ANGELIQ - PACKAGE LEAFLET - LEAFLETS

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Angeliq - Package Leaflet

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

Active ingredients: Estradiol, Drospirenone

ANGELIQ 1 mg / 2 mg film-coated tablets

Indications Why is Angeliq used? What is it for?

Angeliq is a Hormone Replacement Therapy (HRT). It contains two types of female hormones, an estrogen and a progestin. Angeliq is used in postmenopausal women who have had at least 1 year since their last natural period.

Angeliq is used for:

Relief from symptoms that occur after menopause

During menopause, the amount of estrogen produced by a woman's body decreases. This can cause symptoms such as heat in the face, neck and chest ("hot flashes"). Angeliq relieves these symptoms after menopause. Angeliq will be prescribed if your symptoms seriously affect your daily life.

Prevention of osteoporosis

After menopause, some women may develop bone fragility (osteoporosis). You should discuss all available options with your doctor. If you are at high risk of fractures due to osteoporosis and cannot take other medicines, you can use Angeliq for the prevention of osteoporosis after menopause.

Contraindications When Angeliq should not be used

Do not take Angeliq

if any of the conditions listed below are present.

If you are unsure of the conditions described below, consult your doctor before taking Angeliq.

Do not take Angeliq

If you have or have ever had breast cancer, or if you are suspected of having it
If you have cancer that is sensitive to estrogen such as cancer of the lining of the womb (endometrium), or if you suspect you have it
If you have any vaginal bleeding of an undetermined nature
If you have excessive thickening of the lining of the womb (hyperplasia of the endometrium)
If you have or have ever had a blood clot in a vein (deep vein thrombosis), such as in the legs (deep vein thrombosis) or in the lungs (pulmonary embolism)
If you have disorders related to blood clots (such as protein C, protein S or antithrombin deficiency)
If you have or have recently had a disease caused by blood clots in the arteries, such as a heart attack, stroke or angina
If you have or have ever had liver disease and your liver function tests have not returned to normal
If you have a rare inherited condition called "porphyria"
If you have severe kidney disease or acute kidney failure
If you are allergic (hypersensitive) to estrogen, progestogens or any of the other ingredients of Angeliq

If any of the above conditions appear for the first time while you are taking Angeliq, stop the treatment immediately and consult your doctor immediately.

Precautions for use What you need to know before taking Angeliq

Medical examination and regular check-ups

The use of HRT carries risks that need to be considered when deciding whether to initiate or continue therapy.

The experience of treating women with premature menopause (due to cessation of ovulation or surgery) is limited. If you have premature menopause the risks of using HRT may be different. Consult your doctor.

Before starting HRT (or starting again), your doctor will ask you a few questions about your personal health history and that of your family members. The doctor may decide to carry out tests. These may include breast examination and / or an internal examination if necessary.

Once you have started treatment with Angeliq, you will need to see your doctor for regular check-ups (at least once a year). At these check-ups, you will discuss with your doctor the benefits and risks of continuing treatment with Angeliq.

Get regular breast exams as recommended by your doctor.

Talk to your doctor or pharmacist before taking Angeliq. Tell your doctor if you have ever had any of the following conditions before starting treatment, as these conditions may recur or worsen during treatment with Angeliq. If this is the case, you should see your doctor more often for checks:

fibroids inside the uterus
growth of the lining of the uterus elsewhere (endometriosis) or a history of overgrowth of the lining of the uterus (endometrial hyperplesia)
increased risk of developing blood clots (see "Blood clots in a vein (thrombosis)")
increased risk of estrogen-sensitive breast cancer (mother, sister or grandmother who have had breast cancer)
high pressure
liver disease such as a benign liver tumor
diabetes
gallbladder stones
migraine or severe headache
a disease of the immune system that affects many organs of the body (systemic lupus erythematosus (SLE)
epilepsy
asthma
a condition affecting the eardrum and hearing (otosclerosis)
very high level of fat in the blood (triglycerides)
water retention due to heart or kidney problems

Stop taking Angeliq and consult your doctor immediately

If you notice any of the following while taking HRT:

any of the conditions described in the "Do not take Angeliq" section
yellowing of the skin or whites of the eyes (jaundice). These can be signs of liver disease
marked increase in blood pressure (symptoms may be headache, tiredness, dizziness)
new onset migraine-type headache
pregnancy
if you notice signs of a blood clot, such as
painful swelling and redness of the legs
sudden pain in the chest
difficulty in breathing

For more information see section "Blood clots in the vein (thrombosis)

"Note: Angeliq is not a contraceptive. If it has been less than 12 months since" your last period or you are "under 50, you may still need to use additional contraceptive measures in order to prevent pregnancy. Ask for advice to the doctor.

HRT and cancer

Excessive thickening of the lining of the womb (endometrial hyperplasia) and cancer of the lining of the womb (endometrial cancer)

Taking estrogen-only HRT increases the risk of thickening of the lining of the womb (endometrial hyperplasia) and cancer of the lining of the womb (endometrial cancer). The presence of a progestogen in Angeliq protects you from this risk. additional.

Irregular bleeding

You may experience irregular bleeding or bleeding (spotting) during the first 3-6 months after taking Angeliq. However, if the irregular bleeding:

continues beyond the first 6 months
it occurs after you have taken Angeliq for more than 6 months
continues after the interruption of Angeliq

go to your doctor as soon as possible.

Breast cancer

It appears that taking estrogen-progestogen HRT, and possibly also estrogen-only HRT, increases the risk of breast cancer. This additional risk depends on the duration of HRT. The additional risk becomes evident after a few years. However it disappears. within a few years (at most 5) after stopping HRT.

Comparison

In women aged 50 to 79 who are not taking HRT, on average, 9-17 in 1000 will be diagnosed with breast cancer over a 5-year period. For women aged 50 to 79 who are taking estrogen / progestogen HRT over the age of 5, there will be 13-23 cases in 1000 users (i.e. an increase of 4-6 cases).

Check your breasts regularly. Make an appointment with your doctor if you notice any changes such as:

orange peel skin or depressions in the skin;
change in the nipples;
any visible or palpable lumps

Additionally, it is recommended that you participate in mammography screening programs when offered to you. For mammography screening, it is important that you tell the nurse / healthcare professional who is actually having the x-ray that you are using HRT, as this treatment can increase breast density which could alter the result of the mammogram. Where breast density has increased, mammography may not detect all lumps.

Ovarian cancer

Ovarian cancer is rare. Long-term HRT of at least 5-10 years is thought to confer a slightly increased risk of ovarian cancer.

In women aged 50 to 79 who are not taking HRT, on average about 2 in 1000 women will be diagnosed with ovarian cancer over a 5-year period. For women aged 50 to 79 who have been taking HRT for 5 years, there will be 2-3 cases in 1000 users (i.e. an increase of 1 case).

Effects of HRT on the heart and circulation

Blood clots in a vein (thrombosis)

HRT may increase the risk of blood clots in the veins by 1.3 to 3 times, especially during the first year of taking.

Blood clots can be dangerous, and if they travel to the lungs they can cause chest pain, sudden lack of air, collapse or even death.

The risk of having a blood clot in your veins increases with increasing age and if any of the following apply to you. Tell your doctor if any of the following apply to you:

unable to walk for a long time due to major surgery, accident or illness (see also section "If you need to have surgery")
are severely overweight (BMI> 30 kg / m2)
have any blood clotting problem that needs long-term treatment with a medicine that prevents blood clots
if a close relative has had a blood clot in the leg, lung or another organ
have systemic lupus erythematosus (SLE)
has cancer

For possible signs of a blood clot, see "Stop using Angeliq and contact your doctor immediately"

Comparison

For women in their 50s who are not taking HRT, on average, over a 5-year period, 4-7 in 1000 cases are expected to have a blood clot in a vein. For women in their 50s who are taking estrogen / progestogen HRT over the age of 5, there will be 9-12 cases in 1000 users (i.e. an increase of 5 cases).

Heart disease (heart attack)

There is no evidence that HRT prevents heart disease.

Women over the age of 60 who use estrogen-progestogen HRT are slightly more likely to develop heart disease than women who are not taking any HRT.

Stroke

The risk of having a stroke is about 1.5 times higher in HRT users than in non-users. The number of additional cases of stroke due to HRT use will increase with age.

Comparison

For women in their 50s who are not taking HRT, on average, over a 5-year period, 8 in 1000 have the chance of having a stroke. For women in their 50s who are taking estrogen / progestogen HRT over 5 years, there will be 11 cases in 1000 users (i.e. an increase of 3 cases).

Other conditions

HRT does not prevent memory loss. The risk of memory loss may be higher in women who start using HRT after the age of 65. Ask your doctor for advice.
If you have kidney disease and have elevated serum potassium levels, particularly if you are taking other medicines that increase serum potassium, your doctor may check your blood potassium levels during the first month of treatment.
If you have high blood pressure, treatment with Angeliq can lower it. Angeliq should not be used to treat high blood pressure.
If you have a tendency to develop discolored patches (chloasma) on your face, you should avoid exposure to the sun or ultraviolet light while taking Angeliq.

Interactions Which drugs or foods can modify the effect of Angeliq

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

Some medicines can interfere with the effects of Angeliq and cause irregular bleeding. This concerns the following medicines:

medicines for epilepsy (eg phenobarbital, phenytoin, carbamazepine)
medicines for tuberculosis (e.g. rifampicin and rifabutin)
medicines for HIV infections (eg nevirapine, efavirenz, nelfinavir and ritonavir) and hepatitis C virus infections
the herbal remedy St. John's wort (Hypericum perforatum)
medicines to treat fungal infections (such as itraconazole, voriconazole, fluconazole)
medicines to treat bacterial infections (such as clarithromycin, erythromycin)
medicines to treat certain heart diseases, high blood pressure (such as verapamil, diltiazem)
Grapefruit juice

The following medicines can cause small increases in serum potassium:

medicines used to treat:
inflammation or pain (e.g. aspirin, ibuprofen);
certain types of heart disease or hypertension (eg diuretics, ACE inhibitors (eg enalapril), angiotensin II receptor antagonists (eg losartan). If you are being treated for hypertension and take Angeliq you may experience a " further decrease in blood pressure.

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines including medicines obtained without a prescription, herbal remedies or other natural products.

Laboratory tests

If you need a blood test tell your doctor or the laboratory staff that you are taking Angeliq, as this medicine can affect the results of some tests.

Warnings It is important to know that:

Pregnancy and breastfeeding

Angeliq is intended for use in postmenopausal women. If you become pregnant, stop taking Angeliq immediately and contact your doctor.

Driving and using machines

There is no reason to believe that the use of Angeliq affects the ability to drive or use machines.

Angeliq contains lactose

Angeliq contains lactose (a type of sugar). If you have an intolerance to some sugars, check with your doctor before taking Angeliq.

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

Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist. Your doctor will decide how long you need to take Angeliq for.

Take one tablet a day, preferably at the same time. Swallow the tablet whole with some water. You can take Angeliq with or without food. Start the next pack of tablets the day after you finish the current pack.

Do not stop taking it between the two packs.

If you are taking other HRT preparations: Continue until you have finished your current pack and have taken all your tablets for that month. Take the first Angeliq tablet the next day. Do not leave a gap between old tablets and Angeliq tablets

If this is your first HRT treatment: You can start with Angeliq tablets any day.

Overdose What to do if you have taken too much Angeliq

If you take more Angeliq than you should

If you have taken too many Angeliq tablets by mistake, you may feel sick, vomit or have a menstrual-like bleeding. No specific treatment is necessary, but if you are concerned, consult your doctor or pharmacist.

If you forget to take Angeliq

If you forget to take a tablet at the usual time, and it has been less than 24 hours, take the tablet as soon as possible. Take the next tablet at the usual time.

If it has been more than 24 hours, leave the forgotten tablet in the pack. Continue taking the rest of the tablets at the usual time each day. Do not take a double dose to make up for a forgotten tablet.

If you forget to take your tablet for several days, irregular bleeding may occur.

Whether to discontinue treatment with Angeliq

You may start to still experience typical menopausal symptoms, which may include hot flashes, sleep disturbances, nervousness, dizziness, or vaginal dryness. You will also start losing bone mass by stopping Angeliq. If you want to stop taking Angeliq, ask your doctor or pharmacist. If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

If you need to have surgery

If you have surgery planned, tell the surgeon that you are taking Angeliq. You may need to stop taking Angeliq about 4-6 weeks before your operation to reduce the risk of a thrombosis (see also section 2 "Blood clots in a vein"). Ask your doctor when you can start taking Angeliq again.

Side Effects What are the side effects of Angeliq

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

Women who use HRT have a slightly higher risk of developing the following diseases than women who do not use it:

breast cancer
overgrowth or cancer of the lining of the womb (endometrial hyperplasia or cancer)
ovarian cancer
blood clots in the veins of the legs or lungs (venous thromboembolism)
heart disease
stroke
probable memory loss if HRT is started after age 65.

For more information about these side effects see section 2. Like all medicines, Angeliq can cause side effects, although not everybody gets them. The following side effects have been associated with the use of Angeliq.

Most frequent side effects (affecting more than 1 in 10 patients):

unexpected menstrual-like bleeding (see also section 2 "Angeliq and cancer / mucosal cancer of the" uterus "
breast sensitivity
breast pains. Unexpected menstrual-like bleeding occurs during the first months of treatment with Angeliq. They are usually temporary and usually disappear with continued treatment. If not, contact your doctor.

Common side effects (affecting 1 to 10 out of 100 patients):

depression, mood swings, nervousness
headache
stomach pain, nausea, stomach dilation
breast lumps (benign breast neoplasm), breast swelling
increase in the size of uterine fibroids
non-cancerous growth of cells in the cervix (benign cervical growth)
irregularities in vaginal bleeding
vaginal discharge
loss of energy, localized water retention.

Uncommon side effects (affecting 1 to 10 out of 1000 patients):

weight gain or decrease, loss or increase in appetite, increased blood fat
sleep disturbances, anxiety, decreased sexual interest
burning or tingling sensation, decreased concentration, dizziness
eye problems (e.g. red eyes), vision disturbances (e.g. blurred vision)
palpitations
thrombosis, venous thrombosis (see also section 2 "Angeliq and thrombosis"), high blood pressure, migraine, inflammation of the veins, varicose veins
breathlessness
stomach upset, diarrhea, constipation, vomiting, dry mouth, wind, taste disturbances
altered liver enzymes (visible in blood tests)
skin problems, acne, hair loss, itchy skin, hirsutism
back pain, joint pain, pain in limb, muscle cramps
urinary tract disorders and infections
breast cancer, thickening of the lining of the uterus, unusual benign growth in the uterus, thrush, vaginal dryness and itching
breast lumps (fibrocystic mastopathy), diseases of the ovaries, cervix and uterus, pelvic pain
generalized water retention, chest pain, generally feeling unwell, increased sweating.

Rare side effects (affects 1 to 10 users in 10,000):

anemia
dizziness
ringing in the ears
gallbladder stones
muscular pain
inflammation of the fallopian tubes
secretion of milk from the nipples
chills.

The following side effects occurred in clinical trials in women with high blood pressure:

high potassium levels (hyperkalaemia) sometimes causing muscle cramps, diarrhea, nausea, dizziness or headache
heart failure, dilation of the heart, rapid heartbeat, effects on the rhythm of the heart
increase in aldosterone in the blood.

The following side effects have been reported with other HRTs:

gallbladder disease
a variety of skin pathologies:
discoloration of the skin, especially of the face or neck, known as "pregnancy mask" (chloasma)
painful reddish skin nodules (erythema nodosum)
rash with target lesions or ulcers (erythema multiforme)

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

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 the safety of this medicine.

Expiry and Retention

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

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

Angeliq does not require any particular storage conditions.

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 Angeliq

The active substances are estradiol (as estradiol hemihydrate) and drospirenone; each tablet contains 1 mg of estradiol and 2 mg of drospirenone.

The other ingredients are lactose monohydrate, maize starch, pregelatinised maize starch, povidone and magnesium stearate (E470b). The other ingredients in the tablet coating are hypromellose (E464), macrogol 6000, talc (E553b), titanium dioxide (E171) and iron oxide (E172).

Description of what Angeliq looks like and contents of the pack

Angeliq tablets are coated, red, round, convex tablets. One face is marked with the letters "DL" in a regular hexagon.

They are available in blister packs of 28 tablets with the days of the week printed on the blister.

Angeliq is available in packs of 1 and 3 blisters.

Not all pack sizes may be marketed.

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

More information about Angeliq 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 the ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical data of 06.0 PHARMACEUTICAL PARTICULARS 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 HOLDER OF THE ALL AUTHORIZATION "PLACING ON MARKETING 08.0 AUTHORIZATION NUMBER" PLACING ON MARKET09.0 DATE OF PR IMA 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 RADIOPharmaceuticals, ADDITIONAL DETAILED INSTRUCTIONS ON ESTEMPORAN PREPARATION AND QUALITY CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

ANGELIQ 1 MG / 2 MG TABLETS COATED WITH FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 1 mg of estradiol (as estradiol hemihydrate) and 2 mg of drospirenone.

Excipient with known effect: 46 mg of lactose.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Film-coated tablet.

Red, round tablet with convex faces, one of which is marked with the letters DL inside a regular hexagon.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Hormone replacement therapy for estrogen deficiency symptoms in postmenopausal women, if more than 1 year has passed since menopause.

Prevention of osteoporosis in postmenopausal women at high risk of future fractures who have intolerances or contraindications to other drugs authorized for the prevention of osteoporosis.

(See also section 4.4).

Experience in the treatment of women over the age of 65 is limited.

04.2 Posology and method of administration

Women not on HRT, or those switching from continuous therapy with another combination product, can start treatment at any time. Women switching from a cyclical therapy regimen (HRT) to a sequential combination product should start treatment on the day following the last of the previous treatment cycle.

Dosage

One tablet a day. Each blister covers 28 days of treatment.

Method of administration

The tablets should be swallowed whole with some liquid, regardless of food intake. Treatment is continuous, so the next pack should be used immediately and follow the previous one without interruption. The tablets should preferably be taken at the same time each day. If you forget to take a tablet, it should be taken as soon as possible. If it has been more than 24 hours, you do not need to take another tablet. If you miss more tablets, vaginal bleeding is possible.

The lowest effective dose should be used for the treatment of postmenopausal symptoms.

At the beginning and throughout the duration of treatment, which should be as short as possible, the lowest effective dose should be used (see also section 4.4).

Additional information for particular categories of patients

Pediatric population

Angeliq is not intended for use in children and adolescents

Elderly patients

There are no data indicating the need for dose adjustment in elderly patients. For women over 65 years of age, see section 4.4.

Patients with impaired hepatic function

In women with mild or moderate hepatic impairment, drospirenone is well tolerated (see section 5.2 Pharmacokinetic properties). Angeliq is contraindicated in women with severe liver disease (see section 4.3).

Patients with impaired renal function

A slight increase in drospirenone exposure has been observed in women with mild or moderate renal impairment, which is not thought to be of clinical relevance (see section 5.2). Angeliq is contraindicated in women with severe renal disease (see section 4.3). .

04.3 Contraindications

• Undiagnosed genital bleeding.

• Known, past or suspected breast cancer.

• Known or suspected estrogen-dependent malignant tumors (eg endometrial cancer).

• Untreated endometrial hyperplasia.

• Previous or current episodes of venous thromboembolism (deep vein thrombosis, pulmonary embolism).

• Current or recent arterial thromboembolism (eg angina, myocardial infarction).

• Acute liver disease or history of liver disease until liver function test values have returned to normal.

• Known thrombophilic states (eg protein C, protein S or antithrombin deficiency, see section 4.4)

• Severe or acute renal failure.

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

• Porphyria

04.4 Special warnings and appropriate precautions for use

For the treatment of postmenopausal symptoms, HRT should only be started for symptoms that impair quality of life. In any case, a careful evaluation of the risks and benefits of treatment should be performed at least annually, and HRT should only be continued as long as the benefit obtained outweighs the risk.

There are limited data on the risks associated with HRT in the treatment of early menopause. However, in view of the low level of absolute risk in younger women, the risk / benefit ratio for these women may be more favorable than for older women.

Medical examination / follow-up

Before initiating or resuming HRT, a complete "personal and family medical history" should be taken. Physical examination (including a pelvic and breast examination) should be performed with consideration for contraindications and warnings for use of the product. During the treatment, it is recommended to carry out periodic medical checks of a nature and frequency adapted to the individual patient. Women should be instructed on which changes found in their breasts should be reported to the physician or nursing staff. Clinical investigations, including the use of appropriate diagnostic imaging tools, such as mammography, should be performed in line with currently accepted clinical protocols and the clinical needs of the individual case.

Conditions that require special attention

The patient should be closely monitored if any of the conditions listed below are present or have occurred in the past and / or worsened during pregnancy or previous hormone therapy. It should be borne in mind that these conditions may recur or worsen during therapy with Angeliq, in particular:

• Leiomyomas (uterine fibroids) or endometriosis.

• Risk factors for thromboembolic disorders (see below).

• Risk factors for estrogen dependent cancers, eg. hereditary predisposition (1st degree relatives with breast cancer).

• Hypertension.

• Hepatopathies (eg hepatic adenoma).

• Diabetes mellitus with or without vascular involvement.

• Cholelithiasis.

• Migraine or headache (severe).

• Systemic lupus erythematosus.

• History of endometrial hyperplasia (see below).

• Epilepsy.

• Asthma.

• Otosclerosis.

Cases requiring immediate discontinuation of therapy

Therapy should be discontinued in the presence of contraindications and in the following situations:

• Jaundice or deterioration of the function hepatic.

• Significant increase in blood pressure.

• New onset migraine-type headache.

• Pregnancy.

Endometrial hyperplasia and carcinoma

In women with an intact uterus, the administration of estrogen alone for prolonged periods increases the risk of endometrial hyperplasia and carcinoma. The risk of endometrial cancer among estrogen-only users increases 2 to 12 times compared to non-users, depending on the duration of treatment and the dose of estrogen (see section 4.8). Upon cessation of treatment the risk may remain elevated for at least 10 years.

In non-hysterectomised women, adding a progestogen cyclically for at least 12 days per month / 28-day cycle or continuous estrogen-progestogen therapy prevents the increased risk associated with estrogen-only HRT.

Flaking bleeding and small breakthrough bleeding (spotting) may occur during the first months of treatment. If these episodes appear some time after the start of therapy, or continue after the interruption of treatment, the causes must be sought, possibly also by endometrial biopsy, to rule out a malignant tumor of the endometrium.

Breast cancer

The overall evidence suggests an increased risk of breast cancer in women taking estrogen / progestogen, and possibly estrogen-only HRT, which is dependent on the duration of HRT.

The Women's Health Initiative (WHI) randomized placebo-controlled trial and epidemiological studies are in agreement that they detect an increased risk of breast cancer in women taking estrogen / progestogen HRT, which occurs after approximately 3 years of use (see section 4.8). The increased risk occurs after a few years of treatment, but returns to baseline within a few (maximum five) years of stopping treatment.

Hormone replacement therapy, especially estrogen-progestogen combinations, increases the density of mammographic images, which can make radiological detection of a breast cancer more difficult.

Venous thromboembolism

HRT is associated with a 1.3 to 3-fold relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. These events are more likely to occur in the first year of HRT than in subsequent years (see section 4.8).

Generally recognized risk factors for VTE include estrogen use, older age, major surgery, personal or family history, obesity (BMI> 30 kg / m2), pregnancy / postpartum period , systemic lupus erythematosus (SLE) and cancer. There is no consensus on the possible role of varicose veins in VTE.

Patients with known thrombophilic states have an increased risk of VTE and HRT may increase this risk. HRT is therefore contraindicated in these patients (see section 4.3).

As in all operated patients, careful attention must be paid to prophylactic measures to prevent postoperative VTE episodes. When prolonged immobilization is anticipated following elective surgery, temporary discontinuation of HRT should be considered, if possible 4-6 weeks prior to surgery. HRT should not be resumed until the woman is completely mobilized.

In the absence of a "personal history of VTE, women with a first degree relative with a history of thrombosis at a young age can be offered to undergo screening, after having been informed of its limitations (screening allows to identify only a part of the defects If a thrombophilic defect is identified that segregates with thrombosis in a family member, or if the defect is 'severe' (e.g. antithrombin, protein S, protein C deficiency, or a combination of defects) HRT is contraindicated.

Women already on chronic anticoagulant treatment require careful assessment of the benefit-risk ratio of HRT.

If VTE develops after initiation of therapy, drug administration should be discontinued. Patients should be instructed to contact their physician immediately in case of symptoms potentially due to venous thromboembolism (eg swollen and painful lower limb , sudden chest pain, dyspnoea).

Coronary heart disease (CAD)

Randomized controlled trials show no protection against myocardial infarction in women with or without coronary artery disease who have received estrogen / progestogen HRT or estrogen-only HRT. The relative risk of coronary artery disease during use of estrogen / progestogen HRT is slightly increased. Since the baseline absolute risk is largely age-dependent, the number of additional cases of coronary artery disease due to estrogen / progestogen use is very small in healthy women recently postmenopausal, but increases in later life.

Ischemic stroke

Estrogen / progestogen or estrogen-only therapies are associated with a 1.5-fold increased risk of ischemic stroke. The relative risk does not change with age or the time since menopause. However, as the baseline absolute risk is largely age-dependent, the overall risk of stroke in women who use HRT will increase with age. advancing age (see section 4.8).

Ovarian cancer

Ovarian cancer is much rarer than breast cancer. Long-term (at least 5-10 years) HRT with estrogen alone has been associated with a slightly increased risk of ovarian cancer (see section 4.8). Some studies, including the WHI study, suggest that long-term HRT with combination products may confer a similar or slightly lower risk (see section 4.8).

Other conditions

Estrogen can cause water retention, so patients with heart or kidney dysfunction should be carefully monitored.

Women with pre-existing hypertriglyceridaemia should be followed closely during estrogen therapy or hormone replacement therapy since rare cases of significant increases in plasma triglycerides with consequent pancreatitis have been reported in the presence of this condition with estrogen therapy.

Estrogen induces an increase in thyroxine-binding globulin (TBG), resulting in an increase in total circulating thyroid hormone, calculated on the basis of protein-bound iodine (PBI), T4 levels (determined by column or radioimmunoassay) or T3 levels (determined by radioimmunoassay). Resin adsorption of T3 is decreased as a consequence of increased TBG. Free T4 and T3 concentrations remain unchanged. Serum increase of other binding proteins is possible. such as corticosteroid-binding globulin (CBG) and sex hormone-binding globulin (SHBG), resulting in an increase in circulating corticosteroids and sex steroids respectively. Concentrations of free or biologically active hormones remain unchanged. Others also remain unchanged. plasma proteins may be increased (angiotensinogen / renin substrate, alpha-1-antitrypsin, ceruloplasmin).

HRT does not improve cognitive function. There is evidence of an increased risk of probable dementia in women who start using combination or estrogen-only therapy after age 65.

The progestogen component of Angeliq is an aldosterone antagonist with weak potassium-sparing properties. In most cases, increases in serum potassium levels are not to be expected. In a clinical study, however, in some patients with impaired function. mild or moderate kidney who used potassium-sparing medicines (such as ACE inhibitors, angiotensin II receptor antagonists or NSAIDs), serum potassium levels increased slightly, but not significantly, while taking Therefore, in patients with renal insufficiency and serum potassium prior to treatment in the upper part of the reference range, and particularly during concomitant use of potassium-sparing medicinal products, it is recommended that serum potassium be monitored during the first course of treatment (see also section 4.5).

Women with elevated blood pressure may experience a decrease in blood pressure due to the aldosterone antagonist activity of drospirenone during treatment with Angeliq (see section 5.1). Angeliq should not be used to treat hypertension. Hypertensive women should be treated according to hypertension guidelines.

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet rays during hormone replacement therapy.

Each tablet of this medicine contains 46 mg of lactose. Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption who are on a lactose-free diet should take this rate into account.

04.5 Interactions with other medicinal products and other forms of interaction

Effects of other medicinal products on Angeliq

Substances that increase the clearance of HRT (reduced efficacy of HRT by enzyme induction)

The metabolism of estrogens (and progestins) can be increased by the simultaneous use of substances known to induce drug metabolism enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (eg. phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

Ritonavir and nelfinavir, although known to be potent inhibitors, by contrast exhibit induction properties when used concomitantly with steroid hormones. Herbal preparations based on St. John's wort (Hypericum perforatum) they can induce the metabolism of estrogens (and progestogens).

Clinically, the increased metabolism of estrogens and progestogens can cause a decrease in their effect and changes in the uterine bleeding profile.

Substances with variable effects on the clearance of HRT

When co-administered with HRT, many HIV / HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors may increase or decrease plasma concentrations of estrogen or progestogen or both. These changes may be clinically relevant in some cases.

Substances that decrease the clearance of HRT (enzyme inhibitors)

Strong or moderate CYP3A4 inhibitors such as azole antifungals (eg itraconazole, voriconazole, fluconazole), verapamil, macrolides (eg clarithromycin, erythromycin), diltiazem and grapefruit juice may increase plasma or progestogen or estrogen concentrations both. In a multiple dose study with a drospirenone (3 mg / day) / estradiol (1.5 mg / day) combination, co-administration for 10 days of the strong CYP3A4 inhibitor ketoconazole increased AUC (0 24h ) of drospirenone by 2.30 times (90% CI: 2.08, 2.54). No change was observed for estradiol, although the AUC (0 24h) of its less potent metabolite estrone was increased 1.39-fold (90% CI: 1.27; 1.52).

Effects of Angeliq on other medicinal products

In vitro, drospirenone is able to weakly to moderately inhibit the cytochrome P450, CYP1A1, CYP2C9, CYP2C19 and CYP3A4 enzymes.

Based on interaction studies conducted "in vivo"In female volunteers using omeprazole, simvastatin or midazolam as marker substrates, a clinically relevant interaction of drospirenone at a dose of 3 mg with cytochrome P450 enzyme mediated metabolism of other drugs is unlikely.

Concomitant use of Angeliq with NSAIDs or ACE inhibitors / angiotensin II receptor antagonists is unlikely to increase serum potassium. However, concomitant use of these three types of drugs together can cause a modest increase in serum potassium, which is more pronounced in diabetic women.

A further decrease in blood pressure may occur in hypertensive women taking Angeliq and antihypertensive drugs (see section 4.4).

04.6 Pregnancy and lactation

Pregnancy

Angeliq is not indicated during pregnancy. If pregnancy occurs while using Angeliq, treatment should be stopped immediately. No clinical data on exposed pregnancies are available. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. The results of most epidemiological studies conducted to date on accidental fetal exposure to combinations of estrogens and other progestogens have not shown teratogenic or toxic effects on the fetus.

Feeding time

Angeliq is not indicated during lactation.

04.7 Effects on ability to drive and use machines

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

04.8 Undesirable effects

The following table lists the undesirable effects classified by MedDRA system organ (MedDRA SOC). Frequencies are derived from clinical studies. Undesirable effects were reported in 7 phase III clinical trials (n = 2424 women) and considered to be at least possibly causally related to Angeliq (estradiol 1 mg / drospirenone 0.5; 1; 2 or 3 mg).

The most common side effects reported are breast pain (> 10%) and, during the first months of treatment, bleeding and spotting (> 10%). Irregular bleeding usually decreases with continued treatment (see section 5.1). The frequency of bleeding decreases with the duration of treatment.

System and organ classification Common (≥ 1/100, Uncommon (≥ 1/1000, Rare ( Disorders of the blood and lymphatic system Anemia Metabolism and nutrition disorders Weight gain or weight loss, anorexia, increased appetite, hyperlipemia Psychiatric disorders Depression, emotional lability, nervousness Sleep disturbances, anxiety, decreased libido Nervous system disorders Headache Paresthesia, decreased ability to concentrate, dizziness Vertigo Eye disorders Pathology of the eye, visual disturbances Ear and labyrinth disorders Tinnitus Cardiac pathologies palpitations Vascular pathologies Embolism, venous thrombosis, hypertension, migraine, thrombophlebitis, varicose veins Respiratory, thoracic and mediastinal disorders Dyspnea Gastrointestinal disorders Abdominal pain, nausea, abdominal swelling Gastrointestinal disorder, diarrhea, constipation, vomiting, dry mouth, flatulence, taste disturbance Hepatobiliary disorders Abnormal liver function tests Cholelithiasis Skin and subcutaneous tissue disorders Skin pathology, acne, alopecia, pruritus, rash, hirsutism, hair system pathology Musculoskeletal and connective tissue disorders Pain in extremities, back pain, arthralgia, muscle cramps Myalgia Renal and urinary disorders Pathology of the urinary tract, infections of the urinary tract Diseases of the reproductive system and breast Benign breast neoplasm, breast enlargement, uterine fibroid enlargement, benign cervical neoplasm, menstrual disorder, vaginal discharge Breast cancer, endometrial hyperplasia, benign uterine neoplasia, fibrocystic mastopathy, uterine disorder, ovarian disorder, cervical disorder, pelvic pain, vulvovaginal disorder, vaginal candidiasis, vaginitis, vaginal dryness Salpingite, galactorea General disorders and administration site conditions Asthenia, localized edema Generalized edema, chest pain, malaise, increased sweating Chills

The most appropriate MedDRA term is used to describe a specific reaction, its synonyms and related conditions.

Additional information for special patient populations

The following undesirable effects, classified by the investigator as at least possibly related to treatment with Angeliq, were recorded in two clinical trials in hypertensive women.

Metabolism and nutrition disorders

Hyperkalemia

Cardiac pathologies

Heart failure, atrial flutter, prolonged QT interval, cardiomegaly.

Diagnostic tests

Increased plasma concentration of aldosterone.

The following undesirable effects have been reported in association with hormone replacement therapy products: erythema nodosum, erythema multiforme, chloasma and haemorrhagic dermatitis.

Breast cancer risk

An increased risk of having breast cancer diagnosed is reported in women taking estrogen / progestogen therapy for more than 5 years, which can be up to double that of non-users. The increased risk in users of estrogen-only therapy is significantly lower than that observed in users of estrogen / progestogen combinations. The level of risk depends on the duration of use (see section 4.4). Results from the placebo-controlled study (WHI study) and the larger epidemiological study (MWS) are shown below.

MWS - Estimated additional risk of breast cancer after 5 years of use

Age range (years) Additional cases per 1000 non-users of HRT over 5 years a Relative risk b Additional cases per 1000 HRT users over 5 years (95% CI) Estrogen-only HRT 50-65 9-12 1,2 1-2 (0-3) Estrogen-progestin associations 50-65 9-12 1,7 6 (5-7) a Taken from base incidence rates in developed countries b Overall relative risk. The relative risk is not constant, but increases with the duration of use. Note: As the underlying incidence of breast cancer differs in different European countries, the number of additional cases will change proportionally.

US WHI Studies - Additional risk of breast cancer after 5 years of use

Age range (years) Incidence per 1000 women in the placebo arm over 5 years Relative Risk & 95% CI Additional cases per 1000 HRT users over 5 years (95% CI) Estrogen-only HRT (EEC) 50-79 21 0,8 (0,7 - 1,0) -4 (-6 - 0) a Estrogen-progestogen combinations (CEE + MPA) b 50-79 17 1,2 (1,0 - 1,5) +4 (0 - 9)

a WHI study in women without a uterus, which did not show an increased risk of breast cancer.

b When the analysis was restricted to women who had not used HRT prior to the study there was no increased risk during the first 5 years of treatment: after 5 years the risk was higher than in non-users.

Endometrial cancer risk

Postmenopausal women with the uterus

The risk of endometrial cancer is approximately 5 in 1000 women with a uterus who are not using HRT.

In women with a uterus, the use of estrogen-only HRT is not recommended as it increases the risk of endometrial cancer (see section 4.4).

Depending on the duration of use and the dose of estrogen, the increased risk of endometrial cancer in epidemiological studies varies between 5 and 55 additional cases per 1000 women between 50 and 65 years.

Adding a progestogen to estrogen-only therapy for at least 12 days per cycle may prevent this increased risk. In the Million Women Study, the use of estrogen / progestogen HRT (sequential or combined) did not increase the risk of endometrial cancer (RR 1.0 (0.8-1.2)).

Ovarian cancer

Long-term use of estrogen-only or estrogen-progestogen HRT was associated with a small increased risk of ovarian cancer. In the Million Women Study, 5 years of HRT resulted in 1 additional case per 2500 users.

Risk of venous thromboembolism

HRT is associated with a 1.3 to 3 relative risk of developing VTE, i.e. deep vein thrombosis or pulmonary embolism. These events are more likely to occur during the first year of use (see section 4.4). The results of the WHI studies are shown below:

WHI Studies - Additional risk of VTE after 5 years of use

Age range (years) Incidence per 1000 women in the placebo arm over 5 years Relative Risk & 95% CI Additional cases per 1000 HRT users over 5 years (95% CI) Estrogen-only oral HRT a 50-59 7 1,2 (0,6 - 2,4) 1 (-3 - 10) Oral estrogen-progestogen combinations 50-59 4 2,3 (1,2 - 4,3) 5 (1 - 13)

a WHI study in women with no uterus

Risk of coronary heart disease

The risk of coronary artery disease is slightly increased in users of estrogen / progestogen HRT over the age of 60 (see section 4.4).

Risk of ischemic stroke

The use of estrogen-only or estrogen-progestogen therapies is associated with an increased relative risk of ischemic stroke of up to 1.5. The risk of haemorrhagic stroke does not increase during HRT use.

This relative risk is independent of age or duration of use. However, as the baseline risk is highly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see section 4.4).

WHI studies combined - Additional risk of ischemic stroke a after 5 years of use

Age range (years) Incidence per 1000 women in the placebo arm over 5 years Relative Risk & 95% CI Additional cases per 1000 HRT users over 5 years (95% CI) 50-59 8 1,3 (1,1 - 1,6) 3 (1 - 5)

a No distinction was made between ischemic and haemorrhagic stroke.

Other adverse reactions have been described in association with estrogen / progestogen treatment:

• Cholecystopathy.

• Skin and subcutaneous tissue disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura.

• Probable dementia after 65 years of age (see section 4.4).

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

In clinical studies conducted in male volunteers, doses up to 100 mg of drospirenone were well tolerated. Based on general experience with COCs, symptoms that may occur are nausea and vomiting and, in young girls and some women, vaginal bleeding. There are no specific antidotes, so treatment should be symptomatic.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: estrogen-progestogen fixed combinations.

ATC code G03FA17.

Estradiol

Angeliq contains synthetic 17β-estradiol, which is chemically and biologically identical to endogenous human estradiol. It compensates for the loss of estrogen production in postmenopausal women and relieves menopausal symptoms. Estrogen prevents bone loss after menopause. or after oophorectomy.

Drospirenone

Drospirenone is a synthetic progestin.

Since estrogen promotes the growth of the endometrium, estrogen alone increases the risk of endometrial hyperplasia and carcinoma. The addition of a progestogen reduces, but does not eliminate, the risk of estrogen-induced endometrial hyperplasia in non-hysterectomised women.

Drospirenone exhibits an "antagonistic activity against" aldosterone. Thus it is possible to observe an increase in the excretion of sodium and water and a decrease in the excretion of potassium. Studies in animals, drospirenone did not show any estrogenic, glucocorticoid or antiglucocorticoid activity.

Information on clinical studies

• Alleviation of estrogen deficiency symptoms and bleeding patterns.

Alleviation of menopausal symptoms was achieved during the first weeks of treatment.

Amenorrhea was observed in 73% of women between the 10th and 12th months of treatment.

Breakthrough bleeding and / or small intra-menstrual bleeding (spotting) appeared in 59% of the women during the first three months of treatment, while in 27% of the women these appeared between the 10th and 12th months of treatment.

• Prevention of osteoporosis

Menopausal estrogen deficiency is associated with increased bone turnover and bone loss. The effect of estrogen on bone mineral density is dose-dependent. Protection appears to be effective as long as treatment lasts. After stopping HRT, bone loss is similar to that in untreated patients.

Results from the WHI study and meta-analyzes of clinical trials show that the use of HRT, alone or in combination with a progestogen, prescribed to predominantly healthy patients, reduces the risk of hip, vertebrae and other fractures. osteoporotic fractures. HRT can also prevent fractures in women with low bone density and / or overt osteoporosis, but the evidence for this hypothesis is limited.

After 2 years of treatment with Angeliq, the increase in hip bone mineral density (BMD) was 3.96 ± 3.15% (mean ± SD) in osteopenic patients and 2.78 ± 1.89% (mean ± SD) in non-osteopenic patients. The percentage of women who maintained or improved bone mineral density (BMD) in the hip area during treatment was 94.4% in osteopenic patients and 96.4% in non-osteopenic patients.

Angeliq was also effective on lumbar spine BMD. The increase after 2 years was 5.61 ± 3.34% (mean ± SD) in osteopenic patients and 4.92 ± 3.02% (mean ± SD) in non-osteopenic patients. maintained or improved lumbar BMD during treatment was 100%, versus 96.4% in non-osteopenic women.

• Antimineralocorticoid activity

Drospirenone has aldosterone antagonistic properties which may result in a decrease in blood pressure in hypertensive women. In a double-blind, placebo-controlled study, in postmenopausal hypertensive women treated with Angeliq (n = 123) for 8 weeks. a significant decrease in systolic / diastolic blood pressure values is observed ("in office" measurement towards baseline -12 / -9 mmHg, corrected for placebo effect -3 / -4 mmHg; ambulatory measurement in 24 hours towards baseline -5 / -3 mmHg, corrected for the placebo effect -3 / -2 mmHg).

Angeliq should not be used to treat hypertension. Women with hypertension should be treated according to hypertension guidelines.

05.2 "Pharmacokinetic properties

Drospirenone

• Absorption

After oral administration, drospirenone is rapidly and completely absorbed. With a single administration, peak serum levels of approximately 21.9 ng / mL are reached approximately 1 hour after dosing. Upon repeated administration, a maximum steady-state concentration of 35 is reached after approximately 10 days. 9 ng / ml. The absolute bioavailability is between 76 and 85%.Simultaneous food intake has no influence on bioavailability.

• Distribution

After oral administration, drospirenone serum levels decrease in two phases characterized by a mean terminal half-life of approximately 35-39 hours. Drospirenone binds to serum albumin, but not to sex hormone binding globulin (SHBG) or globulin. corticosteroid binding (CBG). Only 3-5% of the total serum concentration of the drug is present in the free steroid form. The mean apparent volume of distribution of drospirenone is 3.7-4.2 L / kg.

• Biotransformation

After oral administration, drospirenone is largely metabolised. The major metabolites in plasma are the acid form of drospirenone, produced by opening the lactone ring, and 4,5-dihydro-drospirenone-3-sulfate, formed by reduction and subsequent sulfation. Both major metabolites are pharmacologically inactive. drospirenone is also subject to CYP3A4 catalysed oxidative metabolism.

• Elimination

The metabolic clearance of drospirenone in serum is 1.2-1.5 ml / min / kg, with interindividual variability of approximately 25%. Drospirenone is eliminated only in trace amounts in the unchanged form. The metabolites of drospirenone are excreted in the faeces and urine with an excretion ratio of approximately 1.2-1.4. The elimination half-life of metabolites in urine and faeces is approximately 40 hours.

• Steady state conditions and linearity

Following daily oral administration of Angeliq, drospirenone concentrations reach steady-state in approximately 10 days. Serum levels of drospirenone showed accumulation of a factor of approximately 2-3 as a result of the relationship between the terminal half-life and the interval between doses. At steady state, mean serum levels of drospirenone fluctuate between 14 and 36 ng / ml after administration of Angeliq. The pharmacokinetics of drospirenone are dose proportional over a dose range of 1 to 4 mg.

Estradiol

• Absorption

After oral administration, estradiol is rapidly and completely absorbed. During absorption and the first passage through the liver, estradiol is largely metabolised, so that the absolute bioavailability of estrogen after oral administration is reduced to approximately 5%. of the dose. Maximum concentrations of approximately 22 pg / ml were reached 6-8 hours after a single oral administration of Angeliq. Food intake had no effect on estradiol bioavailability compared to taking the medicine on an empty stomach.

• Distribution

After oral administration of Angeliq there is only a gradual change in serum estradiol levels over a 24 hour dosing interval. Due to the large pool of glucuronides and estrogen sulphates circulating on one side and enterohepatic recirculation from Otherwise, the terminal half-life of estradiol represents a composite parameter that depends on all these processes and is included in a range of 13-20 hours after oral administration.

Estradiol nonspecifically binds to serum albumin and specifically to sex hormone binding globulin (SHBG). Only about 1-2% of the circulating estradiol is present in the form of free steroid, 40-45% is linked to SHBG. The apparent volume of distribution of estradiol after a single intravenous administration is approximately 1 l / kg.

• Biotransformation

Estradiol is rapidly metabolised and, in addition to estrone and estrone sulfate, numerous other metabolites and conjugated compounds are formed. Estrone and estriol are known as pharmacologically active metabolites of estradiol; only estrone is found in plasma in relevant concentrations. Estrone reaches serum levels about 6 times higher than those of estradiol. The serum levels of the conjugated compounds of estrone are about 26 times higher than the corresponding concentrations of free estrone.

• Elimination

Metabolic clearance was found to be approximately 30 mL / min / kg. The metabolites of estradiol are eliminated in the urine and bile with a half-life of approximately 1 day.

• Steady state conditions and linearity

Following daily oral administration of Angeliq, estradiol concentrations reach steady state after approximately five days. Serum levels of estradiol rise approximately 2-fold. Orally administered estradiol induces the formation of SHBG. This influences its distribution relative to serum proteins, causing an increase in the SHBG-bound fraction and a decrease in the albumin-bound and unbound fractions, thus highlighting a non-linear pharmacokinetics of estradiol after oral administration of Angeliq. Over a 24-hour dosing interval, mean steady-state serum estradiol levels fluctuate in the range of 20-43 pg / mL following Angeliq administration. The pharmacokinetics of estradiol are dose proportional at doses of 1 and 2 mg.

Special categories of patients

• Impaired liver function

Pharmacokinetics of a single oral dose of 3 mg drospirenone (DRSP) in combination with 1 mg estradiol (E2) was evaluated in 10 women with moderate hepatic impairment (Child Pugh B) and in 10 age-matched healthy women. , weight and smoking habits. The mean serum concentration profile of DRSP as a function of time was comparable in the two groups of women during the absorption / distribution phases with similar values of Cmax and tmax, suggesting that the rate of absorption is not affected by impaired hepatic function. The mean terminal half-life was approximately 1.8 times longer and, in volunteers with moderate hepatic impairment, an approximately 50% decrease in apparent oral clearance (CL / f) was observed, compared to those with normal hepatic function. .

• Impaired renal function

The effects of renal impairment on DRSP pharmacokinetics (3 mg daily for 14 days) were studied in women with normal renal function and mild and moderate renal impairment. At steady state during DRSP treatment, serum levels of DRSP in the mildly impaired renal function group (creatinine clearance CLcr, 50-80 mL / min) were comparable to those in the normal renal function group (CLcr,> 80 mL / min). on average 37% higher in the group with moderate renal impairment (creatinine clearance CLcr, 30-50 mL / min), compared to those in the group with normal renal function. Linear regression analysis of AUC values ( 0-24 hours) of the DRSP in relation to creatinine clearance revealed a 3.5% increase with a 10 ml / min decrease in creatinine clearance. increase is of clinical relevance.

05.3 Preclinical safety data

Animal studies with estradiol and drospirenone have shown the expected estrogenic and progestogenic effects. There are no preclinical data of relevance to the prescriber other than those already included in other sections of the Summary of Product Characteristics.