GRACIAL - PACKAGE LEAFLET - LEAFLETS

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Gracial - Package Leaflet

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

Active ingredients: Desogestrel, Ethinylestradiol

Gracial tablets

Indications Why is Gracial used? What is it for?

Composition and type of pill

Gracial is a combined oral contraceptive also called a pill. Each tablet contains a small amount of two different female hormones. These are desogestrel (a progestin) and ethinylestradiol (an estrogen). Due to the low concentration of hormones, Gracial is considered a low-dose oral contraceptive. Since the two hormones in the blue tablets are present in different dosages than those present in the white tablets, Gracial is considered a biphasic combined oral contraceptive.

Why use Gracial

Gracial is used for the prevention of conception.

When used correctly (without forgetting any tablets), the chance of pregnancy is very low.

Contraindications When Gracial should not be used

General notes

Before you start using Gracial you should read the information on blood clots in section 2. It is especially important that you read the symptoms of a blood clot (see section 2 "Blood clots").

Do not use Gracial Do not use Gracial

Do not use Gracial if you have any of the conditions listed below. If you have any of the conditions listed below, please contact your doctor. Your doctor will discuss 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 be lying 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 blood vessel injury
- very high blood pressure
- very high level of fat (cholesterol or triglycerides) in the blood
- a disease known as hyperhomocysteinemia
if you have (or have ever had) a type of migraine called 'migraine with aura';
if you have or have suffered in the past from pancreatitis (inflammation of the pancreas) associated with high levels of fat in the blood;
if you have jaundice (yellowing of the skin) or have severe liver disease;
if you have or have suffered in the past from a type of cancer that grows under the influence of sex hormones (such as breast or genital organ cancer);
if you have or have suffered in the past from liver cancer;
if you have vaginal bleeding of unknown origin;
if you have endometrial hyperplasia (abnormal growth of the lining of the uterus);
if you are pregnant or suspect you are pregnant;
if you are allergic to the active substances or to any of the ingredients of Gracial.
If any of these conditions appear for the first time while taking the pill, stop taking it immediately and tell your doctor. In the meantime, use non-hormonal methods of contraception.
Do not use Gracial if you have Hepatitis C and are taking the combined ombitasvir / paritaprevir / ritonavir drug regimen, with or without dasabuvir (see section "Other medicines and Gracial").

Precautions for use What you need to know before taking Gracial

When to be especially careful with Gracial

General notes: In this leaflet, some situations are described in which the taking of the pill should be stopped or in which a reduction in the effectiveness of the pill may occur. In these situations, you should not have sexual intercourse or you should take additional non-hormonal contraceptive precautions, such as using a condom or other barrier method. Do not use rhythm or basal temperature methods. These methods may be unreliable because the pill it alters the normal changes in temperature and cervical mucus that occur during the menstrual cycle.

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 a stroke (see section below " Blood clot (thrombosis) ").

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

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

Gracial should not normally be used to postpone a period. However, if in exceptional cases it is necessary to delay a period, please contact your doctor.

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

If this condition appears or worsens while you are using Gracial you should inform your doctor.

if you smoke;
if you have diabetes;
if you are overweight;
if you have high blood pressure;
if you have a heart valve disorder or certain heart rhythm disorders;
if you have "inflammation of the veins under the skin (superficial thrombophlebitis);
if you have varicose veins;
if you have a history of thrombosis, heart attack or stroke in close family members;
if you suffer from migraines;
if you suffer from depression;
if you suffer from epilepsy;
if you have liver or gallbladder disease;
if you have Crohn's disease or ulcerative colitis (chronic inflammatory bowel disease);
if you have systemic lupus erythematosus (SLE; a disease affecting the natural defense system);
if you have haemolytic uremic syndrome (HUS, a blood clotting 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 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 are going to lie down for a long time (see section 2" 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 Gracial;
if any of your immediate family members have had breast cancer;
if you have disorders that first appeared or worsened during pregnancy or as a result of previous sex hormone therapy (eg hearing loss, a disease called porphyria, a skin disease called herpes gestationis, a disease called Sydenham's Korea);
if you have or have ever had chloasma (yellowish-brown pigmented patches on the skin, especially on the face).

In this case, avoid excessive exposure to the sun or ultraviolet rays.

Interactions Which drugs or foods can modify the effect of Gracial

Pill and thrombosis

BLOOD CLOTS: Using a combined hormonal contraceptive such as Gracial increases your risk of developing a blood clot compared with not using it. 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).

Recovery 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 Gracial 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 the color of the skin of the leg, such as pa

Deep vein thrombosis

sudden and unexplained shortness of breath or rapid breathing;
sudden cough without 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 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 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 drug or a different drug) 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 Gracial your 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 Gracial 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, about 5-7 will develop a blood clot in a year.
Out of 10,000 women who are using a combined hormonal contraceptive that contains desogestrel, such as Gracial, about 9-12 will develop a blood clot in a year.
The risk of a blood clot forming 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 Gracial About 9-12 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 Gracial is low but some conditions cause it to increase. 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 Gracial a few weeks before the surgery or during the period where you are less mobile. If you have to stop taking Gracial, 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 of this type.

Air travel (lasting> 4 hours) may 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 that Gracial needs to be stopped.

If any of the above conditions change while you are using Gracial, 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 Gracial is very low but can increase:

with increasing age (over 35 years);

if you smoke. When using a combined hormonal contraceptive such as Gracial 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 any 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 Gracial, 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.

Very occasionally a thrombosis can cause serious permanent disability or can be fatal.

Pill and cancer

Breast cancer is diagnosed slightly more often in women who use the pill than in women who do not. This slight increased risk gradually disappears over 10 years after stopping the use of the pill. It is not known whether the pill is the cause of this difference. This may be due to the fact that women are seen much more often. and therefore breast cancer is likely to be diagnosed earlier.

Benign liver tumors and, even more rarely, malignant liver tumors have been observed in rare cases in women using the Pill. These tumors can cause internal bleeding. Contact your doctor immediately if you experience any severe abdominal pain.

Cervical cancer is caused by a "human papillomavirus (HPV) infection. It is more common in women who use the pill for a long time. It is not known whether this is due to" use of hormonal contraceptives or sexual behavior or to other factors (such as better screening of the cervix).

Other medicines and Gracial

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines or herbal preparations, including those obtained without a prescription. This way they can tell you if and for how long you need to use additional contraceptive methods. Some medicines can affect the blood levels of Gracial and make it less effective in preventing pregnancy or causing unexpected bleeding.

These include medicines for treatment:

of epilepsy and narcolepsy (eg: primidone, hydantoins, phenytoin, barbiturates, carbamazepine, oxcarbazepine, topiramate, felbamate, modafinil);
tuberculosis (e.g. rifampicin, rifabutin),
HIV or hepatitis C virus infections (so-called non-nucleoside protease inhibitors and reverse transcriptase inhibitors, such as ritonavir, nevirapine, efavirenz) and / or combinations with hepatitis C virus (HCV) medicines ( eg boceprevir, telaprevir) or other infections (griseofulvin);
for high blood pressure in the blood vessels of the lungs (bosentan) and preparations of St. John's wort (Hypericum perforatum), used mainly for the treatment of depression.

The pill may also interfere with the activity of other medicines (eg cyclosporine and lamotrigine).

Co-administration of strong inhibitors of the CYP3A4 enzyme (eg ketoconazole, itraconazole, clarithromycin) or moderate inhibitors of the CYP3A4 enzyme (eg fluconazole, diltiazem, erythromycin) may increase blood concentrations of estrogen or progestins, including etonogestrel. , product of the active metabolism of desogestrel.

Do not use Gracial if you have Hepatitis C and are taking the combined drug regimen ombitasvir / paritaprevir / ritonavir, with or without dasabuvir as this may lead to increases in blood test results for liver function (increased ALT liver enzyme). it can be started again approximately 2 weeks after the end of treatment with the combined drug regimen (see section "Do not use Gracial").

Warnings It is important to know that:

Laboratory analysis

If you need a blood test, tell your doctor or laboratory that you are taking the pill, as oral contraceptives can affect the results of some blood tests.

Pregnancy and breastfeeding

Pregnancy

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 taking this medicine. Gracial should not be used by women who are pregnant or suspect pregnancy. If you suspect that you are pregnant while taking Gracial, you must stop treatment immediately and contact your doctor as soon as possible.

Feeding time

The use of Gracial is not recommended while breastfeeding. If you want to take the pill while breastfeeding, you will need to contact your doctor.

Driving and using machines

Gracial does not affect the ability to drive or use machines.

Gracial 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.

When to contact your doctor

Periodic checks

While you are using the pill, your doctor will ask you to come to periodic check-ups. Usually you have to undergo a check-up at least every year.

Contact your doctor as soon as possible if:

observe any changes in your state of health, in particular with regard to what is stated in this leaflet (see also sections "Do not use Gracial" and "What you need to know before you use Gracial". Do not forget the changes in the health status of close family members)
you feel a lump in your breast;
you experience symptoms of angioedema such as swelling of the face, tongue and / or throat and / or difficulty swallowing or hives along with difficulty breathing;
you must use other medicines (see also section "Other medicines and Gracial");
you must be immobilized or have to undergo surgery (tell your doctor at least four weeks in advance); you have intense and unusual vaginal bleeding;
she forgot to take the tablets during the first week of the pack and had sex in the previous seven days;
to severe diarrhea;
have not had a period for two consecutive cycles or suspect pregnancy (do not start a new pack without first checking with your doctor).

Stop taking the tablets and see your doctor immediately if you notice possible signs of thrombosis such as: unusual cough; severe pain in the chest which may radiate to the left arm; shortness of breath; unusual, severe or prolonged headache or a fit of migraine; partial or complete loss of vision or double vision; stammering or inability to speak; sudden changes in hearing, smell and taste; dizziness or fainting; weakness or numbness of any part of the body; severe pain in the "abdomen; severe pain or swelling in one leg.

Use in children and adolescents

There are no clinical data on efficacy and safety in children and adolescents below 18 years of age.

Dosage and method of use How to use Gracial: Dosage

When and how to take the tablets Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.

The Gracial pack contains 22 tablets: 7 blue tablets (marked with numbers 1-7) and 15 white tablets (marked with numbers 8-22). Take the tablet at about the same time every day, with a little water if needed. Whenever you start a new pack of Gracial, always start with the blue number 1 tablet in the upper left corner of the blister. . Mark the day of the week you start taking the pill by engraving the aluminum of the corresponding socket in the green part of the blister. This way you can easily check if the tablets have been taken correctly. Follow the direction of the arrows until all 22 tablets have been used up. Take all the blue tablets first, then all the white ones. Do not take pills for the next 6 days. Menstruation should appear during these 6 days (withdrawal bleeding). They typically start 2-3 days after taking the last Gracial tablet. Start the new pack on the seventh day, even if your period has not yet finished. In this way, the new pack will always be started on the same day of the week and the withdrawal bleeding will always occur on approximately the same days of the week, every month.

How to start the first pack of Gracial

If you have not used any hormonal contraceptive pills in the previous month. You start taking Gracial on the first day of your period, which is the first day of your period, Gracial is effective right away, so you don't need any additional contraceptive methods.

It can also be started between the second and fifth day of the cycle, but in this case an additional contraceptive method (barrier method) must be used for the first 7 days of taking the tablets in the first cycle.

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

You can start taking Gracial the day after the last pill of your previous contraceptive (ie without observing any tablet-free interval). If your previous contraceptive pack also contains inactive tablets, you can take Gracial the day after taking the last one. active tablet (if in doubt, ask your doctor or pharmacist). It can also start later, but never later than the day after the pill-free interval (or the day after the last inactive tablet) of the previous contraceptive. use a vaginal ring or a transdermal patch, it is preferable to start taking Gracial on the day of the removal of the ring or patch. You can also start the day scheduled for the next ring application at the latest. or the patch.

If you have used the pill, patch or ring consistently and correctly and if you are sure you are not pregnant, you can also stop taking the pill or remove the ring or patch on any day and start using Gracial immediately.

If you follow these instructions, you do not need to resort to the use of additional contraceptive methods.

Switching from progestogen-only pill (minipill)

You can stop taking the minipill on any day and start taking Gracial the next day at the same time.However, if you have sex, use an additional method of contraception (barrier method) for the first 7 days of taking Gracial.

Changing from an injection contraceptive or progestogen-only implant or progestogen-releasing intrauterine device (IUS)

You can start Gracial when your next injection is due or on the day of removal of the implant or IUS. However, if you have sex, use an additional method of contraception (barrier method) for the first 7 days of taking Gracial. .

After giving birth

After having a baby your doctor may tell you to wait until your first normal menstrual period before you start using Gracial. Sometimes it is possible to start even earlier. Your doctor will give you instructions. If you are breastfeeding and want to use Gracial, talk to your doctor first.

After a spontaneous or induced abortion

Your doctor will give you instructions.

WHAT TO DO IF ...

… You forget to take your tablets

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 then take the next tablets 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 that the contraceptive effect will be reduced.
The risk of pregnancy is particularly high if you forget pills at the beginning and at the end of the pack. So you will have to follow the instructions below (see also the chart below).

If you have forgotten to take more than one tablet in a pack

Ask your doctor for instructions.

If you forgot 1 tablet 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. Contact your doctor immediately.

1 tablet forgotten in week 2 Take the forgotten tablet as soon as you remember (even if that means that you have to take two tablets at the same time) and continue as usual. The contraceptive safety of the pill is maintained. No other additional contraceptive measures need to be used.

One tablet forgotten in week 3 (8 days)

You can choose one of the following alternatives, without the need for additional contraceptive precautions.

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 breakthrough bleeding (spotting) or breakthrough bleeding may occur during the second pack; or
Withdraw the tablets from the current pack, and observe an interval of 6 days or less (include 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 week on which you usually start.

If you have forgotten to take one or more tablets from a pack and in the first pill-free interval, you do not have a period, it is possible that you are pregnant. In this case, you should contact your doctor before starting the new pack.

…… .if you suffer from gastrointestinal complaints (such as vomiting or severe diarrhea) If you are vomiting or have severe diarrhea, the active substances in the Gracial tablet may not be fully absorbed. If you vomit within 3-4 hours of taking the tablet, a situation similar to that of a forgotten tablet occurs. You should follow the instructions given for forgetting tablets. In case of severe diarrhea, contact your doctor. .... ... if you want to postpone the start day of your period You can delay the start of your period if you start taking the white tablets of a new pack of Gracial immediately after finishing the current pack. You can continue with the new pack until as long as you like, until the end of the second pack (maximum 15 days). When you want to start your period, stop taking the tablets. While using the second pack you may experience breakthrough bleeding or spotting during the period. taking the tablets Start the next pack after the usual 6-day tablet-free break.

....... in case you want to change the start day of your period. If you take the tablets correctly, you will have your period about the same day every 4 weeks. If you want to change this day, you just have to shorten (never lengthen) the period. subsequent period of the pill-free interval. For example, if your periods usually appear on a Friday and you want them to appear on a Tuesday in the future (3 days earlier), you should start the next pack 3 days earlier than usual. If you shorten your tablet-free interval a lot (eg 3 days or less) you may not have bleeding during that interval. You may have breakthrough bleeding or spotting while using the next pack. …… if you have unexpected bleeding With all oral contraceptives, in the first months of taking, you may have irregular vaginal bleeding (spotting or breakthrough bleeding) between periods. You may need to use sanitary pads; but you must continue to take the tablets normally. The irregular bleeding usually disappears once the body gets used to the pill (usually after about 3 months). Consult your doctor if bleeding persists, becomes intense or recurs at intervals.

…… in case of missed menstruation If you have taken all the tablets correctly and have not vomited or taken any other medicines, it is very unlikely that you are pregnant. Continue to take Gracial as usual. If your period does not occur twice in a row, you may have become pregnant. Contact your doctor immediately. Do not start the new Gracial pack until your doctor has ruled out that you are pregnant. .

If you want to stop using Gracial

You can stop taking Gracial at any time. If you still want to avoid becoming pregnant, ask your doctor for advice on other methods of birth control. If you want to stop taking Gracial to get pregnant, you must wait the onset of a natural menstruation before starting to try to conceive. This will help you determine when the baby will be born.

Overdose What to do if you have taken an overdose of Gracial

After taking several Gracial tablets at once, no serious harmful effects have been reported. If you have taken several tablets at the same time, you may have nausea, vomiting or vaginal bleeding. If you find that a child has taken Gracial, ask your doctor for instructions.

Side Effects What are the side effects of Gracial

Like all medicines, Gracial 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 Gracial, 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 section 2' What you need to know before you take Gracial '.

As with all COCs, changes in the characteristics of vaginal bleeding may occur, especially in the first months of treatment. These changes may include changes in the frequency (absent, reduced, more frequent or continuous), in the intensity (reduced or increased) or in the duration of bleeding.

Serious reactions associated with "pill use and related symptoms" are described in the sections "Pill and thrombosis" and "Pill and cancer".

The following side effects have been seen in women using the Pill: Common (may affect more than 1 in 100 women):

depressed mood, mood change
headache
nausea, abdominal pain
breast pain, breast tension
weight gain.

Uncommon (may affect more than 1 in 1,000 women and less than 1 in 100 women):

fluid retention
decreased sexual desire
migraine
vomiting, diarrhea
skin reactions, hives
breast enlargement.

Rare (may affect less than 1 in 1,000 women):

harmful blood clots in a vein or artery, for example:
- in a leg or foot (DVT)
- in one lung (PE)
- heart attack
- stroke
- mini-stroke or temporary stroke-like symptoms, 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 2 for more information on conditions that increase the risk of blood clots and the symptoms of a blood clot).

hypersensitivity reactions
increased sexual desire
intolerance to contact lenses
erythema nodosum, erythema multiforme (skin diseases)
breast discharge, vaginal discharge
decrease in body weight.

Compliance with the instructions contained in the package insert 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

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

Do not store above 30 ° C. Do not freeze. Store in the original package to protect from light and moisture.

Do not use this medicine if there are any changes in the color of the tablets, crumbling of the tablets or any other visible signs of deterioration.

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

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 Gracial contains

The active ingredients are:

blue tablets: desogestrel (0.025 mg) and ethinyl estradiol (0.040 mg)

white tablets: desogestrel (0.125 mg) and ethinyl estradiol (0.030 mg)

The other ingredients are: blue tablets:

anhydrous colloidal silica, lactose monohydrate, potato starch, povidone, stearic acid, alpha-tocopherol and indigo carmine (E132);

white tablets: anhydrous colloidal silica, lactose monohydrate, potato starch, povidone, stearic acid and alpha-tocopherol.

Description of the appearance of Gracial and contents of the package

Gracial is available in packs of 1, 3 and 6 blister packs of 22 tablets (7 blue tablets and 15 white tablets), placed in an aluminum sachet and packed in a carton.

The tablets are biconvex, round and 6 mm in diameter. Each tablet is labeled with TR8 (white tablet) or TR9 (blue tablet) on one side and Organon * on the other side.

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.

Further information on Gracial 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

GRACIAL TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

• each blue tablet contains 0.025 mg of desogestrel and 0.040 mg of ethinylestradiol.

• each white tablet contains 0.125 mg of desogestrel and 0.030 mg of ethinylestradiol

Excipients: lactose

For the full list of excipients see section 6.1.

03.0 PHARMACEUTICAL FORM

Tablets.

Round, flat tablets with beveled edges and a diameter of 6 mm. The tablets are labeled with on one side and plain on the other side. "TR8" (for white tablets) or "TR9" (for blue tablets).

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Contraception.

The decision to prescribe Gracial should take into consideration the individual woman's current risk factors, particularly those related to venous thromboembolism (VTE) and the comparison between the risk of VTE associated with Gracial and that associated with other CHCs, Combined Hormonal Contraceptives ( see sections 4.3 and 4.4).

04.2 Posology and method of administration

How to take Gracial

The tablets should be taken in the order indicated on the blister, every day at about the same time and, if necessary, with some liquid. The tablets should be taken every day for 22 consecutive days, starting with the blue tablets for 7 days and continuing with white for another 15 days. Subsequent packs should be started after a 6-day pill-free interval, during which withdrawal bleeding usually occurs. Such bleeding usually occurs 2-3 days after "last tablet" and may still be present when starting the next pack.

How to start treatment with Gracial

No hormonal contraceptive treatment (in the previous month)

Taking the tablets should 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 also use a barrier method in the first seven days of taking the tablets.

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

The first tablet of Gracial should preferably be taken the day after the last active tablet of the previous combined oral contraceptive (ie the last tablet containing the active substance) or at the latest the day after the usual tablet-free or placebo-free interval of the previous combined oral contraceptive. In the case of previous use of a vaginal ring or transdermal patch, Gracial should preferably be taken on the day of removal of the device, or at the latest on the day scheduled for the next application.

If the woman has used the previous contraceptive method consistently and correctly and is reasonably certain that she is not pregnant, she can also switch from the previous combined hormonal contraceptive treatment to the new one, on any day of the cycle.

The hormone-free interval of the previous method should never be extended beyond the recommended time period.

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 from the minipill (from an implant or an IUS on the day of its removal, from an injectable on the day the next injection should be given), but in any case she should be advised to also use a barrier method of contraception for the first 7 days of tablet-taking.

After a first trimester abortion

You can start immediately without the need for additional contraceptive measures.

After a birth or second-trimester abortion

For breastfeeding women see section 4.6.

The contraceptive should not be started until the 21st-28th day after delivery or after a second trimester abortion. If the intake is postponed, the woman should be advised to also use a barrier method in the first 7 days taking the tablets. However, if intercourse has occurred in the meantime, pregnancy must be ruled out or the first menstruation should be awaited before actually starting the COC.

Irregular intake

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 the delay in taking any tablet is more than 12 hours, contraceptive protection may be reduced. In this case, the behavior to be followed can be guided by the following two basic rules:

1. failure to take the tablets should never last more than six days

2. to obtain an "adequate suppression of the hypothalamus-pituitary-ovary axis, it is necessary to take the tablets continuously for 7 days.

As a result, 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 in the 7 days preceding the first missed tablet all tablets have been taken correctly. 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 therefore observe a pill-free interval of up to 6 days, including those in which tablets have been missed, and then continue with a new one. packaging.

If the woman has forgotten to take tablets and does not experience withdrawal bleeding in the first regular tablet-free interval, the possibility of pregnancy should be considered.

Recommendations in case of gastrointestinal disorders

In the presence of severe gastrointestinal disturbances, absorption may not be complete and additional contraceptive measures must be used.

If vomiting occurs within 3-4 hours of taking the tablet, follow the recommendations, if applicable, regarding not taking tablets in the section "Irregular intake". If the woman does not want to change the usual dosage regimen, she should take one or more more extra tablets from a new pack.

Mode for skipping or postponing a period

Postponing a period is not an indication of the product. However, if in exceptional cases it is necessary to postpone a period, one should continue taking Gracial white tablets from another pack, without observing the pill-free interval. The tablet-taking can be continued as long as desired until the end of the second pack for up to 15 days. During this period, breakthrough bleeding or spotting may occur. "Gracial assumption.

To shift your period so that it starts on a different day of the week than usual, you can shorten the duration of the next pill-free interval by as many days as you like. The shorter the interval, the greater the risk of not having withdrawal bleeding but rather breakthrough bleeding or spotting while taking the second pack (such as when postponing a period).

Pediatric population

There are no data available on safety and efficacy in adolescents below 18 years of age.

04.3 Contraindications

Combined hormonal contraceptives (COCs) should not be used in the following conditions. If any of these conditions appear for the first time during the use of the COC, the intake of the product must be stopped immediately.

• Presence or risk of venous thromboembolism (VTE)

o Venous thromboembolism - current VTE (with anticoagulant intake) or history (e.g. deep vein thrombosis [DVT] or pulmonary embolism [PE])

o 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

o Major surgery with prolonged immobilization (see section 4.4)

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

• Presence or risk of arterial thromboembolism (ATE)

o Arterial thromboembolism - current or past arterial thromboembolism (e.g. myocardial infarction) or prodromal conditions (e.g. angina pectoris)

o Cerebrovascular disease - current or previous stroke or prodromal conditions (e.g. transient ischemic attack (transient ischaemic attack,TIA))

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

o History of migraine with focal neurological symptoms

o 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

• Pancreatitis, current or past, associated with severe hypertriglyceridemia;

• Severe liver disease, either current or past, until liver function values have returned to normal;

• Liver tumors (benign or malignant), current or previous;

• Known or suspected, hormone-dependent malignant diseases (for example, of the genital organs or the breast);

• Endometrial hyperplasia;

• Vaginal bleeding of an undetermined nature;

• Known or suspected pregnancy;

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

• Gracial is contraindicated for use with the combined hepatitis C virus drug regimen ombitasvir / paritaprevir / ritonavir with or without dasabuvir (see section 4.4).

04.4 Special warnings and appropriate precautions for use

Warnings

Should any of the conditions or risk factors mentioned below be present, the suitability of Gracial 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 Gracial should be discontinued.

1. Circulation disorders

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, norgestimate or norethisterone are associated with a lower risk of VTE. The risk associated with others. products such as Gracial can be doubled. The decision to use a product other than those associated with a lower risk of VTE should only be made after discussions with the woman to ensure that she understands the risk of VTE associated with Gracial, the way where your current risk factors influence that risk and the fact that the risk of developing a VTE is highest in the first year of use. There is also some evidence that the risk increases when taking 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 [1] that out of 10,000 women who use a CHC containing desogestrel, between 9 and 12 will develop a VTE in one year; this compares with approximately 6 [2] women using a COC containing levonorgestrel.

[1] These incidences were estimated from the totality of epidemiological study data, using the relative risks for the different products compared with levonorgestrel-containing COCs.

[2] Median value of the range 5 7 per 10,000 women / year, based on a relative risk of approximately 2.3 3.6 for COCs containing levonorgestrel compared with non-use.

In both cases, 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 to 2% of cases.

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).

Gracial is contraindicated if a woman has multiple 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 Gracial 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.

The use of COCs has generally been associated with an increased risk of acute myocardial infarction (AMI) or stroke, which is strongly influenced by the presence of other risk factors (eg smoking, high blood pressure and age) (see also below.) These events occur infrequently.How Gracial modifies the risk of AMI has not been studied.

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). Gracial 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 in elocution or understanding;

- sudden difficulty seeing in one or both eyes, diploidy;

- 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.

2. Very rarely, thrombosis of other vascular areas, such as hepatic, mesenteric, renal or retinal arteries and veins, has been reported in women taking a combined oral contraceptive. Tumors

• Persistent human papillomavirus (HPV) infection is the most important risk factor in cervical cancer. Epidemiological studies indicate that long-term treatment with a combined oral contraceptive contributes to this increased risk; however, there remains uncertainty as to whether this finding is attributable to confounding effects such as cervical screening methodology and differences in sexual behavior, including the use of barrier contraceptives, or a causal association.

• A meta-analysis of 54 epidemiological studies found that women who currently use COCs have a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed and that the excess risk disappears. gradually over the 10 years following discontinuation of treatment. Since breast cancer is rare in women under the age of 40, the extra number of breast cancers diagnosed in women taking or recently taking a combined oral contraceptive is low compared to the overall 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.

• 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.

3. Hepatitis C

• During clinical trials with the combined drug regimen for HCV ombitasvir / paritaprevir / ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medicines such as combined oral contraceptives (COCs). Gracial should be discontinued prior to initiating therapy with the combined ombitasvir / paritaprevir / ritonavir drug regimen with or without dasabuvir (see sections 4.3 and 4.5). Gracial can be started again approximately 2 weeks after ending treatment with the combined drug regimen.

4. Other conditions

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

• Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are a rare event. A relationship between the use of COCs and the occurrence of clinically significant hypertension has not been established. However, if clinically significant and sustained hypertension occurs during the use of a COC, the physician should proceed with caution. taking the combined oral contraceptive and treating hypertension. If appropriate, COC use can be resumed if normal blood pressure values have been achieved with antihypertensive therapy.

• 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 of a correlation between these conditions and the use of COCs: jaundice and / or itching cholestasis, gallstone formation, porphyria, systemic lupus erythematosus, haemolytic uremic syndrome, Sydenham's chorea, herpes gestationis, hearing loss from otosclerosis, angioedema (hereditary).

• 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 that first occurred in pregnancy or during previous treatment with sex steroids requires discontinuation of the combined oral contraceptive.

• Although COCs may affect peripheral insulin resistance and glucose tolerance, there is no evidence for the need for adjustment of the treatment regimen in diabetic patients using low-dose combined oral contraceptives (containing

• Crohn's disease and ulcerative colitis have been reported in association with the use of combined oral contraceptives.

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

• 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 treatment should be stopped if severe depression occurs.

Important information about some of the ingredients.

Gracial contains galactose intolerance, Lapp-lactase deficiency or glucose-galactose malabsorption, which are taken on a lactose-free diet.

When choosing a contraceptive method, all of the above information must be taken into consideration.

Medical examinations / visits

Before initiating or resuming use of Gracial, a complete medical history (including family history) should be taken and pregnancy should be ruled out. Blood pressure should be measured and a clinical examination, guided by contraindications, should be performed (see section 4.3 ) and warnings (see section 4.4). It is important to draw a woman's attention to information relating to venous or arterial thrombosis, including the risk associated with Gracial 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 must be based on established guidelines and must be adapted to the individual woman.

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

Reduction of effectiveness

The efficacy of COCs may decrease, for example, if one or more tablets are missed (section 4.2), gastrointestinal disturbances (section 4.2) or when taking other medicinal products at the same time (section 4.5).

Herbal preparations containing St. John's wort (Hypericum perforatum) should not be used while taking Gracial due to the risk of decreased plasma concentrations and a reduction in the clinical effects of Gracial (see section 4.5 "Interactions with other medicinal products and other forms of interaction").

Reduction of cycle control

Irregular vaginal bleeding (spotting or breakthrough bleeding) may occur while taking any COC, especially in the first months of treatment. Therefore, the evaluation of any irregular vaginal bleeding is only meaningful after a settling phase lasting 4 months. about three courses of treatment.

If irregular bleeding persists or occurs after previously regular cycles, a non-hormonal etiology should be considered and to rule out malignancy or pregnancy, appropriate diagnostic measures should be implemented. These may include curettage.

In some women, withdrawal bleeding may not occur during the tablet-free interval. If the COC has been taken as described in section 4.2, it is unlikely that the woman is pregnant. However, if prior to the missed withdrawal bleed the COC has not been taken according to these indications or if two withdrawal bleeds have not occurred, pregnancy must be ruled out before continuing to take the COC.

04.5 Interactions with other medicinal products and other forms of interaction

Note: The prescribing information of the medicinal products to be taken in combination should be consulted in order to identify potential interactions.

Effects of other medicinal products on Gracial

Interactions may occur with medicinal products that induce microsomal enzymes which may lead to increased clearance of sex hormones and may lead to intermenstrual bleeding and / or failure of oral contraceptive efficacy.

Management

Enzyme induction can already be observed after a few days of treatment. Maximal enzyme induction is generally observed within a few weeks. After discontinuation of therapy, enzyme induction may persist for approximately 4 weeks.

Short-term treatment

Women undergoing enzyme inducer treatments should 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 period 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.

Long-term treatment

Another reliable, non-hormonal method of contraception is recommended for women undergoing long-term treatment with enzyme inducers.

The following interactions have been reported in the literature.

Substances that increase the clearance of COCs (decreased efficacy of COCs by enzyme inducers), for example:

Barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifabutinarifampicin, the HIV drug ritonavir, nevirapine and efavirenz and possibly also felbamate, griseofulvin, oxycarbazepine, modafinil, topiramate and products containing the herbal remedy "St. John's wort" "(Hypericum perforatum).

Substances with variable effect on the clearance of COCs

When co-administered with COCs, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with HCV inhibitors and / or combinations with hepatitis C virus (HCV) medicinal products ( eg boceprevir, telaprevir), may increase or decrease plasma concentrations of estrogen or progestogen. The net effect of these changes in some cases may be clinically relevant.

Accordingly, prescribing information for concomitant HIV / HCV medications should be consulted to identify potential interactions and any related recommendations. If in doubt, the woman undergoing therapy with protease inhibitors or non-nucleoside reverse transcriptase inhibitors should use a barrier method of contraception.

Effects of Gracial on other medicinal products

Oral contraceptives can affect the metabolism of other active ingredients. Consequently, plasma and tissue concentrations may increase (e.g., cyclosporine) or decrease (e.g., lamotrigine).

Concomitant administration of strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin) or moderate (e.g. fluconazole, diltiazem, erythromycin) may increase serum concentrations of estrogen or progestins, including etonogestrel, the active metabolite of desogestrel.

During clinical trials with the combined HCV drug regimen ombitasvir / paritaprevir / ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medicinal products as contraceptives combined oral (COC). Gracial should be discontinued prior to initiating therapy with the combined ombitasvir / paritaprevir / ritonavir drug regimen with or without dasabuvir (see sections 4.3 and 4.4). Gracial can be started again approximately 2 weeks after ending treatment with the combined drug regimen.

Laboratory tests

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

04.6 Pregnancy and breastfeeding

Gracial is not indicated during pregnancy. If pregnancy occurs during treatment with Gracial, its administration should be discontinued. However, most epidemiological studies did not reveal an increased risk of birth defects in babies born to women who had used a COC before pregnancy, nor any teratogenic effects if it was inadvertently taken early in pregnancy. a combined oral contraceptive.

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

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 milk, but there is no evidence that this adversely affects the health of the baby.

04.7 Effects on ability to drive and use machines

No effects on the ability to drive and use machines have been observed.

04.8 Undesirable effects

Description of some adverse reactions

An increased risk of arterial and venous thrombotic and thromboembolic events has been observed in CHC users, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis and pulmonary embolism, hypertension, hormone-dependent tumors (e.g. liver tumors, breast cancer), chloasma and this risk is discussed in more detail in section 4.4.

As with all combined oral contraceptives, changes in the characteristics of vaginal bleeding may occur, especially in the first months of treatment. These changes may include changes in the frequency (absent, reduced, more frequent or continuous), in the intensity (reduced or increased) or in the duration of bleeding.

Undesirable effects possibly related to the product that have been reported in users of Gracial or a combined oral contraceptive in general are listed in the table below1. All adverse reactions are listed by system organ class and frequency: common (≥1 / 100,

System and organ classification common Uncommon Rare Disorders of the immune system Hypersensitivity Metabolism and nutrition disorders Fluid retention Psychiatric disorders Depressed mood, mood changes Reduction of libido Increased libido Nervous system disorders Headache Migraine Eye disorders Contact lens intolerance Vascular pathologies Venous thromboembolism (VTE), arterial thromboembolism (ATE) Gastrointestinal disorders Nausea, abdominal pain Vomiting, diarrhea Skin and subcutaneous tissue disorders Rash, hives Erythema nodosum, erythema multiforme Diseases of the reproductive system and breast Breast pain, breast tenderness Breast hypertrophy Vaginal secretions, breast secretions Diagnostic tests Weight gain Weight loss

1 The MedDRA term best suited to describe a certain adverse reaction is given. No synonyms or related conditions are reported; nevertheless, they too must be taken into consideration.

Interactions

Interaction between oral contraceptives and other drugs (enzyme inducers) may cause intermenstrual bleeding and / or contraception failure (see section 4.5).

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 adverse effects from overdose have been reported.

In this circumstance, symptoms such as nausea, vomiting and in girls, mild vaginal bleeding may occur. There are no antidotes and further treatment should be symptomatic.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Systemic hormonal contraceptives, estrogen-progestogen sequential preparations

ATC code: G03AB05

Gracial is a biphasic oral contraceptive containing desogestrel as a progestin. The biphasic dosing regimen consists in the administration of a low dose of progestogen, then gradually increased, while, at the same time, the dose of estrogen is reduced.

The contraceptive effect of COCs is based on the interaction of various factors; the most important are the inhibition of ovulation and the modifications of the cervical secretion. In addition to protecting against the risk of pregnancy, combined oral contraceptives have several positive properties which, alongside the negative ones (see "Special warnings and precautions for use" and "Undesirable effects"), can be useful in choosing the method of birth control to be adopted. The menstrual cycle is more regular, menstruation is often less painful and blood loss less abundant. The latter situation can lead to a decrease in the incidence of iron deficiency. It also exists with oral contraceptives combined with higher dosages (50 mcg ethinylestradiol) evidence of a reduced risk of fibrocystic breast tumors, ovarian cysts, pelvic inflammatory disease, ectopic pregnancy, and endometrial and ovarian cancer. Whether this also applies to combined oral contraceptives remains to be confirmed. at lower dosages.

Pediatric population

There are no clinical data on efficacy and safety in adolescents below 18 years of age.

05.2 Pharmacokinetic properties

Desogestrel

Absorption

After oral administration, desogestrel is rapidly and completely absorbed and converted to etonogestrel. Peak serum levels are reached in approximately 1.5 hours. Bioavailability is 62-81%.

Distribution

Etonogestrel binds to serum albumin and sex hormone binding globulin (SHBG). Only 2-4% of total serum drug concentrations are present as a free steroid, while 40-70% binds specifically to "SHBG. The" ethinylestradiol-induced increase in SHBG affects distribution relative to serum proteins, resulting in a an increase in the SHBG-bound fraction and a reduction in the albumin-bound fraction. The apparent volume of distribution of desogestrel is 1.5 l / kg.

Metabolism

Etonogestrel is completely metabolised by known metabolic pathways of steroids. The extent of metabolic clearance in serum is approximately 2 ml / min / kg. No interactions were noted with the concomitant administration of ethinylestradiol.

Elimination

Serum levels of etonogestrel decrease in a biphasic manner. The final phase of terminal elimination is characterized by a half-life of approximately 30 hours. Desogestrel and its metabolites are excreted via the urinary and biliary routes, at a ratio of approximately 6: 4.

Steady state conditions

The pharmacokinetics of etonogestrel are influenced by SHBG levels, which are tripled by ethinylestradiol. After daily administration, serum levels of the drug increase approximately 2 to 3-fold, reaching steady state in the second half of the treatment cycle.

Ethinylestradiol

Absorption

Orally administered ethinylestradiol is rapidly and completely absorbed. Peak serum levels are reached in 1-2 hours. Absolute bioavailability after presystemic conjugation and first pass metabolism is approximately 60%.

Distribution

Ethinylestradiol is highly but nonspecifically bound to serum albumin (approximately 98.5%) and induces an increase in serum SHBG concentrations. An apparent volume of distribution of approximately 5 L / kg has been determined.

Metabolism

Ethinylestradiol is subject to presystemic conjugation at the level of both the mucosa of the small intestine and the liver. The main metabolic pathway of ethinylestradiol is aromatic hydroxylation but a wide range of hydroxylated and methylated metabolites are also formed, present as free metabolites and conjugated with glucuronides and sulphates. The extent of metabolic clearance is approximately 5 ml / min / kg.

Elimination

Serum levels of ethinylestradiol decrease in a biphasic manner, and the elimination phase is characterized by a half-life of approximately 24 hours. Unchanged drug is not excreted, ethinylestradiol metabolites are excreted via the urinary and biliary routes with a ratio of of 4: 6. The half-life of metabolite excretion is approximately 1 day.

Steady state conditions

Steady state concentrations are reached after 3-4 days, when serum drug levels are 30-40% higher than single administration.

05.3 Preclinical safety data

Preclinical data did not reveal any specific risks for humans when COCs are taken as recommended. This is the finding of conventional studies on repeated dose toxicity, genotoxicity, carcinogenic potential and reproductive toxicity. However, it should be remembered. that sex steroids can promote the growth of certain hormone-dependent tissues and tumors.