DIANE - PACKAGE LEAFLET - LEAFLETS

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Diane - Package Leaflet

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

Active ingredients: Cyproterone (cyproterone acetate), Ethinylestradiol

Diane 2 mg + 0.035 mg coated tablets

Why is Diane used? What is it for?

The use of Diane is reserved for cases where it is necessary to treat the androgen-dependent diseases described in the indications. Although due to its composition Diane also has a contraceptive effect, it must not be used for this purpose. Therefore after complete resolution of the conditions for which the medicine has been prescribed it is recommended that Diane is not further used for contraceptive purposes alone. All information regarding combined oral contraceptives is included in this leaflet. Patients being treated with Diane should not use any other hormonal contraceptives because this would expose the patient to excessive doses of hormones without any need for effective contraceptive treatment.

Diane is used to treat skin conditions such as acne, very oily skin and excessive hair growth in women of childbearing age. Due to its contraceptive properties, the medicine should only be prescribed if the doctor deems it appropriate. treatment with a hormonal contraceptive (birth control pill).

You should only take Diane if your skin disease has not improved with other acne treatments, including local therapies and antibiotics.

Although Diane also has contraceptive effect, it cannot be prescribed for such purposes; use should instead be reserved in cases where treatment of the androgen-dependent diseases described above is necessary. It is recommended that treatment be suspended three to four cycles after the complete resolution of the conditions for which the drug was prescribed and that Diane it is not further used for contraceptive purposes only.Further courses of treatment with Diane may be given if the androgen-dependent conditions recur.

Contraindications When Diane should not be used

General notes

Diane contains the progestogen cyproterone acetate and the estrogen ethinyl estradiol, and is administered for twenty-one days in monthly cycles. Therefore it is essentially analogous to a combined oral contraceptive. This leaflet describes some situations in which it is necessary to stop taking the medicine or in which there may be a reduction in the efficacy of the drug itself. In such situations, therefore, the contraceptive action is also lacking; therefore, if you wish to avoid pregnancy, you must not have sexual intercourse or take additional 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 estrogen-progestin associations such as Diane alter the normal changes in temperature and cervical mucus that occur during the menstrual cycle.

Before starting or restarting to take Diane it is advisable to carry out a thorough medical examination. It is also advisable to carry out periodic check-ups while using the medicine. The frequency and type of visit will be established by the doctor and aimed in particular at blood pressure control, an examination of the breasts, abdomen and gynecology in general, including a Pap test and related blood tests.

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

Diane is prescribed for personal use and must not be available to more than one person at the same time.

Don't use Diane

Tell your doctor before you start using Diane if any of the following apply to you. In this case, your doctor may prescribe a different treatment:

if you are using another hormonal contraceptive;
if you have (or have had in the past) a blood clot in the leg (thrombosis), in the lungs (pulmonary embolism) or in another part of the body;
if you have (or have had in the past) a disease which may herald a heart attack in the future (eg angina pectoris, which causes severe chest pain) or a 'mini-stroke' (transient ischemic attack);
if you have (or have had in the past) a heart attack or stroke;
if you have a disease which may increase the risk of a blood clot in the arteries. This happens in the following diseases:

o diabetes affecting blood vessels,

o very high blood pressure,

o very high levels of fats (lipids) in the blood (cholesterol or triglycerides);

if you have blood clotting problems (for example Protein C deficiency);
if you have (or have had in the past) a 'migraine accompanied by visual disturbances.
if you are allergic to cyproterone acetate, ethinyl estradiol or any of the other ingredients of this medicine
if you suffer from cardiovascular disorders: coronary artery disease, valvulopathies, rhythm disturbances that can originate thrombi.
if you have sickle cell anemia (an inherited disease of the red blood cells);
if you have or have ever had jaundice (yellowing of the skin) or severe liver disease;
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;
if you are breast-feeding (see 'Pregnancy and breast-feeding').
if you have suffered from Herpes gestationis (autoimmune skin disease affecting women during pregnancy or in the immediate postpartum period).
if you have had hearing loss from otosclerosis during pregnancy;
if you are a young woman and have a menstrual cycle that has not yet stabilized.
if you have vascular eye problems

If any of these conditions appear for the first time while using the medicine, stop taking it immediately and consult your doctor.

Diane is not to be used in humans.

Precautions for use What you need to know before you take Diane

Talk to your doctor or pharmacist before using Diane.

The effectiveness of Diane may be affected if you forget to take tablets or if you vomit and / or diarrhea (see "How to use Diane"), or if you take other medicines at the same time (see "Other medicines and Diane ").

When to contact your doctor

Stop taking the tablets and contact your doctor immediately if you notice any possible signs of a clot. The symptoms are described in the section "Blood clots (thrombosis)".

Reasons requiring immediate discontinuation of treatment with Diane:

first onset, or worsening, of migraines or increased frequency of headaches of unusual intensity;
sudden disturbances in vision or hearing or other disturbances in perception;
early symptoms of thrombophlebitis or thromboembolic symptoms (formation of blood clots in the blood vessels) (e.g. unusual pain or edema in the lower limbs, stinging when breathing or cough of an unknown nature). Feeling of pain and constriction in the chest;
six weeks before major surgery (e.g. abdominal, orthopedic) including lower limb surgery and variceal sclerosing therapy, and for the duration of a state of immobilization, such as in the event of an accident or surgery. Treatment with Diane can be resumed two weeks after full recovery of ambulatory. In case of emergency interventions, preventive antithrombotic treatment will be indicated, such as subcutaneous administration of heparin;
onset of jaundice (yellowish discoloration of the skin, mucous membranes and whites of the eyes), hepatitis, generalized itching;
increased seizures;
noticeable increase in blood pressure;
onset of severe depression;
severe pain in the upper abdominal region or enlarged liver;
worsening of conditions that are known to worsen during use of oral contraceptives or during pregnancy;
pregnancy is a reason for immediate discontinuation of treatment, as a slight increase in the risk of fetal malformations cannot be excluded.

If any of the conditions listed below are present, the use of Diane may require close medical supervision. You should therefore warn your doctor of any of the following conditions before starting to use Diane:

smoke;
diabetes;
overweight;
hypertension (high blood pressure);
heart valve defects or certain heart rhythm disturbances;
superficial phlebitis (venous inflammation);
varicose veins;
history of thrombosis, heart attack or stroke (even among close family members);
migraine (headache on one side only);
depression;
epilepsy;
a history of high levels of cholesterol and triglycerides (fats) in the blood (including in close family members);
breast lumps;
family history (including close relatives) of breast cancer;
liver or gallbladder disease;
if you have Crohn's disease or ulcerative colitis (chronic inflammatory bowel disease);
if you have Systemic Lupus Erythem atosus (SLE, a disease that affects the skin all over the body);
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);
porphyria (metabolic blood abnormality);
if you have or have had chloasma (yellowish-brown pigmented patches on the skin, especially on the face). In this case, avoid prolonged exposure to the sun or ultraviolet rays;
if you suffer from fluid retention
if you have a reduction in folate levels
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;
hereditary angioedema (the appearance of swelling of the skin, mucous membranes and internal organs).

If any of the above conditions appear for the first time, come back or worsen while using Diane, consult your doctor.

Do not take hypericum preparations (Hypericum perforatum) as the effectiveness of medicines containing oral contraceptives may be decreased (see "Other medicines and Diane"). The use of Diane can affect the results of some blood tests. Tell the doctor who ordered the tests that you are taking this medicine.

Diane is also an oral contraceptive. Together with your doctor, you should consider all aspects relating to the safe use of oral hormonal contraceptives.

Blood clots (thrombosis)

Taking Diane may slightly increase the risk of a blood clot (thrombosis). The likelihood of a blood clot is only slightly increased if you take Diane compared to women who do not take Diane or any other pill. contraceptive: Thrombosis does not always heal and in 1-2% of cases it can cause death.

Blood clots in a vein

A blood clot in a vein (venous thrombosis) can block the vein. This can happen in the veins of the legs, lungs (pulmonary embolism) or any other organ.

The use of a combined birth control pill increases a woman's risk of developing a clot compared to women who are not taking any combined birth control pills. The risk of developing a blood clot in a vein is highest in the first year of using the pill. This risk is lower than the risk of developing a blood clot during pregnancy.

In users of a combined birth control pill, the risk of a blood clot forming in a vein is further increased:

with increasing age;
if you smoke. It is strongly recommended that you stop smoking if you are using a hormonal contraceptive such as Diane, particularly if you are over 35;
if a member of your family has had a blood clot in the legs, lungs or other part of the family when they are young;
if you are overweight;
if you need to have surgery, if you have to stay in bed for a long time due to an accident or illness or if you have a leg in a cast.

In these cases, it is important that you tell your doctor that you are using Diane so that the treatment can be stopped. If necessary, your doctor will tell you to stop using Diane several weeks before surgery or while you have reduced mobility. Your doctor will also tell you when you can resume using Diane once you are on your feet again.

Blood clots in an "artery

A clot in an artery can cause serious problems. For example, a clot in an artery in the heart can cause a heart attack, while in the brain it can cause a stroke.

Use of a combined birth control pill has been associated with an increased risk of blood clots in the arteries. The risk further increases:

with increasing age;
if you smoke. It is strongly recommended that you stop smoking if you are using a hormonal contraceptive such as Diane, particularly if you are over 35;
if you are overweight;
if you have high blood pressure;
if a member of your family had a heart attack or stroke when you were young;
if you have high levels of fats (lipids) in the blood (cholesterol or triglycerides);
if you suffer from migraines;
if you have a heart problem (heart valve disease, rhythm disturbances).

Arterial thromboembolism events can be life-threatening or can have a fatal outcome.

Symptoms of blood clots

Stop taking the tablets and see your doctor immediately if you notice any possible signs of a clot, such as:

unusual sudden cough;
severe pain in the chest, which may radiate to the left arm;
breathlessness;
any unusual, severe or persistent headache, or worsening of migraine;
partial or total blindness, or double vision;
difficulty or inability to speak;
sudden changes in hearing, smell or taste;
dizziness or fainting;
weakness or numbness in any part of the body;
intense pain in the abdomen;
severe pain or swelling in one leg.

After a clot has formed, healing is not always complete. Severe and permanent disabilities may rarely appear and the clot can even cause death. Immediately after delivery, the risk of clots forming is increased; therefore, you should ask your doctor how long you need to wait after having a baby before you can start taking Diane.

If you have a combination of risk factors or show greater severity for a single risk factor, there may be a greater potential risk of thrombosis than the simple cumulative risk of the factors.

Diane must not be prescribed if the benefit / risk assessment is negative (see "Do not use Diane").

Tumors

Breast cancer diagnoses are slightly more frequent in women who use an oral estrogen-progestogen combination than in age-matched women who do not. The slight increase in the number of breast cancer diagnoses gradually disappears over the course of ten years after discontinuation of treatment. It is not known whether the difference is due to the oral estrogen-progestogen combination.

This increase could be due to an earlier diagnosis, as women are seen more frequently, to the biological effect of the oral estrogen-progestogen combination or to both factors. Breast cancer diagnosed in women treated with an oral estrogen-progestogen combination tends to be clinically less advanced than that diagnosed in women who do not use it.

Benign liver tumors and even more rarely malignant liver tumors have been reported in women treated with an oral estrogen-progestogen combination. These tumors can cause internal bleeding. Consult your doctor immediately in case of severe abdominal pain. Tumors can be life-threatening or can have fatal outcomes.

Cancer of the neck of the uterus (cervix) has been reported to be more common in women on long-term oral estrogen-progestogen treatment. This may not depend on the oral estrogen-progestogen association, but on sexual behavior and other factors involved in the development of tumors in general.

Periodic checks

While using Diane, your doctor will ask you to come for periodic check-ups.

See your doctor as soon as possible:

if you notice any changes in your health, in particular as reported in this leaflet (see also "Do not use Diane" 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 Diane");
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 have forgotten to take the tablets in the first week of use and have had sexual intercourse 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.

Girls and teenagers

Diane is indicated only after menarche (the onset of the first menstrual cycle).

Older women

Diane is not indicated after menopause (the cessation of the menstrual cycle).

Women with impaired hepatic (liver) function

Do not use Diane if you have severe liver disease. See also section "Precautions for use".

Women with impaired renal function

Tell your doctor if you have kidney problems.

Interactions What drugs or foods can change the effect of Diane

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

Some medicines can prevent Diane from working effectively. These include:

primidone, phenytoin, barbiturates, carbamazepine (used to treat epilepsy). Other antiepileptic medicines (oxcarbazepine, topiramate, felbamate) are also likely to reduce the effectiveness of Diane.
rifampicin (used to treat tuberculosis);
ampicillin, tetracyclines, griseofulvin (antibiotics used for the treatment of infectious diseases);
ritonavir, nevirapine (used to treat HIV infections and hepatitis C); in these cases there may be increases or decreases in estrogen and progestogen
modafinil and flunarizine;
products containing St. John's wort ("Hypericum perforatum"). Do not take preparations containing St. John's wort (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 effect may persist for at least two weeks after stopping treatment with hypericum-based products

Diane, like other estrogen-progestogen combinations, may interfere with the action of other medicines such as cyclosporine (immunosuppressive medicine) and lamotrigine (antiepileptic medicine).

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

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 Diane during known or suspected pregnancy.

Diane is not advised while breastfeeding.

Driving and using machines

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

Diane 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 medicine.

Dosage and method of use How to use Diane: Dosage

Always take this medicine exactly as your doctor or pharmacist has told you.

If in doubt, consult your doctor or pharmacist. Having a composition similar to that of COCs, Diane inhibits ovulation and therefore prevents conception. Therefore, she should not use other hormonal contraceptives as this would expose her to excessive doses of hormones without any need for effective contraceptive treatment. For the same reason, if you want to get pregnant you shouldn't take Diane.

Diane should be taken regularly as irregular intake can lead to intermenstrual bleeding and a loss of contraceptive properties.

The tablets should be taken with some liquid, at approximately the same time each day, in the order indicated on the package.

Beginning of the first pack

Start taking Diane on the first day of your period with the tablet marked with the corresponding day of the week; for example one tablet marked Friday if your period starts on Friday. Then follow the days in order, taking one tablet without chewing it, every day at the same time, preferably in the evening, until exhaustion. The pack contains twenty-one tablets.

Subsequent courses of treatment

When all twenty-one tablets are used up, stop taking it for seven days during which your period should begin. Resume treatment on the eighth day, even if your period continues. In this way, the new package will start on the same day of the week as the previous one.

Duration of use

Your doctor will tell you how long to take Diane for.

The duration of treatment depends on the severity of your condition; treatment should normally be continued for several months.

If a recurrence occurs again after weeks or months of stopping, consult your doctor who will resume treatment with Diane. If Diane is resumed (following a pill-free interval of 4 weeks or more), an increased risk of venous thromboembolism should be considered (see also "Warnings and precautions").

Special situations

Switching from an oral contraceptive to Diane

Start taking Diane on the first day of your period which occurs after the last tablet of your previous oral contraceptive and then follow the instructions above.

Taking Diane after childbirth or after an abortion

Normally, after a birth or abortion, Diane should only be prescribed after the completion of the first normal menstrual cycle.

If immediate and reliable contraceptive effect is required for medical reasons, treatment with Diane can be started on the twelfth (but not earlier than the seventh) day after delivery or no later than the fifth day after the abortion.

When oral estrogen-progestogen combinations are given in the period immediately following delivery or abortion, the increased risk of thromboembolic disease should be considered.

If you are breastfeeding and want to take Diane, talk to your doctor first.

Absence of withdrawal bleeding (menstruation)

If, in exceptional cases, withdrawal bleeding does not occur, the possibility of an ongoing pregnancy must be ruled out before continuing to take Diane, which would require immediate interruption of treatment.

Measures in case of irregular bleeding

Sometimes slight bleeding (spotting) or intermenstrual bleeding is observed, particularly during the first three months of use, which usually ceases spontaneously. Continue to take Diane even in case of irregular bleeding. If the bleeding persists or recurs, medical interventions are recommended to rule out organic causes and the possible need for a curettage.

This also applies to minor bleeding that recurs at irregular intervals in several consecutive cycles or occurs for the first time after prolonged use of Diane.

In case of vomiting or diarrhea

In case of vomiting or diarrhea within 3 or 4 hours after taking the tablet, the active substances may not be absorbed adequately. becoming pregnant which would require immediate interruption of treatment.

Overdose What to do if you have taken too much Diane

If you take more medicine than you should

There have been no reports of serious side effects when taking several tablets at the same time. In this case, nausea, vomiting or vaginal bleeding may occur

If you accidentally swallow / take an overdose of Diane, notify your doctor immediately or go to the nearest hospital.

If you forget to take Diane

If you forget to take a Diane tablet at the usual time, you will have to take it within the next twelve hours. If more than 36 hours have passed since taking the last tablet, the contraceptive property of Diane is no longer guaranteed. resume your normal daily intake but take additional contraceptive precautions for the rest of the cycle to avoid becoming pregnant which would require immediate interruption of treatment.

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

Side Effects What are the side effects of Diane

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

If you experience any side effects, especially if they are severe and persistent, or if you change your health condition that you think may be caused by Diane, please tell your doctor.

Serious side effects

The following serious side effects associated with the use of estrogen-progestogen combinations, and related symptoms, are described in the section "Warnings and precautions": "Blood clots (Thrombosis)" and "Cancers":

hypertension
hypertriglyceridemia
diabetes
liver tumors (benign and malignant)
liver problems
chloasma
angioedema
cholestatic jaundice and / or pruritus, gallstone formation, porphyria, systemic lupus erythematosus, hemolytic uremic syndrome, Sydenham's chorea, herpes gestationis, otosclerosis hearing loss, Crohn's disease, ulcerative colitis, cervical cancer.

For more information, read these sections and consult your doctor immediately.

Other side effects

In women using oral estrogen-progestogens, such as Diane, the following side effects have been reported based on their frequency:

Common side effects (≥1 / 100): may affect more than 1 in 100 people

nausea, abdominal pain, changes in body weight (increased weight) headache mood changes breast pain

Uncommon side effects (≥1 / 1000 and

vomiting, diarrhea,

fluid retention

breast hypertrophy (breast enlargement which can make the breasts tight)

skin reactions, hives

migraine (one-sided headache)

decreased sexual desire

Rare side effects (

contact lens intolerance hypersensitivity reactions (allergy)

changes in body weight (decreased weight)

increased sexual desire

vaginal secretions

breast secretions

erythema nodosum, erythema multiforme or polymorphic thromboembolism

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 https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects you can help provide more information on 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 the word "EXP." The expiry date refers to the last day of that month. This date refers to the product in intact packaging, correctly stored.

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

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.

What Diane contains
The active ingredients are: cyproterone acetate and ethinyl estradiol. Each coated tablet contains 2.0 mg of cyproterone acetate and 0.035 mg of ethinylestradiol.
The other ingredients are: lactose, corn starch, povidone 25,000, talc, magnesium stearate, sucrose, povidone 700,000, macrogol 6,000, calcium carbonate, glycerol 85%, ethylene glycol ester of montanic acid, titanium dioxide, yellow iron oxide.

Description of Diane's appearance and contents of the package

Blister with 21 coated 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 Diane 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 lactation Pregnancy04.7 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 DE THE FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIATION DRUGS, FURTHER DETAILED INSTRUCTIONS ON QUALITY PREPARATION

01.0 NAME OF THE MEDICINAL PRODUCT

DIANE 2 MG + 0.035 MG COATED TABLETS

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

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

21 coated tablets

Each coated tablet contains: 2.0 mg of cyproterone acetate and 0.035 mg of ethinylestradiol. For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Coated tablet.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Treatment of moderate to severe acne related to androgen sensitivity (with or without seborrhea) and / or hirsutism in women of childbearing age.

For the treatment of acne, Diane should only be used after topical therapy or systemic antibiotic treatment has failed.

Since Diane is also a hormonal contraceptive, it must not be used in combination with other hormonal contraceptives (see section 4.3).

04.2 Posology and method of administration

Method of administration

Oral use

Dosage

Having a composition similar to that of the combined oral contraceptives Diane inhibits ovulation and therefore prevents conception.Therefore, patients being treated with Diane should not use other hormonal contraceptives as this would expose the patient to excessive doses of hormones without any need for effective contraceptive treatment.

For the same reason, women wishing to plan a pregnancy should not take Diane.

Diane must be taken regularly to achieve the desired therapeutic effect and contraceptive protection. The dosage regimen of Diane is similar to that of most combined oral contraceptives. The same rules must therefore be followed for administration. orals, taken correctly, have a failure rate of about 1% per year. The irregular intake of Diane can lead to intermenstrual bleeding and can compromise therapeutic and contraceptive reliability.

Before starting Diane, a complete general medical and gynecological examination (including breast and Papanicolau smear) and family history should be carefully evaluated.

If any family member has had thromboembolic diseases (such as deep vein thrombosis, stroke, myocardial infarction) at a young age, any bleeding disorders should be ruled out.

Rule out a state of pregnancy.

The tablets should be taken with some liquid, at approximately the same time each day, in the order indicated on the package.

• First cycle

Taking the tablets from the first pack of Diane should start on the first day of your period, ie the first day of your period.

The treatment will continue with the intake of 1 tablet in each of the following 21 days, followed by an interval without treatment of 7 days, during which a withdrawal bleeding will occur.

• Subsequent cycles

Tablet-taking from the next pack will resume after the seven-day interval, on the same day of the week on which the first pack was started.

• Switching from an oral contraceptive to Diane

The first tablet of Diane should be taken on the first day of the bleeding that occurs after taking the last tablet of the patient's previous oral contraceptive.

• Irregular employment

If the patient forgets to take a Diane tablet at the usual time, she will have to take it within the next twelve hours. If more than 36 hours have passed since taking the last tablet, contraceptive protection is no longer guaranteed. normal daily intake, but take additional contraceptive precautions for the rest of the cycle to avoid becoming pregnant which would require immediate discontinuation of treatment.

• Post-partum and post-abortum use

Normally, after a birth or abortion, Diane should only be prescribed after the completion of the first normal menstrual cycle.

If medical reasons also require an immediate and reliable contraceptive effect, treatment with Diane can be started within the twelfth (but not earlier than the seventh) day after delivery or no later than the fifth day after the abortion.

When oral contraceptives are given in the period immediately following delivery or abortion, the increased risk of thromboembolic disease should be considered.

• Absence of withdrawal bleeding

• Measures in case of irregular bleeding

Sometimes slight bleeding (spotting) or intermenstrual bleeding is observed, particularly during the first three months of use, which usually ceases spontaneously. The woman can therefore continue taking Diane even in the case of irregular bleeding. If the bleeding persists or recurs, diagnostic interventions are recommended to exclude organic causes and the possible need for a curettage.

This also applies to minor bleeding that recurs at irregular intervals in several consecutive cycles or occurs for the first time after prolonged use of Diane.

• Gastrointestinal disorders

In the case of severe gastrointestinal disturbances, absorption may be incomplete. If vomiting or diarrhea occurs within three to four hours of taking the tablet, contraceptive efficacy may decrease, as if a tablet had been missed, so continue taking the tablet. normal daily intake, but take additional contraceptive precautions for the remainder of the cycle, to avoid becoming pregnant which would require immediate discontinuation of treatment (see also section 4.4 "Reduction or loss of efficacy"). If the gastrointestinal disturbance continues, other contraceptive methods should be considered.

Duration of use

The duration of use depends on the severity of the clinical picture and the response to treatment, and treatment should normally be continued for several months.

Acne and seborrhea usually respond faster than hirsutism.

If symptoms recur after weeks or months of discontinuation, treatment with Diane should be restarted.

The time it takes to relieve symptoms is at least three months. The need for continued treatment should be evaluated periodically by the physician.

If Diane is resumed (following a pill-free interval of 4 weeks or more), an increased risk of venous thromboembolism (VTE) should be considered. See section 4.4 Special warnings and precautions for use.

Additional information for particular categories of patients

Pediatric population

Diane is indicated only after the menarche.

Geriatric population

Not relevant. Diane is not indicated after menopause.

Patients with impaired hepatic function

Diane is contraindicated in patients with severe liver disease. See also section 4.3.

Patients with impaired renal function

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

04.3 Contraindications

Estrogen-progestogen preparations should not be used in the presence of any of the conditions listed below.

• Known or suspected pregnancy.

• Feeding time.

• Young women whose menstrual cycles have not yet stabilized.

• Personal or family history of idiopathic venous thromboembolic disease (VTE), when family history refers to VTE in relatively young siblings or parents.

• Thrombotic or venous embolic processes in progress.

• Current or previous arterial thrombotic or embolic processes.

• A high risk of venous and arterial thrombosis (see 4.4 "Special warnings and precautions for use").

• Cardiovascular disorders: hypertension, coronary heart disease, valvulopathies, rhythm disturbances that can cause thrombus.

• Sickle cell anemia.

• History of migraine with focal neurological symptoms.

• Diabetes mellitus complicated by micro or macroangiopathies.

• Ophthalmic pathology of vascular origin.

• Lipid metabolism disorders.

• Severe disturbances in liver function, until liver function indices have returned to normal, jaundice or severe itching in pregnancy in history, Dubin-Johnson syndrome, Rotor syndrome.

• Current or previous liver tumors (benign or malignant).

• Breast dysplastic diseases ascertained with a specialist medical examination.

• Known or suspected hormone-dependent malignancies of the genital organs or the breast.

• Vaginal bleeding of an unknown nature.

• Herpes gestationis in the anamnesis.

• Worsening of otosclerosis during pregnancy.

• Hypersensitivity to any of Diane's components.

• Concomitant use of another hormonal contraceptive (see section 4.1)

• Presence or history of venous thrombosis (deep vein thrombosis, pulmonary embolism)

• Presence or history of arterial thrombosis (eg myocardial infarction) or prodromal conditions (eg angina pectoris and transient ischemic attack)

• Presence or positive history of cerebrovascular accident

• Presence of severe or multiple risk factors for venous or arterial thrombosis (see section 4.4), such as:

• diabetes mellitus with vascular symptoms

• severe hypertension

• severe dyslipoproteinemia

• Hereditary or acquired predisposition to venous or arterial thrombosis, such as resistance to activated protein C (activated protein C, APC), antithrombin III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia and antiphospholipid antibodies (anticardiolipin antibodies, lupus-like anticoagulant)

If any of these conditions appear for the first time while using Diane, the intake should be discontinued immediately.

Diane is not to be used in humans.

04.4 Special warnings and appropriate precautions for use

Diane is composed of the progestin cyproterone acetate and estrogen ethinyl estradiol and is administered for 21 days of the menstrual cycle. Its composition is similar to that of combined oral contraceptives. Clinical and epidemiological experience with estrogen / progestogen combinations such as Diane is predominantly based on combined oral contraceptives. Therefore, the following warnings relating to the use of combined oral contraceptives also apply to Diane.

Duration of use

The time it takes to relieve symptoms is at least three months. The need for continued treatment should be evaluated periodically by the physician (see section 4.2).

Warnings:

Cigarette smoking increases the risk of serious cardiovascular side effects associated with the use of COCs or Diane. This risk increases with age and with the number of cigarettes smoked (fifteen or more cigarettes per day), and is more marked in women over 35 years of age. Women using COCs or Diane should be strongly advised not to smoke.

Medical examination

Before starting or restarting the administration of Diane a complete medical history should be taken and a medical examination should be performed, based on the indications under "Contraindications" (section 4.3) and "Warnings" and should be repeated periodically. A periodic medical examination is important because some contraindications (for example a transient ischemic attack, etc.) or risk factors (for example a "family history of venous or arterial thrombosis) may appear for the first time while using Diane. The frequency and type of these visits should be individually tailored to the patient, but should generally pay particular attention to blood pressure, breast, abdominal and pelvic organs, including cervical cytology and relevant laboratory tests.

Women should be warned that preparations such as Diane do not protect against HIV infection (AIDS) or other sexually transmitted diseases.

If any of the following conditions or risk factors are present, the benefits of using Diane should be weighed on a case-by-case basis against the possible risks and discussed with the woman before she decides to start taking Diane. In case of worsening, exacerbation or first appearance of any of the conditions or risk factors mentioned, the woman should contact her doctor. The physician will then have to decide whether the use of Diane should be discontinued.

Circulatory disorders

• The use of Diane carries an increased risk of venous thromboembolism (VTE) compared with not using it. other treatment after an intake interval of at least one month. Venous thromboembolism can be fatal in 1-2% of cases.

• Epidemiological studies have shown that the incidence of VTE is 1.5 to 2 times higher in users of Diane compared to users of combined oral contraceptives containing levonorgestrel and may be similar to the risk related to combined oral contraceptives containing desogestrel / gestodene. / drosperinone.

• The group of users of Diane is likely to include patients who may be at increased risk for inherited cardiovascular events, such as polycystic ovary syndrome.

• Epidemiological studies also show an "association" between the use of hormonal contraceptives and an increased risk of arterial thromboembolism (myocardial infarction, transient ischemic attack).

• In extremely rare cases, thrombosis affecting other blood vessels has been reported in users of hormonal contraceptives, eg. hepatic, mesenteric, renal, cerebral or retinal veins and arteries.

• Symptoms of venous or arterial thrombosis or a cerebrovascular accident may include: unusual unilateral pain and / or swelling in the lower limb; sudden and intense pain in the chest, with or without irradiation to the left arm; sudden wheezing; sudden fits of cough ; any unusual, severe and prolonged headache; sudden partial or total loss of vision; diplopia; dysarthria or aphasia; vertigo; collapse with or without focal seizure; sudden weakness or very marked numbness on one side or part of the body; motor disturbances; acute abdomen.

• The risk of venous thromboembolic events increases with:

- increasing age;

- smoking (the risk increases further in heavy smokers and with increasing age, particularly in women over 35 years of age. Women over the age of 35 should be advised not to smoke if they wish to use Diane );

- a positive family history (ie previous venous thromboembolism in a brother / sister or parent at a relatively young age). In case of suspected hereditary predisposition, the woman should consult a specialist before deciding on the use of any hormonal contraceptive;

- prolonged immobilization, major surgery, any surgery on the lower limbs or major trauma. In such situations it is advisable to discontinue its use (in the case of elective surgery, at least four weeks in advance) and not to resume it until two weeks have elapsed after complete mobilization. An antithrombotic treatment should be considered if the " Diane's use hasn't been discontinued.

- obesity (body mass index greater than 30 kg / m2);

• The risk of arterial thromboembolic complications or a cerebrovascular accident increases with:

- increasing age;

- dyslipoproteinemia;

- obesity (body mass index greater than 30 kg / m2);

- hypertension;

- migraine;

- heart valve disease;

- atrial fibrillation;

- positive family history (previous arterial thrombosis in a brother / sister or parent at a relatively young age). In case of suspected hereditary predisposition, the woman must consult a specialist before deciding to use any hormonal contraceptive.

• Other medical conditions that have been associated with adverse circulatory events include diabetes mellitus, systemic lupus erythematosus, haemolytic uremic syndrome, chronic inflammatory bowel disease (eg Crohn's disease or ulcerative colitis) and sickle cell anemia.

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

• An increase in the frequency or severity of migraine (which may be prodromal to a cerebrovascular event) during use of Diane may be grounds for immediate discontinuation of its use.

Users of Diane should be specifically instructed to contact their doctor in case of possible symptoms of thrombosis. In the event of a suspected or confirmed thrombosis, the use of Diane should be discontinued. Adequate contraception must be started due to the teratogenicity of anticoagulant therapy (coumarins).

Arterial thromboembolism events can be life-threatening or can have a fatal outcome.

In women who have a combination of risk factors or who exhibit greater severity for a single risk factor, the potential for a synergistic increased risk of thrombosis should be considered.

This increased risk may be greater than the simple cumulative factor risk.

Diane should not be prescribed if the benefit / risk assessment is negative (see "Contraindications).

Tumors

Carcinoma of the reproductive organs and breast

An increased risk of cervical cancer has been reported in some epidemiological studies in women using oral estrogen-progestogen combinations for prolonged periods; 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 who are using oral estrogen-progestogen combinations have a slightly increased relative risk (RR = 1.24) of being diagnosed with breast cancer. The excess risk gradually disappears over the 10 years following discontinuation of treatment.Since breast cancer is a rare event in women under 40 years of age, the higher number of breast cancer diagnoses in women taking or recently taking an oral estrogen-progestogen combination is low compared to the risk of breast cancer that it runs during a woman's entire life. These studies provide no evidence of a causal relationship. The observed increase in risk may be due to an earlier diagnosis of breast cancer in women taking oral estrogen-progestogen combinations, the biological effects of the same or a combination of both factors. users of oral estrogen-progestogen combinations, tends to be less clinically advanced than that diagnosed in women who have never used an "oral estrogen-progestogen combination."

Hepatic neoplasia

Benign liver tumors and, even more rarely, malignant liver tumors have been reported rarely in women taking oral estrogen-progestogen combinations. In isolated cases, these tumors have resulted in "life-threatening intra-abdominal haemorrhage. If a woman taking an oral estrogen-progestogen" combination should have severe pain in the upper abdomen, hepatomegaly or signs suggestive of intra-abdominal haemorrhage, the differential diagnosis must take into account the possibility that it is a liver tumor.

Cancers can be life-threatening or can have a fatal outcome.

Other conditions

Liver function

Acute or chronic disturbances of liver function may require discontinuation of treatment with Diane until markers of liver function have returned to normal. Return of cholestatic jaundice already occurring in pregnancy or during previous sex steroid treatment requires discontinuation of Diane. .

Diseases of the gallbladder

Previous studies have reported an increased relative risk of gallbladder surgery in women using oral estrogen-progestogen and estrogen combinations. However, more recent studies have shown that the relative risk of developing gallbladder disease in women using oral estrogen-progestogen combinations may be minimal.

Eye injuries

Cases of retinal thrombosis have been reported during the use of oral estrogen-progestogen combinations. If there is an unexplained partial or complete loss of vision, the onset of proptosis or diplopia, papilledema or vascular lesions of the retina, of Diane should be discontinued and the cause should be assessed immediately.

Headache

The onset or exacerbation of migraine or the development of headache with a new feature that is recurrent, persistent and severe are situations that require discontinuation of Diane and evaluation of the cause.

Effects on the metabolism of lipids and carbohydrates

Although oral estrogen-progestogen combinations may affect peripheral insulin resistance and glucose tolerance, there is no evidence for the need for regimen adjustment in diabetic patients using estrogen-progestogen combinations. However while taking Diane diabetic patients must be carefully followed.

Women with hypertriglyceridaemia or a family history of this condition may be at increased risk of pancreatitis when taking oral estrogen-progestogen combinations.

Folate level

Serum folate levels may be decreased by oral estrogen-progestogen combination therapy. This could be of clinical significance if the woman becomes pregnant shortly after Diane's termination.

Fluid retention

Oral estrogen-progestogen combinations should be prescribed with caution to women whose medical conditions may be aggravated by fluid retention.

High blood pressure

The use of oral estrogen-progestogen combinations is contraindicated in women with a history of hypertension or with hypertension-related or kidney disease (see section 4.3). If hypertensive women choose to use Diane, they should be closely monitored and if there is a significant increase in blood pressure, Diane should be stopped.

Although a small rise in blood pressure has been reported in many women taking oral estrogen-progestogen combinations, a clinically relevant increase is rare. A relationship between the use of oral estrogen-progestogens and hypertension has not been established. However, if clinically significant hypertension occurs during use of an oral estrogen-progestogen combination, as a precaution the physician should discontinue use of the product and treat the hypertension. If appropriate, the use of the oral estrogen-progestogen combination can be resumed if normal blood pressure values have been obtained following antihypertensive therapy.

Pathology of the intestine

Crohn's disease and ulcerative colitis have been reported concomitantly with the use of oral estrogen-progestogen combinations.

Disorders of the emotional sphere

Women who become significantly depressed while taking oral estrogen-progestogen combinations should stop treatment to determine if this symptom is drug-related. Women with a history of depression should be monitored and treatment discontinued if have severe depression.

Irregular bleeding

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

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

In some women, withdrawal bleeding may not occur during the treatment-free interval. If Diane has been taken as described in section 4.2, it is unlikely that she is pregnant. taken correctly or if two withdrawal bleeds have not occurred, pregnancy must be ruled out before continuing to take Diane.

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

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

Angioedema

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

Reduction or loss of efficacy

The efficacy of oral estrogen-progestogen combinations may decrease in case of forgetting to take tablets (section 4.2) or in case of vomiting and / or diarrhea (section 4.2), or in case of concomitant use of other medicinal products (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 estrogen-progestogen combinations. , digoxin, theophylline, carbamazepine, phenobarbital, phenytoin (see section 4.5 "Interactions").

Reasons requiring immediate discontinuation of treatment with Diane:

1. first-time onset, or exacerbation, of migraines or increased frequency of headaches of unusual intensity;

2. sudden disturbances of vision or hearing or other disturbances of perception;

3. early symptoms of thrombophlebitis or thromboembolic symptoms (eg unusual pain or edema in the lower limbs, stinging pain when breathing or cough of an unknown nature). Feeling of pain and constriction in the chest;

4. six weeks prior to major surgery (eg abdominal, orthopedic) including lower limb surgery and variceal sclerosing therapy, and for the duration of a state of immobilization, such as in the event of an accident or surgery. Treatment with Diane can be resumed two weeks after full recovery of ambulatory. In case of emergency interventions, antithrombotic prophylaxis such as subcutaneous heparin will be indicated;

5. onset of jaundice, hepatitis, generalized itching;

6. increase in epileptic seizures;

7. significant increase in blood pressure;

8. onset of severe depression;

9. severe pain in the upper abdominal region or enlarged liver;

10. worsening of conditions that are known to worsen during use of oral contraceptives or during pregnancy;

11. Pregnancy is a reason for immediate discontinuation of treatment, as some studies suggest that oral contraceptives taken in early pregnancy may slightly increase the risk of fetal malformations. Other trials have not highlighted this risk. However, this possibility cannot. be excluded, even if the risk is certainly very low.

The medicinal product contains lactose and is therefore not suitable for individuals with lactase deficiency, galactosemia or glucose / galactose malabsorption syndrome.

The medicinal product contains sucrose is therefore not suitable for people with sucrase-isomaltase deficiency, fructose intolerance or glucose / galactose malabsorption syndrome.

04.5 Interactions with other medicinal products and other forms of interaction

Interaction may occur with medicinal products that induce microsomal enzymes which may lead to increased clearance of sex hormones and which may lead to breakthrough bleeding or reduce the efficacy of the oral contraceptive.

Women undergoing treatment with one or more drugs belonging to any of the aforementioned classes must temporarily adopt a barrier method of contraception for the entire duration of concomitant intake of the drug and for 28 days after discontinuing therapy.

If concomitant drug administration continues after one pack of Diane is finished, the next contraceptive pack should be started without observing the usual tablet-free interval.

The following interactions have been reported in the literature.

Substances which increase the clearance of Diane (decreased efficacy of Diane due to enzyme induction) eg.:

Phenytoin, barbiturates, primidone, carbamazepine, rifampicin and probably also oxcarbazepine, topiramate, felbamate, griseofulvin and products containing St. John's wort).

Substances with variable effect on Diane clearance, for example:

When administered with Diane, many HIV / HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors can increase or decrease the plasma concentration of estrogens and progestogens. The changes may be clinically relevant in some cases.

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.

Estrogen-progestin combinations such as Diane can interfere with the metabolism of other drugs. Therefore, their plasma or tissue concentrations can be affected, either by an increase (e.g. cyclosporine) or a decrease (e.g. lamotrigine).

Consult the instructions of the concomitant drug.

Laboratory tests

The use of Diane may 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 lipid / lipoprotein fractions, parameters of glucose metabolism, coagulation and fibrinolysis Variations are generally within the range of normal laboratory values.

Laboratory personnel should be informed of the use of Diane when laboratory tests are required.

04.6 Pregnancy and lactation

Pregnancy

Taking Diane is contraindicated in pregnancy.

If you become pregnant while taking Diane, stop taking the preparation immediately.

Pregnancy

The use of Diane is contraindicated during breastfeeding. Cyproterone acetate passes into breast milk. Approximately 0.2% of the maternal dose is absorbed by the infant through milk, corresponding to a dose of approximately 1 mcg / kg. During breastfeeding, 0.02% of the maternal daily dose of ethinylestradiol can be transferred with milk to the infant.

04.7 Effects on ability to drive and use machines

No studies on the ability to drive or use machines have been performed. No effects on ability to drive or use machines have been observed in users of Diane.

04.8 Undesirable effects

The undesirable effects that have been reported in COC users but for which the association has neither been confirmed nor disproved are:

Organic System Classification Common (≥1 / 100) Uncommon (≥1 / 1000 and Rare ( Eye disorders Contact lens intolerance Gastrointestinal disorders Nausea Abdominal pain Vomiting Diarrhea Disorders of the immune system Hypersensitivity Diagnostic tests Increased weight Weight decreased Metabolism and nutrition disorders Fluid retention Nervous system disorders Headache Migraine Psychiatric disorders Depressed mood Altered mood Decreased libido Increased libido Diseases of the reproductive system and breast Breast pain, breast tenderness Breast hypertrophy Vaginal discharge Breast discharge Skin and subcutaneous tissue disorders Urticaria rash Erythema nodosum Erythema multiforme or polymorphic Vascular pathologies Thromboembolism

There is an increased risk of thromboembolism for all women taking Diane (see section 4.4).

The following serious events discussed in section 4.4 Special warnings and precautions for use have been reported in women taking Diane:

• venous thromboembolic pathologies

• arterial thromboembolic pathologies

The following serious side effects have been reported in women using COCs and are discussed in section 4.4:

• arterial thromboembolic accidents

• venous thromboembolic accidents

• cerebrovascular accidents

• hypertension

• hypertriglyceridemia

• alterations in glucose tolerance or effects on peripheral insulin resistance

• liver tumors (benign and malignant)

• changes in liver function

• chloasma

• in women with hereditary angioedema, exogenous estrogens can induce or aggravate the symptoms of angioedema

• appearance or aggravation of conditions for which there is no conclusive evidence of an association with the use of COCs: cholestatic jaundice and / or pruritus, gallstone formation, porphyria, systemic lupus erythematosus, haemolytic-uremic syndrome , Sydenham's chorea, herpes gestationis, otosclerosis hearing loss, Crohn's disease, ulcerative colitis, cervical cancer.

The frequency of breast cancer diagnoses is very slightly increased in oral contraceptive users. Because breast cancer is a rare occurrence in women under the age of 40, the increased number of cases is low compared to a woman's lifetime risk of breast cancer. It is not known whether there is a causal relationship to COCs For more information, see sections 4.3 and 4.4.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows for 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 https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.

04.9 Overdose

No serious adverse effects from overdose have been reported.

In this circumstance, however, symptoms such as nausea, vomiting and, in young girls, slight vaginal bleeding may occur.

There are no antidotes and any treatment must be symptomatic.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: antiandrogens and estrogens, ATC code: G03HB01.

The cyproterone acetate contained in Diane inhibits the action of androgens which are also produced by the female organism. It is therefore possible to treat pathologies whose etiology derives both from an increased production of androgens and from a particular sensitivity to these hormones.

While taking Diane there is a reduction in the increased function of the sebaceous glands which play an important role in the etiology of acne and seborrhea. This leads - usually after 3-4 months of therapy - to a reduction in acne manifestations. The excessive presence of grease on the hair and on the skin usually disappears more quickly. Treatment with Diane is indicated in women of reproductive age who manifest mild forms of hirsutism and in particular slight increases in facial hair; however these results to be evident require many months of recruitment.

Cyproterone acetate, in addition to the described antiandrogenic activity, shows a marked progestin activity. The administration of cyproterone acetate alone would therefore lead to cycle irregularities which are avoided by its association with the ethinyl estradiol in Diane. This is achieved by cyclical intake according to the instructions. The contraceptive action of Diane is based on the interactions of central and peripheral mechanisms, the most important of which are the inhibition of ovulation and changes in the cervical mucus.

05.2 Pharmacokinetic properties

Cyproterone acetate

Following oral administration, cyproterone is completely absorbed.

The intake of Diane leads to a maximum serum level of 15 ng of cyproterone acetate / ml after 1.6 hours. Then the serum levels are reduced in two phases characterized by a half-life of 0.8 hours and 2.3 days. Total clearance of cyproterone acetate from serum was estimated to be 3.6 ml / min / kg. Cyproterone acetate is metabolised by various metabolic pathways including hydroxylation and conjugation. The major metabolite in human plasma is the 15 beta-hydroxy derivative.

A portion is excreted unchanged with the bile. Most of the dose is excreted as urinary and biliary metabolites with a ratio of 3: 7. Biliary and renal excretion occur with a half-life of 1.9 days. The metabolites are cleared from plasma with a similar rate (half-life 1.7 days). Cyproterone acetate is almost completely bound to plasma albumin. Approximately 3.5-4.0% of total drug levels are in free form. Since protein binding is not specific, changes in SHBG levels do not affect the pharmacokinetics of cyproterone acetate.

As a consequence of the long half-life of the terminal disposition phase from plasma (serum) and the daily intake, cyproterone acetate accumulates during a course of therapy. The mean values of the maximum serum drug levels increase from 15 ng / ml (day 1) at 21 ng / mL and 24 ng / mL at the end of therapy cycles 1 and 3, respectively.

The area below the concentration / time graph increases by 2.2 times (at the end of the first cycle) and 2.4 times (at the end of the third cycle). Equilibrium conditions were reached after about 10 days. During long-term treatments duration, cyproterone acetate accumulates over the course of treatment cycles with a factor of 2. The absolute bioavailability of cyproterone acetate is almost total (88% of the dose).

The relative bioavailability of cyproterone acetate from Diane was 109% when compared to a microcrystalline aqueous suspension.

Smoking does not affect the pharmacokinetics of cyproterone acetate or ethinylestradiol.

Ethinylestradiol

Orally administered ethinylestradiol is rapidly and completely absorbed. Following ingestion of Diane maximum serum levels of the drug were approximately 80 pg / ml after 1.7 hours. Subsequently, the serum levels of ethinylestradiol decrease according to two phases characterized by a "half-life of 1-2 hours and about 20 hours, respectively.

Due to the limitations of the analytical procedures these indices can only be calculated by administering higher doses. An apparent volume of distribution of approximately 5 l / kg and a metabolic clearance rate of plasma of approximately 5 ml / min / kg was determined for ethinylestradiol. Ethinylestradiol binds highly but not specifically with albumin. serum. About 2% of the circulating drug is present in free form. During the absorption and first pass hepatic processes, ethinylestradiol is metabolized with a consequent variable reduced bioavailability after oral administration.

The drug is not excreted in unchanged form. Metabolites of ethinylestradiol are excreted in the urine and biliary at a ratio of 4: 6, with a half-life of approximately one day.

Based on the half-life of the terminal distribution phase from serum and daily intake, equilibrium serum levels are reached after 3-4 days and are approximately 30-40% higher when compared with those resulting from a single dose.

The relative bioavailability (referred to an aqueous microcrystalline suspension) of ethinyl estradiol from Diane is almost total.

The systemic availability of ethinylestradiol can be affected in both directions by other drugs. However, there is no interaction with high doses of vitamin C. During continued use, ethinylestradiol induces hepatic synthesis of SHBG and CBG. The degree of induction. of SHBG depends on the chemical structure and dose of associated progestogens.

While taking Diane the serum concentrations of SHBG increase from approximately 100 nmol / l to 300 nmol / l and the serum concentrations of CBG increase from approximately 50 mcg / ml to 95 mcg / ml.

05.3 Preclinical safety data

Animal toxicity studies for human risk assessment were performed both on each component of the preparation and on their association.

No experimental studies have been conducted in animals on a possible sensitizing effect of ethinylestradiol and cyproterone acetate.

Ethinylestradiol

The toxicological profile of ethinylestradiol is well known. There are no preclinical data relevant to the prescriber that could provide safety information that is not already reported in other sections of this Summary of Product Characteristics.

Cyproterone acetate

• Systemic toxicity

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity.

• Embryotoxicity / teratogenesis

Embryotoxicity or teratogenesis studies conducted using the combination of the two active ingredients did not demonstrate any general teratogenic action following the treatment during organogenesis before the development of the external genital organs.

The administration of cyproterone acetate during the hormone-sensitive phase of differentiation of the genital organs (after about the 45th day of pregnancy) can induce signs of feminization in male fetuses following high doses. Observation of newborn males who were exposed in utero to cyproterone acetate showed no sign of feminization. However, pregnancy is a contraindication to the use of Diane.

Although the studies in vitro and in vivo indicate genotoxic effects of cyproterone acetate on rat hepatocytes, studies on mutagenic effects did not reveal any mutagenic potential. In light of the current state of knowledge, this finding does not suggest any relevant mutagenic potential in humans.

• Genotoxicity and carcinogenesis

Genotoxicity studies of recognized validity conducted on cyproterone acetate gave negative results. Further tests on rat and monkey hepatocytes, and also on freshly isolated human hepatocytes, have however shown that cyproterone acetate is able to form adducts with DNA and to increase DNA repair activity, while the level of adducts of DNA in dog liver cells was extremely low.

This formation of DNA adducts occurs following an exposure which can also be achieved at the currently recommended posologies. The in vivo consequences of cyproterone acetate treatment were an "increased incidence of focal hepatic lesions, possibly pre-neoplastic, in which cellular enzymes in female rats were altered, and an increased mutation rate in transgenic rats bearing a bacterial gene. as a target for mutations.

The clinical relevance of these observations is uncertain. Clinical experience to date does not support an "increased incidence of liver tumors in humans". Studies on the carcinogenicity of cyproterone acetate on rodents have not shown any specific carcinogenic potential. At the same time it must be remembered that sex steroids can promote the growth of some hormone-dependent tissues and tumors Overall, the available data do not show any objection to the use of Diane in humans if used in accordance with the provisions for the intended indications and at the recommended dose.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Lactose, corn starch, povidone 25,000, talc, magnesium stearate, sucrose, povidone 700,000, macrogol 6,000, calcium carbonate, glycerol 85%, ethylene glycol ester of montanic acid, titanium dioxide, yellow iron oxide.