from? Swelling of one leg or along a vein in the leg or foot, especially when accompanied by:

• pain or tenderness in the leg which may only be felt when standing or walking
• increased sensation of heat in the affected leg
• change in color of the skin on the leg, such as turning pale, red or blue.

Deep vein thrombosis

• shortness of breath or sudden, unexplained rapid breathing;
• sudden cough with no obvious cause, possibly causing blood to be emitted;
• sharp chest pain which may increase with deep breathing;
• severe light headedness or dizziness;
• rapid or irregular heartbeat;
• severe pain in the stomach

If you are unsure, tell your doctor as some of these symptoms such as coughing or shortness of breath may be mistaken for a milder condition such as a "respiratory infection (eg a" common cold "). Pulmonary embolism Symptoms that occur most frequently in one eye:

• immediate loss of vision or
• painless blurring of vision which can progress to loss of vision

Retinal vein thrombosis (blood clot in the eye)

• chest pain, discomfort, feeling of pressure or heaviness;
• sensation of squeezing or fullness in the chest, arm or below the breastbone;
• feeling of fullness, indigestion or choking;
• upper body discomfort radiating to the back, jaw, throat, arms and stomach;
• sweating, nausea, vomiting or dizziness;
• extreme weakness, anxiety, or shortness of breath;
• rapid or irregular heartbeats.

Heart attack

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

Stroke symptoms can sometimes be brief, with almost immediate and complete recovery, but you still need to see a doctor urgently as you may be at risk for another stroke. Stroke

• swelling and pale blue discoloration of one "extremity;
• severe stomach pain (acute abdomen).

Blood 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 linked to an increased risk of blood clots forming in the veins (venous thrombosis). However, these side effects are rare. In most cases they occur in the first year of use. of 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 can form in another organ such as the eye (retinal vein thrombosis).

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

The risk of developing a blood clot in a vein is highest during the first year of taking a combined hormonal contraceptive for the first time. The risk may be even higher if you restart taking a combined hormonal contraceptive (the same medicine or a different medicine) after a break of 4 or more weeks.

After the first year, the risk is reduced but is always slightly higher than if you were not using a combined hormonal contraceptive.

When you stop taking Miranova, the risk of developing a blood clot returns to normal within a few weeks.

What is the risk of developing a blood clot?

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 Miranova is low.

• Out of 10,000 women who are not using any combined hormonal contraceptive and who are not pregnant, about 2 will develop a blood clot in a year.
• Out of 10,000 women who are using a combined hormonal contraceptive that contains levonorgestrel, norethisterone or norgestimate such as Miranova, about 5-7 will develop a blood clot in a year.
• The risk of a blood clot developing depends on your medical history (see under "Factors that increase the risk of a blood clot forming").

Risk of developing a blood clot in one year Women who are not using a combined hormone pill / patch / ring 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 Miranova About 5-7 out of 10,000 women

Factors that increase the risk of developing a blood clot in a vein The risk of developing a blood clot with Miranova is low but some conditions increase the risk. Its risk is greater:

• if you are severely overweight (body mass index or BMI over 30 kg / m2);
• if a close relative has had a blood clot in the leg, lung or other organ at a young age (less than about 50 years). In this case you could have an inherited blood clotting disorder;
• if you are going to have an operation or if you have to lie down for a long time because of an injury or illness or if you have a leg in a cast. You may need to stop taking Miranova a few weeks before the surgery or during the period when you are less mobile. If you have to stop taking Miranova ask your doctor when you can start taking it again;
• as you get older (especially over the age of 35);
• if you gave birth less than a few weeks ago.

The risk of developing a blood clot increases the more conditions you have. Air travel (longer than 4 hours) can temporarily increase the risk of a blood clot, especially if you have some of the other risk factors listed. It is important that you tell your doctor if any of these apply to you, even if you are not sure. Your doctor may decide to have you stop taking Miranova. If any of the above conditions change while you are using Miranova, for example if a close relative has a thrombosis for no known reason or if you gain a lot of weight, contact your doctor. .

BLOOD CLOTS IN AN ARTERY

What can happen if a blood clot forms in an "artery?"

Like blood clots in a vein, clots in an artery can cause serious problems, for example, they can cause a heart attack or stroke.

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

It is important to note that the risk of heart attack or stroke associated with the use of Miranova is very low but can increase:

• with increasing age (over 35 years);
• if you smoke. When using a combined hormonal contraceptive like Miranova you are advised to 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 (less than about 50 years). In this case, you may also be at high risk of having a heart attack or stroke;
• if you or a close relative have a high level of fat in the blood (cholesterol or triglycerides);
• if you suffer from migraines, especially migraines with aura;
• if you have heart problems (valve defect, a heart rhythm disorder called atrial fibrillation);
• if you have diabetes.

If you have more than one of these conditions or if any of them are particularly severe, the risk of developing a blood clot may be even higher.

If any of the above conditions change while you are using Miranova, for example if you start smoking, if a close relative has a thrombosis for no known reason, or if you gain a lot of weight, contact your doctor.

Tumors

Breast cancer diagnoses are slightly more common in women who use the pill than in those of the same age who do not. The slight increase in the number of breast cancer diagnoses gradually disappears over the 10 years following discontinuation of treatment. It is not known if the difference is due to the pill. This increase may be due to earlier diagnosis, as women are seen more frequently, the biological effect of the pill, or both. Breast cancer diagnosed in women taking the pill tends to be less clinically advanced than breast cancer. diagnosed in women who do not use it. Benign liver tumors and even more rarely malignant liver tumors have been reported in women taking the Pill. These tumors can cause internal bleeding. abdomen. Cancer of the neck of the uterus (cervix) has been reported to be more common in women who use the pill for a long time. genesis of tumors in general.

Periodic checks

While using the pill, your doctor will ask you to come to periodic check-ups, usually every year.

See your doctor as soon as possible:

• if you notice any changes in your state of health, in particular as reported in this leaflet (see also "Do not use Miranova" and "Warnings and precautions". Do not forget the references to close family members);
• if you feel a lump in your breast;
• if you need to use other medicines (see also "Other medicines and Miranova");
• if you are immobilized or need to have surgery (consult your doctor at least four weeks before);
• if you have severe and unusual vaginal bleeding;
• if you forgot to take the tablets in the first week of use and had sex in the seven days prior to the forgetfulness;
• if you do not have a period for two consecutive cycles or if you suspect a pregnancy, do not start a new pack without your doctor's permission.

Stop taking the tablets and consult your doctor immediately if you notice possible signs of thrombosis:

• cough that starts suddenly;
• severe pain in the chest that may radiate to the left arm;
• sudden shortness of breath;
• unusual, severe, prolonged headache or migraine attack;
• partial or total loss of vision or double vision;
• slurred speech or inability to speak;
• sudden changes in hearing, smell and taste;
• feeling dizzy or faint;
• weakness or numbness of any part of the body;
• severe abdominal pain;
• severe pain or swelling in one leg.

The above situations and symptoms are illustrated and explained in more detail in other sections of this leaflet.

Children and adolescents

The safety and efficacy of Miranova in children and adolescents below 18 years of age have not been established. There are no data available.

Patients with hepatic (liver) impairment

Do not take Miranova if you have liver disease. See "Do not use Miranova" and "Warnings and precautions".

Patients with renal (kidney) impairment

Miranova has not been specifically studied in patients with impaired kidney function.

Interactions Which drugs or foods can change the effect of Miranova

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Some medicines can prevent the pill from working effectively. These include:

• primidone, phenytoin, barbiturates, carbamazepine, oxycarbamazepine, topiramate, felbamate (used to treat epilepsy),
• rifampicin and rifabutin (used to treat tuberculosis),
• ritonavir, nevirapine (used to treat HIV infections and hepatitis C),
• modafinil (used to treat excessive sleepiness associated with narcolepsy) and flunarizine,
• griseofulvin and azole antifungals, such as itraconazole, voriconazole, fluconazole (used to treat fungal infections),
• macrolide antibiotics such as clarithromycin, erythromycin (used to treat bacterial infections),
• calcium channel blockers such as verapamil and diltizem (used to treat certain heart conditions and high blood pressure),
• etoricoxib (used in the treatment of arthritis, osteoarthritis).

Miranova may interfere with the way some other medicines work, such as:

• medicines containing cyclosporine (used to prevent transplant rejection reactions),
• lamotrigine (used to treat epilepsy),
• melatonin (a hormone)
• midazolam (sedative),
• theophylline (used to widen the airways),
• tizanidine (used to dilate muscles).

Do not take St. John's wort preparations Hypericum perforatum at the same time as oral contraceptives, as this could lead to a loss of contraceptive efficacy. Unwanted pregnancies and resumption of menstruation have been reported. This is due to the induction of enzymes responsible for the metabolism of medicines. by the preparations based on Hypericum perforatum. The induction effect may persist for at least 2 weeks after stopping treatment with Hypericum perforatum products (see "Miranova with food and drink").

Troleandomycin (macrolide antibiotic) may increase the risk of intrahepatic cholestasis (inability of bile to flow from the liver to the duodenum) when administered concomitantly with COCs.

Always tell the doctor who prescribes the pill about the medicines you are already taking, and also tell any other doctors or dentists who prescribe other medicines that you are using Miranova, so they can determine if and for how long it is needed. use additional contraceptive methods.

Using the pill can affect the results of some blood tests, but these changes are usually within the normal range. Therefore, it is advisable to inform the doctor who requested the tests that you are taking the pill.

Miranova with food and drink

Do not take Miranova with grapefruit juice.

While taking oral contraceptives, do not take Hypericum perforatum preparations. Taking it at the same time may lead to a loss of contraceptive efficacy (see "Other medicines and Miranova").

Warnings It is important to know that:

Pregnancy and breastfeeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.

Do not use Miranova if you are pregnant or suspected of being pregnant. If you become pregnant while using Miranova, stop using the medicine immediately.

Miranova is not recommended during breastfeeding. Small amounts of contraceptive steroids and / or their metabolites may be excreted in breast milk. These amounts may affect the baby.

Driving and using machines

Miranova has no or negligible influence on the ability to drive or use machines.

Miranova contains lactose and sucrose

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

Dosage and method of use How to use Miranova: Dosage

Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist. The Miranova pack contains 21 tablets, all marked with the day of the week on which each should be taken. Take the tablet at approximately the same time every day, with a little water if necessary. Follow the direction of the arrows until all 21 tablets have been used up. Do not take pills within the next 7 days, during which they should appear menstruation (withdrawal bleeding), which usually starts 2-3 days after taking the last Miranova tablet. Start the new pack on the eighth day, even if your period has not yet finished. Doing so will always start the new pack on the same day of the week and the withdrawal bleeding will always occur on approximately the same days of the week, every month. COCs, when taken correctly, have a 1% failure rate per year. The failure rate increases when pills are forgotten or not taken correctly.

Beginning of the first pack

• No hormonal contraceptive in the previous month You start taking Miranova on the first day of your period, which is the first day of your period, taking the tablet marked with that day of the week. For example, if your period starts on a Friday, take the pill marked with Friday. Then continue in the order indicated by the arrows. It can also start between the second and fifth day of the cycle, but in this case use an additional method of contraception (barrier method) for the first seven days of taking the tablets in the first cycle.
• Changing from another combined-type pill from a vaginal ring, or a patch You can start taking Miranova the day after the last pill of your previous contraceptive (ie without observing any interval). If your previous contraceptive pack also contains inactive tablets, you can take Miranova the day after the last active tablet (if in doubt, ask your doctor). It can also start later, but never later than the day after the tablet-free interval. (or the day after the last inactive tablet) of the previous contraceptive. If you have used a vaginal ring or patch, you should start using Miranova preferably on the day of removing the last ring or patch of a cycle, or at the latest. when the next application should be done.
• Changing from a progestogen-only pill (minipill) You can stop the minipill on any day and start taking Miranova the next day at the same time. However, in the first seven days of taking the tablets, you use an additional method of contraception (barrier method) when having intercourse.
• Changing from an injection or implantation contraceptive or a progestogen-releasing intrauterine system (IUS) You start using Miranova on the day you need your next injection or the day the implant is removed. However, in the first seven days. days of tablet-taking, use an additional method of contraception (barrier method) when having sex.
• After childbirth The start of taking the pill after childbirth must be determined by your doctor. He will decide whether to start the treatment in the period between the 21st and the 28th day, or later. In the latter case, it is advisable to use an additional barrier method during the first 7 days of taking the tablets. However, if you have had sexual intercourse in the meantime, before actually starting the pill, you must rule out pregnancy or wait for the first to appear. menstruation. If you are breastfeeding and want to take Miranova, talk to your doctor first (see "Pregnancy and breastfeeding").
• After a miscarriage or induced abortion Follow your doctor's prescription.

If you forget to take Miranova

• If less than 12 hours have passed since the time of usual intake, the reliability of the pill is maintained. Take the forgotten tablet as soon as you remember and continue as usual.
• If more than 12 hours have passed since the time of usual intake, the reliability of the pill may be reduced. The greater the number of consecutively forgotten tablets, the greater the risk of the contraceptive effect being reduced. The risk of pregnancy is particularly high if you forget pills at the beginning and at the end of the pack. Follow the instructions below (see also the diagram below).

More than one tablet forgotten in a pack. Consult your doctor.

One tablet forgotten in the first week

Take the tablet as soon as you remember (even if that means taking two tablets at the same time) and continue as usual. Use additional contraceptive methods (barrier method) for the next 7 days.

If you have had sexual intercourse in the week preceding the forgetfulness, there is a possibility that you have become pregnant. Tell your doctor immediately.

One tablet forgotten in the second week

Take the forgotten tablet as soon as you remember (even if that means taking two tablets at the same time) and continue as usual. The reliability of the pill is preserved. No additional contraceptive precautions need to be taken.

One tablet forgotten in week 3 You can choose one of the following alternatives, without the need for additional contraceptive precautions.

1. Take the forgotten tablet as soon as you remember (even if that means taking two tablets at the same time) and continue as usual. Start the new pack as soon as you finish the current one, with no gap between the two packs. Withdrawal bleeding may not occur until the second pack is finished, but intermenstrual bleeding (spotting) may occur during the days of intake. Or
2. Stop taking the tablets from the current pack, observe an interval of 7 days or less (also count the day of the missed pill) and continue with a new pack. If you choose this alternative, you can always start the new pack on the same day of the pack. week in which it usually starts.

If you forget to take one or more tablets and you do not have a period in the first pill-free interval, it is possible that you are pregnant. Consult your doctor before starting the new pack.

In case of gastrointestinal disturbances (e.g. vomiting and / or diarrhea)

If you vomit or have severe diarrhea within 3-4 hours of taking Miranova, it is possible that the active substance has not been completely absorbed. It is as if the tablet has been forgotten. Therefore, follow the instructions given in case of missed tablets.

Delayed menstruation: what you need to know

Although not recommended, it is possible to delay your period by continuing with a new pack of Miranova without observing the 7-day interval. You may experience breakthrough bleeding or spotting while using this second pack. Continue with the next pack after the usual 7-day interval.

Ask your doctor for advice before deciding to delay your period.

Changing the start day of your period: what you need to know If you take the tablets according to the instructions, your period will start around the same day of the week. If you have to change this day, you can shorten (never lengthen) the normal break between two packs For example, if your period usually starts on Friday and you want it to start on Tuesday (3 days earlier), you will need to start the next pack 3 days early. If you make the break between two cycles too short (for example 3 days or less), you may not have a period during this interval, in which case you may experience breakthrough bleeding or spotting during the next course of treatment.

Please ask your doctor if you are unsure how to proceed.

In case of unexpected bleeding

With all oral contraceptives, vaginal bleeding can occur in the first months of taking it between menstruation. Normally, irregular bleeding disappears once the body has become accustomed to the pill (usually after about 3 cycles of assumption).

Consult your doctor if such bleeding persists, becomes intense or recurs at intervals.

In case of missed menstruation

If all the tablets have been taken correctly, no vomiting has occurred or other medicines have been taken, it is very unlikely that you are pregnant. Continue using the medicine as usual.

If your period does not occur twice in a row, it is possible that you are pregnant.

Consult your doctor immediately. Do not start the new pack until your doctor has ruled out that you are pregnant.

If you stop taking Miranova

You can stop using Miranova at any time. If you do not want to become pregnant, consult your doctor about other methods of pregnancy control.

If you want to stop using Miranova because you want motherhood, talk to your doctor. In this case it is generally advisable to wait until your period is regular again before attempting to conceive.

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

Overdose What to do if you have taken too much Miranova

There have been no reports of serious side effects when taking several tablets at the same time. In this case, nausea, vomiting and mild vaginal bleeding may occur in young girls. In case of accidental ingestion / intake of an overdose of Miranova, notify your doctor immediately or go to the nearest hospital.

Side Effects What are the side effects of Miranova

Like all medicines, this medicine can cause side effects, although not everybody gets them. If you get any side effects, especially if they are severe or persistent, or if there is any change in your health that you think might be due to Miranova, please tell your doctor. An increased risk of developing blood clots in the veins (venous thromboembolism (VTE)) or blood clots in the arteries (arterial thromboembolism (ATE)) is present in all women taking combined hormonal contraceptives. For more detailed information on the different risks of "taking combined hormonal contraceptives, see" Warnings and precautions ".

Serious side effects

Serious side effects associated with the use of the pill, and related symptoms, are described in the sections “When to take special care with Miranova”, “Blood clots” and “Cancers.” For more information read these sections and consult your doctor immediately.

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

Common (may affect up to 1 in 10 people)

• nausea,
• abdominal pain,
• weight gain,
• headache,
• depressed mood,
• mood alteration,
• breast sensitivity,
• breast pain.

Uncommon (may affect up to 1 in 100 people)

• He retched,
• diarrhea,
• fluid retention,
• migraine (one-sided headache),
• decreased sexual desire,
• breast enlargement,
• skin reactions (rash, hives).

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

• contact lens intolerance,
• hypersensitivity reactions (allergy),
• weight reduction,
• increased sexual desire,
• breast discharge,
• vaginal discharge,
• skin diseases (erythema nodosum, erythema multiforme).
• harmful blood clots in a vein or artery, for example: in a leg, foot (DVT), lung (PE), heart attack, stroke, mini-stroke temporary symptoms similar to those of " stroke, known as a transient ischemic attack (TIA), blood clots in the liver, stomach / intestines, kidneys or eye.

The chance of developing a blood clot may be higher if you have any other conditions that increase this risk (see section "Warnings and precautions" for more information on conditions that increase the risk of blood clots and the symptoms of a blood clot) .

Other side effects:

• oligomenorrhea (increase in the time interval between one menstruation and the next),
• amenorrhea (absence of menstruation),
• intermenstrual bleeding.

In women with hereditary angioedema (a rare inherited disease characterized by swelling [edema] of the skin, mucous membranes and internal organs) exogenous estrogens (hormone replacement therapy) can induce or aggravate the symptoms of angioedema.

Compliance with the instructions contained in this leaflet reduces the risk of undesirable effects.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at www.agenziafarmaco.it/it/responsabili. By reporting 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 carton (blister, carton) after "EXP." The expiry date refers to the last day of that month. The expiry date refers to the unopened product, correctly stored.

Do not use the medicine if you notice a change in color or crumbling of the tablet, or if you have any other visible signs of deterioration.

Store at a temperature not exceeding 30 ° C. Store in the original package to protect the medicine from moisture.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Other Information

What Miranova contains

The active ingredients are: levonorgestrel and ethinyl estradiol. Each coated tablet contains 0.1 mg of levonorgestrel and 0.02 mg of ethinylestradiol.

The other ingredients are: lactose monohydrate, maize starch, pregelatinised starch, povidone 25, magnesium stearate, sucrose, povidone 90, macrogol 6,000, calcium carbonate, talc, glycerol 85%, titanium dioxide, red iron oxide (E172), oxide yellow iron (E172), ethylene glycol ester of montanic acid (E wax).

Description of what Miranova looks like and contents of the pack

Coated tablets for oral use

The product is packaged in a calendar blister containing 21 tablets.

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 Miranova 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

MIRANOVA 0.1 MG + 0.02 MG COATED TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains:

Active principles:

0.1 mg levonorgestrel, 0.02 mg ethinyl estradiol.

Excipients with known effects: lactose, sucrose

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Coated tablets.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Prevention of conception.

The decision to prescribe Miranova must take into account the individual woman's current risk factors, particularly those related to venous thromboembolism (VTE) and the comparison between the risk of VTE associated with Miranova and that associated with other combined hormonal contraceptives (COCs). (see sections 4.3 and 4.4).

04.2 Posology and method of administration

Method of administration

Oral use

Method of recruitment

COCs, when taken correctly, have a 1% failure rate per year. The failure rate increases when pills are forgotten or not taken correctly.

The tablets must be taken in the order indicated on the package, every day at the same time, if necessary with a little liquid; the dosage is one tablet per day for 21 consecutive days. Each subsequent pack should be started after a 7-day tablet-free interval during which a withdrawal bleed usually occurs. This usually starts 2-3 days after the last tablet and may not have finished before the next pack is started.

Methods of starting the treatment

No hormonal contraceptive treatment in the previous month

The intake of the tablets must begin on the first day of the natural menstrual cycle (ie the first day of menstruation). It is also possible to start between the second and fifth day of the cycle but, in this case, during the first cycle it is recommended to use also a barrier method in the first seven days of taking the tablets.

Changing from another hormonal contraceptive (combined oral contraceptive, vaginal ring or patch)

The first tablet should preferably be taken on the day after the last active tablet of the previous contraceptive or at the latest on the day after the usual tablet-free break or the day after the last placebo tablet of the previous contraceptive. In case of changing from a vaginal ring or a patch, the woman should start taking Miranova preferably on the day of the removal of the last ring or patch of a cycle of applications, or at the latest when the next application would have been scheduled.

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

The woman can change at any time if she is coming from the minipill, and she must start taking Miranova the next day. In the case of an implant, taking Miranova must start on the same day the implant is removed or, in the case of an implant. case of an injectable, on the day the next injection should be given. In all these cases the woman should also be advised to also use a supportive non-hormonal method of contraception for the first seven days of tablet-taking.

After a first trimester abortion

It is possible to start immediately without the need for additional contraceptive measures.

After childbirth or second-trimester abortion

Since the immediate postpartum period is associated with an increased thromboembolic risk, the use of COCs should not commence earlier than the 21st-28th day after delivery or after a second trimester abortion. also use a supportive non-hormonal method of contraception during the first seven days of taking the tablets. However, if intercourse has occurred in the meantime, pregnancy must be ruled out or the first menstruation should be waited for before starting the COC.

For breastfeeding women see section 4.6.

Irregular intake

Contraceptive safety may decrease if tablets are forgotten, particularly if the forgotten occurs during the first few days of the treatment cycle.

If she is less than 12 hours late in taking any tablet, contraceptive protection is not reduced. The forgotten tablet should be taken as soon as she remembers and the following tablets should be taken at the usual pace.

If you are more than 12 hours late in taking any tablet, contraceptive protection is no longer ensured.

If you forget a tablet, the following principles apply:

1. Tablet-taking must never be interrupted for more than 7 days.

2. It takes 7 days of uninterrupted tablet-taking to achieve "adequate suppression of the hypothalamus-pituitary-ovarian axis."

Consequently, the following tips can be given in daily practice.

• First week

The last missed tablet should be taken as soon as the woman remembers, even if this means taking two tablets at the same time. The other tablets should be taken at the usual rhythm. In addition, a barrier method, such as a condom, should be used for the next 7 days. If intercourse took place in the previous week, the possibility of a pregnancy should be considered. The greater the number of missed tablets and the shorter the pill-free interval, the greater the risk of pregnancy.

• Second week

The last missed tablet should be taken as soon as the woman remembers, even if this means taking two tablets at the same time. The other tablets should be taken at the usual rhythm. It is not necessary to use any additional contraceptive methods, provided that, in the 7 days preceding the first missed tablet, the tablets have been taken correctly; however, if not, or if more than one forgotten tablet, the use of additional precautions for 7 days should be recommended.

• Third week

Given the imminence of the pill-free interval, the risk of reduced contraceptive reliability is greater. However, by changing the pattern of taking the pill, the reduction in contraceptive protection can still be prevented. By adopting either of the following two options, there is therefore no need to use additional contraceptive methods as long as all tablets have been taken correctly in the 7 days preceding the first missed tablet. Otherwise it should be recommended to follow the first of the two options and also to use additional precautions for the next 7 days.

1. The last missed tablet should be taken as soon as the woman remembers, even if this means taking two tablets at the same time. The other tablets should be taken at the usual rhythm. The next pack should be started immediately after finishing the previous one, i.e. without observing the tablet-free interval between the two packs. In this case, withdrawal bleeding is unlikely to occur before the end of the second pack; however, spotting or breakthrough bleeding may occur while taking the tablets.

2. You may also be advised to stop taking tablets from the current pack. You should then observe a pill-free interval of up to 7 days, including those in which tablets have been missed, and then continue with a new one. packaging.

If tablets have been missed and no withdrawal bleeding occurs in the first regular tablet-free interval, the possibility of an existing pregnancy should be considered.

Recommendations in case of gastrointestinal disorders

In the case of severe gastrointestinal disorders, absorption may be impaired and additional contraceptive measures must be used.

If vomiting and / or diarrhea occurs within 3-4 hours of taking the tablet, absorption may not be complete. In this case, the recommendations outlined in the section "Irregular intake". If you do not want to change your usual dosing schedule, you should take one or more extra tablets from a new pack.

How to move your period from suspension

To delay a menstruation, the patient must continue to take the tablets by taking them from another pack of Miranova without interruption. The delay can be extended according to the patient's wishes until the end of the second pack of tablets. During this prolonged intake, the patient can have breakthrough bleeding or spotting. Miranova should be resumed regularly after the usual 7 day break.

To shift the period to another day of the week than the expected day according to the patient's schedule, the treatment-free interval can be shortened to the desired days. The shorter the tablet-free interval, the greater the possibility of do not have a flow, but breakthrough bleeding or spotting may occur while taking the next pack (such as when you want to delay your period).

Special populations

Pediatric population

The safety and efficacy of Miranova in children and adolescents below 18 years of age have not been established. There are no data available.

Hepatic impairment

Miranova is contraindicated in women with severe liver disease. See section 4.3.

Renal impairment

Miranova has not been specifically studied in patients with impaired renal function.

04.3 Contraindications

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

Combined hormonal contraceptives (COCs) should not be used in the following conditions.

Should any of these conditions appear for the first time during COC use, treatment should be stopped immediately.

- Presence or risk of venous thromboembolism (VTE)

• Venous thromboembolism - current (with anticoagulant intake) or previous VTE (eg deep vein thrombosis [DVT] or pulmonary embolism [PE])

• Known hereditary or acquired predisposition to venous thromboembolism, such as resistance to activated protein C (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 or previous arterial thromboembolism (eg myocardial infarction) or prodromal conditions (eg angina pectoris)

• Cerebrovascular disease - current or previous stroke or prodromal conditions (eg transient ischemic attack (TIA))

• Known hereditary or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinaemia and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant)

• History of migraine with focal neurological symptoms

• A high risk of arterial thromboembolism due to the presence of multiple risk factors (see section 4.4) or the presence of a serious risk factor such as:

• diabetes mellitus with vascular symptoms

• severe hypertension

• severe dyslipoproteinemia

- ophthalmic pathology of vascular origin

- severe liver disease, either current or past, until liver function values ​​have returned to normal;

- liver tumors, current or past, benign or malignant;

- Known or suspected malignant diseases, dependent on sex steroids (eg of the genital organs or the breast);

- undiagnosed vaginal bleeding;

- confirmed or suspected pregnancy;

- association with Ritonavir;

04.4 Special warnings and appropriate precautions for use

Warnings

If any of the conditions or risk factors mentioned below are present, the suitability of Miranova should be discussed with the woman.

In the event of worsening or first appearance of any of these risk factors or conditions, the woman should contact her physician to determine whether the use of Miranova should be discontinued.

Risk of venous thromboembolism (VTE)

The use of any combined hormonal contraceptive (COC) results in an increased risk of venous thromboembolism (VTE) compared with no use. Products that contain levonorgestrel (including Miranova), norgestimate or norethisterone are associated with a lower risk of VTE. A decision to use Miranova should only be made after discussions with the woman to ensure that she understands the risk of VTE associated with Miranova, how her current risk factors affect this risk, and the fact that the risk of developing a VTE it is highest in the first year of use. There is also some evidence that the risk increases when a COC is resumed after a break of 4 or more weeks.

About 2 in 10,000 women who do not use a CHC and who are not pregnant will develop a VTE over a period of one year. In a single woman, however, the risk can be much higher, depending on her underlying risk factors (see below).

It is estimated that out of 10,000 women who use a CHC that contains levonorgestrel, about 6 will develop a VTE in a year.

Recent evidence suggests that the risk of VTE with COCs containing norgestimate is similar to the risk induced by COCs containing levonorgestrel.

The number of VTEs per year is less than the number expected in pregnancy or in the postpartum period.

VTE can be fatal in 1-2% of cases.

Very rarely, thrombosis has been reported in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral or retinal veins and arteries.

Risk factors for VTE

The risk of venous thromboembolic complications in CHC users may increase substantially if additional risk factors are present, especially if there are more than one risk factors (see table).

Miranova is contraindicated if a woman has several risk factors that increase her 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 this case her total risk of VTE should be considered. If the benefit-risk ratio is considered to be negative, a COC should not be prescribed (see section 4.3).

Table: Risk factors for VTE

Risk factor Comment Obesity (body mass index (BMI) above 30 kg / m2 The risk increases considerably as the BMI increases. Particularly important to consider if other risk factors are also present Prolonged immobilization, major surgery, any type of leg and pelvis surgery, neurosurgery or major trauma Note: Temporary immobilization, including air travel lasting> 4 hours, can also be a risk factor for VTE, especially in women with other risk factors In these situations it is advisable to stop using the patch / pill / ring (in case of elective surgery at least four weeks earlier) and not restart it until two weeks after complete resumption of mobility. To avoid unwanted pregnancy, another method of contraception must be used. If Miranova has not been discontinued earlier, antithrombotic treatment should be considered. Positive family history (venous thromboembolism in a sibling or parent, especially at a relatively young age, i.e. before age 50). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding to take any COCs. Other medical conditions associated with VTE Cancer, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell anemia. Old age Particularly above the age of 35

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

The increased risk of thromboembolism in pregnancy, particularly the 6-week period of the puerperium, must be considered (for information on "Pregnancy and lactation" see section 4.6).

Symptoms of VTE (deep vein thrombosis and pulmonary embolism)

If symptoms of this type occur, women should seek immediate medical attention and inform them that they are 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 only be felt when standing or walking;

- increased sensation of heat in the affected leg; skin on the leg that is red or discolored.

Symptoms of pulmonary embolism (PE) can include:

- sudden and unexplained onset of shortness of breath and rapid breathing;

- sudden cough which may be associated with hemoptysis;

- sharp pain in the chest;

- severe light headedness or dizziness;

- rapid or irregular heartbeat.

Some of these symptoms (such as "shortness of breath" and "cough") are non-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 or a pale blue discoloration of one "extremity.

If the occlusion takes place in the eye, symptoms can range from painless blurring of vision to loss of vision. Sometimes vision loss occurs 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 accidents (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 CHC users increases in the presence of risk factors (see table). Miranova is contraindicated if a woman has one serious risk factor or multiple risk factors for ATE that increase her 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 this case her total risk should be considered. If the benefit-risk balance is believed to be negative, a CHC should not be prescribed (see section 4.3).

Table: Risk factors of ATE

Risk factor Comment Old age Particularly above the age of 35 Smoke Women should be advised not to smoke if they wish to use a CHC. 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 (BMI) above 30 kg / m2) The risk increases considerably as the BMI increases. Especially important in women with other risk factors. Positive family history (arterial thromboembolism in a sibling or parent, especially at a relatively young age, i.e. before age 50). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding to take any COCs. Migraine An increase in migraine frequency or severity during CHC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation. Other medical conditions associated with adverse vascular events Diabetes mellitus, hyperhomocysteinemia, atrial valvulopathy and fibrillation, dyslipoproteinemia and systemic lupus erythematosus.

Symptoms of ATE

If symptoms of this type occur, women must contact a healthcare professional immediately and inform them that they are taking a CHC.

Symptoms of a cerebrovascular accident can include:

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

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

• sudden confusion, difficulty speaking or understanding;

• sudden difficulty seeing in one or both eyes, diplopia;

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

• loss of consciousness or fainting with or without convulsions.

• acute abdomen

Temporary symptoms suggest it is a transient ischemic 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, arms, stomach;

• feeling of fullness, indigestion or choking;

• sweating, nausea, vomiting or dizziness;

• extreme weakness, anxiety or shortness of breath;

• rapid or irregular heartbeats.

Precautions for use

Medical examinations / visits

Before initiating or resuming use of Miranova, a complete medical history (including family history) must be taken and pregnancy must be ruled out. Blood pressure should be measured and a physical examination guided by the "Contraindications (see section 4.3) and Warnings (see section 4.4) performed; the test must be repeated, during the use of COCs, at least once per day. year. It is important to draw the woman's attention to information relating to venous or arterial thrombosis, including the risk associated with Miranova compared to other CHCs, symptoms of VTE and ATE, known risk factors and what to do in case of suspected thrombosis.

The woman should also be advised of the need to read the package leaflet carefully and to follow its advice. The frequency and type of examinations should be based on established guidelines and should be adapted to the individual woman.

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

Tumors

Carcinoma of the reproductive organs and breast

In some epidemiological studies an increased risk of cervical cancer has been reported in women on long-term treatment with combined oral contraceptives; however, there is still no consensus on the extent to which this finding is attributable to confounding effects due to sexual behavior and other factors such as human papilloma virus (HPV).

A meta-analysis of 54 epidemiological studies found that women currently using COCs have a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed and that the excess risk gradually disappears over the 10 years following the interruption of treatment. Since breast cancer is rare in women under the age of 40, the number of extra cases of breast cancer diagnosed in women taking or recently taking a COC is low compared to the absolute risk of breast cancer. . These studies provide no evidence of this causal relationship.

The observed increased risk may be due to an earlier diagnosis of breast cancer in women taking COCs, the biological effects of COCs, or a combination of both. Breast cancer diagnosed in oral contraceptive users tends to be less clinically advanced than that diagnosed in women who have never used an oral contraceptive.

Hepatic neoplasia

Benign liver tumors and, even more rarely, malignant liver tumors have been reported rarely in women taking COCs. In isolated cases, these tumors have resulted in life-threatening intra-abdominal haemorrhage. If a woman taking a combined oral contraceptive develops severe upper abdominal pain, liver enlargement, or signs suggestive of intra-abdominal haemorrhage, the possibility of liver cancer should be considered in the differential diagnosis.

Other conditions

Liver function

Acute or chronic disturbances of liver function may require discontinuation of COC treatment until markers of liver function have returned to normal. Return of cholestatic jaundice and / or cholestatic pruritus occurring in pregnancy or during previous Sex steroid treatment requires discontinuation of the combined oral contraceptive.

Eye injuries

Cases of retinal thrombosis have been reported during the use of COCs. If there is unexplained partial or complete loss of vision, the onset of proptosis or diplopia, papilledema or vascular lesions of the retina, the use of contraceptive Combined oral therapy should be discontinued and cause should be evaluated immediately.

Headache

The appearance or exacerbation of migraine or the development of headache with the characteristic being recurrent, persistent and severe, constitute situations which require discontinuation of the COC and evaluation of the cause.

Effects on lipid and carbohydrate metabolism

Although COCs may affect peripheral insulin resistance and glucose tolerance, there is no evidence for the need for adjustment of the therapeutic regimen in diabetic patients using COCs. However, diabetic patients should be closely followed especially in first period of taking the combined oral contraceptive.

Women with hypertriglyceridaemia or a family history of this condition may have an increased risk of pancreatitis when taking COCs.

Folate levels

Serum folate levels may be decreased by combined oral contraceptive therapy. This may be of clinical importance if the woman becomes pregnant shortly after stopping the COC.

Fluid retention

COCs should be prescribed with caution to women whose medical conditions may be aggravated by fluid retention.

Blood pressure

The use of oral contraceptives is contraindicated in women with a history of hypertension or with hypertension-related diseases or kidney disease (see section 4.3). Although a small rise in blood pressure has been reported in many women taking COCs, a clinically relevant increase is rare. A relationship between COC use and hypertension has not been established. Only in these rare cases is an "immediate discontinuation" of the use of COCs justified. However, if consistently elevated blood pressure occurs during use of a COC with pre-existing hypertension or with clinically significant hypertension there is no response to antihypertensive treatments, the COC should be discontinued. Where considered appropriate, the COC may be discontinued. Combined oral contraceptive use should be reintroduced if blood pressure returns to normal with antihypertensive therapy.

Pathologies of the intestine

Worsening of Crohn's disease and ulcerative colitis have been reported in association with COC use.

Disorders of the emotional sphere

Women who become significantly depressed while taking COCs should stop treatment and use an alternative method of contraception to determine if this symptom is drug-related. Women with a history of depression should be closely monitored and treated. should be discontinued if severe depression occurs.

Chloasma may occasionally occur while taking COCs, especially in women with a history of chloasma gravidarum; patients with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking COCs.

The onset or worsening of the conditions listed below has been reported both during pregnancy and while taking COCs; however, there is no conclusive evidence regarding the correlation between these conditions and COCs: jaundice and / or pruritus from cholestasis, gallstone formation, porphyria, systemic lupus erythematosus, uraemic-haemolytic syndrome, Sydenham's chorea, herpes gestationis, hearing loss from otosclerosis.

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

Reduction of effectiveness

The efficacy of COCs may decrease in case of forgetting to take tablets (see section 4.2), in case of vomiting and / or diarrhea (see section 4.2) or in case of concomitant use of other medicinal products (see section 4.5).

Hypericum perforatum preparations should not be taken concomitantly with medicinal products containing oral contraceptives, digoxin, theophylline, carbamazepine, phenobarbital, phenytoin due to the risk of decreased plasma levels and decreased therapeutic efficacy of oral contraceptives, digoxin, theophylline, carbamazepine, phenobarbital, phenytoin (see section 4.5).

Reduced cycle control (irregular bleeding)

Irregular blood loss (spotting or breakthrough bleeding) may occur with all oral estrogen progestins, especially in the first months of use. Thus, evaluation of any irregular blood loss becomes meaningful after an adjustment period of approximately three treatment cycles.

If irregular blood loss persists or occurs after previously normal cycles, non-hormonal causes should be considered and appropriate diagnostic measures should be taken to rule out malignancy or pregnancy. Such diagnostic measures may include a curettage.

In some women, contraceptive withdrawal bleeding may not occur during the tablet-free interval. If the oral estrogen progestogen has been taken according to the directions given in section 4.2, it is unlikely that she is pregnant. However, if the COC has not been taken correctly before the missed withdrawal bleed or if two withdrawal bleeds have not occurred, pregnancy must be ruled out before continuing to take the COC.

Important information about some of the excipients

Miranova contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine. Miranova contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase isomaltase insufficiency should not take this medicine.

04.5 Interactions with other medicinal products and other forms of interaction

Effects of other medicinal products on Miranova

Interactions with other drugs that induce microsomal enzymes, resulting in increased clearance of sex hormones, can lead to breakthrough bleeding and / or contraceptive failure.

Women undergoing treatment with one of these drugs must temporarily use a barrier method or another method of contraception in addition to the combined oral contraceptive. The barrier method should be used for the entire time of concomitant drug intake and for 28 days following discontinuation of therapy. If concomitant drug administration continues after the end of a COC pack, the next COC pack should be started without observing the usual tablet-free interval.

Substances increasing the clearance of COCs (decreased efficacy of COCs by enzyme inducers)

Phenytoin, barbiturates, primidone, carbamazepine, rifabutin, rifampicin, and there are also suspicions for oxycarbamazepine, topiramate, felbamate, griseofulvin and products containing "St. John's wort" (Hypericum perforatum).

Preparations based on Hypericum perforatum should not be administered simultaneously with oral contraceptives, as this could lead to a loss of contraceptive efficacy. Unwanted pregnancies and resumption of the menstrual cycle have been reported. This is due to the induction of enzymes responsible for the metabolism of drugs from Hypericum perforatum-based preparations. The induction effect may persist for at least 2 weeks after stopping treatment with Hypericum perforatum products.

Substances with variable effect on the clearance of COCs

Ritonavir and Nevirapine. When given with COCs, some HIV / HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors may increase or decrease plasma concentrations of estrogen and progestogen. These changes may be clinically relevant in some cases.

Substances that reduce the clearance of COCs (enzyme inhibitors)

Plasma concentrations of estrogen, progestogen or both may be increased by strong or moderate inhibitors of CYP3A4 such as azole antifungals (e.g. itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice.

Etoricoxib doses of 60 to 120 mg / day have been shown to increase plasma concentrations of ethinylestradiol by 37% and 60% respectively when taken concomitantly with a combined hormonal contraceptive containing 0.035 mg ethinylesteradiol.

Associations not recommended

• Modafinil: risk of reduced contraceptive efficacy during treatment and for the cycle following discontinuation of treatment.

Associations to be evaluated

In case of long-term treatment with hepatic enzyme inducers, it is recommended to increase the dose of contraceptive steroids. If a high dose of oral contraceptive is not indicated or seems unsatisfactory or unreliable, for example in case of irregular periods, the use of another contraceptive method should be recommended.

Flunarizine: risk of galactorrhea due to the increased sensitivity of the breast tissue to prolactin due to the action of flunarizine.

Troleandomycin may increase the risk of intrahepatic cholestasis when administered concomitantly with COCs.

Oral contraceptives can affect the metabolism of some active ingredients. Increased plasma concentrations of cyclosporine have been reported during concomitant administration of oral contraceptives. COCs have been shown to induce the metabolism of lamotrigine by bringing plasma concentrations of lamotrigine to sub-therapeutic values. Studies conducted to evaluate a possible effect of oral contraceptives on the activity of CYP3A4 are conflicting, this could depend on the type of progestin used.

It appears that the inhibition of CYP2C19 activity induced by a hormonal contraceptive is caused by ethinyl estradiol. Administration of an oral contraceptive containing ethinyl estradiol results in a slight increase in plasma concentrations of CYP3A4 substrates (eg Midazolam).

Plasma concentrations of CYP1A2 substrates (e.g. melatonin and tizanidine) can increase considerably.

In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1 and CYP1A2 as well as an irreversible inhibitor of CYP3A4 / 5, CYP2C8 and CYP2J2.

Other forms of interaction

Laboratory tests

The use of contraceptive steroids can influence the results of some laboratory tests including biochemical parameters of hepatic, thyroid, adrenal and renal function, plasma levels of transport proteins, for example of corticosteroid-binding globulin and of lipid / lipoprotein fractions , parameters of glucose metabolism, coagulation and fibrinolysis.The variations are generally within the range of normal laboratory values.

04.6 Pregnancy and breastfeeding

Pregnancy

The product is not indicated during pregnancy.

In the event of pregnancy occurring while using Miranova, the product should be discontinued immediately. Extensive epidemiological studies have not revealed any increased risk of birth defects in children born to women who used oral contraceptives prior to pregnancy. nor of teratogenic effects in case of accidental intake of oral contraceptives at the beginning of pregnancy.

The increased risk of thromboembolism in the postpartum period should be taken into account when Miranova is restarted (see sections 4.2. And 4.4).

So far, in clinical use, and unlike diethylstilbestrol, the results of numerous epidemiological studies allow us to consider reduced the risk of malformations with estrogens administered at early pregnancy, alone or in combination.

Furthermore, the risks related to the sexual differentiation of the fetus (especially female), which have been described with the first highly androgenomimetic progestogens, cannot be extrapolated to the more recent progestogens (such as that used in this medicinal product), which are markedly less, or not at all, androgenomimetics.

Consequently, the discovery of a pregnancy in a patient taking an "estrogen-progestogen combination" does not justify the abortion.

Feeding time

Breastfeeding can be influenced by COCs, as they can reduce the quantity and change the composition of breast milk. The use of COCs should therefore be discouraged until the end of breastfeeding. Small amounts of steroids. contraceptives and / or their metabolites may be excreted in breast milk.These amounts may affect the baby.

04.7 Effects on ability to drive and use machines

Miranova has no or negligible influence on the ability to drive or use machines.

04.8 Undesirable effects

Summary of the safety profile

The most common adverse reactions with Miranova are nausea, abdominal pain, weight gain, headache, depressive states, mood changes, breast pain, breast tenderness. They occur in ≥ 1% of users.

Serious adverse reactions are arterial and venous thromboembolism.

Table of adverse reactions

The following side effects have been reported in COC users.

Undesirable effects are reported by system organ class with the indicated frequencies:

MedDRA Body District Common (≥ 1/100) Uncommon (≥ 1/1000 e Rare ( Eye disorders intolerance to contact lenses Gastrointestinal disorders nausea, abdominal pain vomiting, diarrhea Disorders of the immune system hypersensitivity reactions Diagnostic tests weight gain weight decrease Metabolism and nutrition disorders fluid retention Nervous system disorders headache migraine Psychiatric disorders depressive states, mood changes decreased libido increased libido Diseases of the reproductive system and breast breast pain, breast tenderness breast hypertrophy vaginal discharge, mammary discharge Skin and subcutaneous tissue disorders rash, hives erythema nodosum, erythema multiforme Vascular pathologies Venous thromboembolism (VTE), arterial thromboembolism (ATE) **

** - Estimated frequency, from epidemiological studies including a group of COCs.

- "Venous thromboembolism (VTE), arterial thromboembolism (ATE)" summarizes the following pathologies: deep peripheral vein occlusion, thrombosis and vascular embolism / occlusion of the lungs, thrombosis, embolism and heart attack / myocardial infarction / cerebral infarction and stroke not specified as hemorrhagic

The more appropriate MedDRA term was used to describe a specific reaction. Synonyms and related conditions are not on the list, but must be taken into consideration.

Description of some 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 CHC users, and this risk is discussed in more detail in section 4.4.

The following serious side effects have been reported in COC users and discussed in section 4.4 "Special warnings and precautions for use":

• venous thromboembolic pathologies

• arterial thromboembolic pathologies

• hypertension

• liver tumors

• Crohn's disease, ulcerative colitis, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham's chorea, uraemic-haemolytic syndrome, cholestatic jaundice.

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

There is an increased risk of venous thromboembolism (VTE) for all women using a combined oral contraceptive. For information on the differences in risk between COCs, see section 4.4.

The following side effects have been reported in women using COCs:

• Relatively rare side effects which however require discontinuation of treatment:

• arterial thromboembolic accidents (in particular myocardial infarction, cerebrovascular accident);

• venous thromboembolic accidents (phlebitis, pulmonary embolism);

• hypertension, coronary heart disease;

• hyperlipidemia (hypertriglyceridemia and / or hypercholesterolemia);

• severe mastodynia, benign mastopathy;

• exacerbation of epilepsy;

• hepatic adenoma, cholestatic jaundice;

• chloasma.

• Most common side effects which generally do not require discontinuation of treatment, but for which the use of an alternative oral contraceptive combination may be considered:

• heaviness in the legs;

• intermenstrual bleeding, oligomenorrhea, amenorrhea.

• Rarely:

• skin disorders (acne, seborrhea, hypertrichosis)

• Other side effects: biliary lithiasis.

• Effects on discontinuation of treatment: post-treatment amenorrhea.

Amenorrhea with absence of ovulation (occurring more frequently in women with previous cycle irregularities) may be observed when treatment is discontinued. It usually resolves spontaneously. If this continues, investigations into the possibility of pituitary disorders are advisable before any further prescription.

The frequency of breast cancer diagnoses among oral contraceptive users increased very slightly. Because breast cancer is rare in women under the age of 40, the extra number of cases is small compared to the overall risk of breast cancer. It is not known whether there is a causal relationship with COCs. For further information see sections 4.3 "Contraindications" and 4.4 "Special warnings and precautions for use".

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili

04.9 Overdose

No serious undesirable effects due to overdose have been reported.

Symptoms that can be caused by overdose are nausea, vomiting and, in young girls, mild vaginal bleeding.

There are no antidotes and any further treatment should be symptomatic.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: progestogens and estrogens, fixed combinations, ATC code: G03AA07.

The contraceptive effect of Miranova is based on the interaction of several factors, the most important of which is the inhibition of ovulation and the variation in cervical mucus secretion. Furthermore, the endometrium is made unsuitable for implantation.

05.2 Pharmacokinetic properties

Levonorgestrel

Absorption

Levonorgestrel, administered orally, is rapidly and completely absorbed. With a single administration, maximum serum levels, corresponding to 2.3 ng / ml, are reached in about 1.3 hours after dosing. Levonorgestrel is completely bioavailable after oral administration.

Distribution

Levonorgestrel is bound to serum albumin and sex hormone binding globulin (SHBG).Only 1.1% of the total concentration is present as a free steroid, about 65% is specifically bound to SHBG and about 34% is non-specifically bound to albumin. The ethinylestradiol-induced increase in SHBG affects the ratio of levonorgestrel bound to serum proteins, causing an increase in the SHBG-bound fraction and a decrease in the albumin-bound fraction. The apparent volume of distribution of levonorgestrel is approximately 129 l after a single intake.

Metabolism

Levonorgestrel is completely metabolised. The most important metabolites in plasma are the conjugated and unconjugated forms of 3a, 5b-tetrahydrolevonorgestrel. Based on in vitro and in vivo studies, CYP3A4 is the major enzyme involved in the metabolism of levonorgestrel.

Metabolic clearance is approximately 1.0 ml / min / kg.

Elimination

Serum levels of levonorgestrel decrease in two stages. The terminal phase is characterized by a half-life of approximately 25 hours. Levonorgestrel is not eliminated in modified form. Its metabolites are eliminated in the faeces and urine in a ratio of approximately 1 to 1. The half-life of excretion of metabolites is approximately 1 day.

Steady State Conditions

Following daily intake of the drug, serum levels increase approximately three-fold reaching steady state during the second half of the treatment cycle. Levonorgestrel pharmacokinetics are affected by SHBG levels, which are increased 1.5-1.6-fold following of intake with ethinylestradiol. At steady state, clearance and volume of distribution are slightly reduced to 0.7 ml / min / kg and approximately 100 l, respectively.

About 0.1% of the dose passes into breast milk.

Ethinylestradiol

Absorption

Ethinylestradiol, administered orally, is rapidly and completely absorbed. With a single administration, maximum serum levels, corresponding to 50 pg / ml, are reached within 1-2 hours after dosing. During absorption and first passage in the liver, ethinylestradiol is further metabolised, resulting in an average oral bioavailability of approximately 45%, with large individual variations of approximately 20-65%.

Distribution

Ethinylestradiol is bound mainly, but not specifically, to serum albumin (approximately 98%) and induces an increase in the serum concentration of SHBG. The apparent volume of distribution has been reported to be approximately 2.8-8.6 L / kg.

Metabolism

Ethinylestradiol undergoes significant intestinal and first pass hepatic metabolism. Ethinylestradiol and its oxidative metabolites are mainly conjugated with glucuronides and sulphates. The metabolic clearance of ethinylestradiol is approximately 2.3-7 ml / min / kg.

Elimination

Serum levels of ethinylestradiol decrease in two phases characterized by half-lives of approximately 1 hour and approximately 10-20 hours, respectively. Ethinylestradiol is not eliminated in modified form, the metabolites of ethinylestradiol are eliminated in faeces and urine in a ratio of about 4 to 6. The half-life of metabolite excretion is about 1 day.

Steady State Conditions

Serum concentrations of ethinylestradiol increase approximately twice after daily intake of Miranova. In accordance with the variable half-life of the terminal disposition phase from serum and daily intake, the steady state of serum levels of ethinylestradiol are reached after approximately one week.

During lactation, approximately 0.02% of the dose can pass into breast milk.

05.3 Preclinical safety data

Non-clinical data, based on conventional repeated dose toxicity studies on genotoxicity, carcinogenic potential and reproductive toxicity, do not report special hazards for humans.

In principle, however, it must be borne in mind that sex steroids can stimulate the growth of hormone-dependent tissues and tumors.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Lactose monohydrate, corn starch, pregelatinised starch, povidone 25; magnesium stearate, sucrose, povidone 90, macrogol 6,000, calcium carbonate, talc, glycerol 85%, red iron oxide (E172), yellow iron oxide (E172), titanium dioxide, ethylene glycol ester of montanic acid (E wax).

06.2 Incompatibility

Not known.

06.3 Period of validity

3 years.

06.4 Special precautions for storage

Store at a temperature not exceeding 30 ° C. Store in the original package to protect from moisture.

06.5 Nature of the immediate packaging and contents of the package

Primary container: polyvinyl chloride / aluminum blister

Packaging: Calendar pack containing 21 tablets

06.6 Instructions for use and handling

No special instructions for disposal.

07.0 MARKETING AUTHORIZATION HOLDER

Bayer S.p.A. - Viale Certosa, 130 - 20156 Milan (MI)

08.0 MARKETING AUTHORIZATION NUMBER

A.I.C. n. 033779012

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

10.04.2000 / 01 June 2010

10.0 DATE OF REVISION OF THE TEXT

AIFA determination of 09/2014

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