Angeliq Estradiol Tablets- Drospirenone

Angeliq®

Film Coated Tablet

Pharmacodynamic properties

Effects of estradiol:

Angeliqidentical to endogenous human estradiol from chemical and biological aspects

contains 17 β-estradiol synthesized. 17 β-estradiol in women with menopauseestrogen

compensates for the loss ofproduction and relieves menopausal symptoms. Estrogensmenopause

prevent bone loss following removal ofor ovaries.

Effects of Drospirenone:

Drospirenone is a synthetic progestagene. Estrogensdevelopment of endometrium

promote the, while estrogens not combined with progestagen in the cycle

increase the risk of endometrial hyperplasia and cancer. Progestagen supplementationhad a hysterectomy

reduces the risk of estrogen-induced endometrial hyperplasia in women who have not,does

butnot completely eliminate them.

Drospirenone shows aldosterone antagonist activity. Thereforesodium and water

, increase inexcretion, decrease in potassium excretion.

Drospirenoneestrogenic, glucocorticoid or antiglucocorticoidanimal studies

did not showeffect in.

Clinical Trial Information:

• Improvement of estrogen deficiency symptoms and bleeding pattern The

relieving of menopausal symptoms occurred in the first few weeks of treatment.

Amenorrhea treatment 10-12. in 73% of women.women in the

Fracture bleeding and / or spotting infirst three months of treatment 59, 10-12.months

27% in.

• Prevention of osteoporosis

Estrogen deficiency in menopause is associated with increased bone turnover and reduced bone mass

. The effect of estrogen on bone mineral density is dose dependent. Theosteoporosis

prevention ofcontinues as long as the treatment is continued.hormone replacement therapy

Loss of bone mass after discontinuation of(HRT) occurs at a similar rate as untreated women

.

The meta-analysis of the WHI study and other studies showed that the use of HRTpredominantly in healthy

alone or in combination with progestagenwomenhip, vertebra and other

reduces the risk ofosteoporotic fractures. HRTlow bone density

can also prevent fractures in women withand / or established osteoporosis, but

there is limited evidence for this.

Pharmacokinetic properties

Drospirenone

Oral drospirenone is rapidly and almost completely absorbed. Thedrug

maximum serum levels of the, 21.9 ng / mlapproximately 1single dose of Angeliq

, are reachedhour after a. After repeated administration, the maximum steady state

concentration of 35.9 ng / ml is reached after about 10 days. The absolute

bioavailability is between 76-85%. Open or full belly ingestionbioavailability

does not affect.

After oral administration, serum drospirenone levelsabout 35-39 hours

are reduced in two phases, characterized by an average terminal half-life of. Drospirenone

binds to serum albumin. It does not bind to SHBG (sex hormone binding globulin) or CBG

(corticoid binding globulin).total serum drug concentrations

Only 3-5% ofare available as free steroids. The distribution volumeis

of drospirenoneabout 3.7-4.2 l / kg.

The main metabolites in plasma are in acid form of drospirenone and are pharmacologically

inactive.

The clearance rate of drospirenone from the serum is approximately 1.2-1.5 ml / min / kg. Drospirenone

is discarded only in very small amounts unchanged. Ithalf-half-

is excreted in the faeces and urine with alifelife of 1.2-1.4.

• Estradiol

Oral estradiol is rapidly and almost completely absorbed.

During absorption and the first liver passage, estradiolintense metabolism

undergoes,absolute bioavailability of estrogen todose after oral administration

causingfall to about 5% of the. Maximumapproximately 22 pg / ml are

concentrations of6-8 hours after single-dose oral administration of Angeliq

reached. Open or full stomach ingestion does not affect the bioavailability of estradiol.

After oral administration of Angeliq, serum levels of estradiol24 hours of

only changed relatively withinadministration.

Estradiol is non-specifically bound to serum albumin and specifically to SHBG.

Only about 1 to 2% of circulating estradiol is found as free steroids, 40% to% being

45SHBG.

Estradiol is rapidly metabolised, as well as estrone and estrone sulphate, as well as numerous other

metabolites and conjugates.

The metabolic clearance was about 30 ml / min / kg. The metabolites of estradiol are excreted by

urine and bile through a half-life of about 1 day.

After oral administration of Angeliq, steady state estradiol

concentrations are reached in about 5 days.

Indications

ofrelated to estrogen deficiency in women with menopause for more than 1 year

Hormone replacement for the treatmentsymptoms.

Prevention of postmenopausal osteoporosis (see Precautions).

Experience in women over the age of 65 is limited.

Contraindications

• Undiagnosed genital bleeding

• Known breast cancer, story or suspected

• malignant tumors known or suspected estrogen-dependent (eg. Endometrial

cancer)

• Untreated endometrial hyperplasia

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

• active or recent arterial thromboembolic disease (eg. angina, myocardial infarction)

• acute liver disease or liver function testsnot yetto normal

hadreturnedliver disease history

• Porphyria

• severe renal insufficiency or acute renal failure

• known hypersensitivity to any of the active or excipient

Warnings For the

treatment of postmenopausal symptoms, hormone replacementonlylife

should be initiatedfor symptoms that negatively affect the quality of. The risk-to-benefitfor all cases

ratioshould be considered at least on an annual basis, and hormone

replacement should only be continued as long as the benefits prevail over risks.

starting or resuming hormone replacement therapy

A complete anamnesis should be obtained before. Physical examination (including gynecologic and breastmeme

)with the patient's history”Contraindications“ and ezi Warnings / Precautionssections

should be performedtaking into consideration the. Itaccording to the frequencyadapted for each patient

is recommended that periodic examinations should be madeand content. Patientstheir breasts

should betodoctor or nurse about the changes in

advisedinform the. Inspections, including mammography,standard

must comply with theguidelines and be personalized for each patient.

If any of the following conditions are present, if they have been seen before,

and / or are aggravated during pregnancy or prior hormone therapy, patients

should be closely monitored. It should be noted that the following conditions maytreatment with Angeliq

recur or worsen during:

• Leiomyoma (uterine fibroids) or endometriosis

• A history of thromboembolic event or risk factors (see below)

• Risk factors for estrogene-dependent tumors, eg. 1st degreebreast cancer

relative to

• Hypertension

• Liver diseases (eg liver adenoma)disease

• Diabetes mellitus with or without vascular

• Cholelithiasis

• Migraine or (severe) headache

• Systemic lupus erythematosus

• History of endometrial hyperplasia (see below)

• Epilepsy

• asthma

• otosclerosis

situations that require immediate cessation of therapy:

Treatment when a contraindication recognized and should be stopped when:

• worsening of jaundice or liver function

• significant increase in blood pressure,

• the occurrence of migraine headaches

•pregnancy

endometrial hyperplasia

endometrial hyperplasia and cancer whenOestrogens long administered alone

increases the risk (see Side effects / Advers effects).a progestagen by at leastper cycle

Addition of12 daysgreatlythis risk in women who have not had a hysterectomy

reduces.

Breaking bleeding and spotting may occur in the first months of treatment. If fracture

bleeding or spottinga period of treatment, or if the treatment

occurs afterpersists after discontinuation, the cause should be investigated. This studyendometrial

may also include endometrial biopsy to excludemalignancy.

Breast cancer

A randomized placebo-controlled trial, the Women's Health Initiative (WHI)

study and Million Women Study (MWS) epidemiological  including the

studies,research,estrogen, estrogen-progestogen combinations or tibolonea  years

breast cancerfewof use have reported an increased risk of (bkz.y the

effects / The risk for all HRT is marked by a few years of use and

increases with continued use, butafter discontinuation of treatment

returns to its original state within a few (five) years.

In MWSrelativebreast cancer with conjugated mare estrogens or estradiol (E2)

, therisk ofa sequential or continuous progestagen wasregardless of the progestagen type

was found to be greater whenadded,. There were no differences inroutes of administration

risk between different.

In the WHI studycontinuous combined conjugated mare estrogene and medroxyprogesterone

, breast cancer sizes were slightly larger and local lymph nodeplacebo withacetate

metastases were found more frequent than.

Hormone replacement therapy, especially estrogen-progestagen combination, may

increase the density of mammographic images andradiologicalbreast cancer

adversely affect thefindings of.

Venous thromboembolism

HRTdeveloping venous thromboembolism (VTE: deep vein thrombosis or pulmonary embolism)

may present a higher relative risk of. In a randomized controlled

trial and epidemiological studies, theHRT users than those who did not

risk was found to be two to three times higher in.

The incidence of VTE in a 5-year period for those who did not use HRTages of 50-59

was 3 for 1000 women between theand 8 for 1000 women between the ages of 60-69.

The number of additional VTE cases in healthy women with 5 years of HRT use is

between 2 and 6 (closest estimate = 4) for 1000 women aged 50-59, and60-69 years of age

between 5 and 15 (closest estimate = 9) between. Thethis eventHRT use

likelihood ofin the first year ofis higher than after.

Generally defined risk factors for VTE are personal history or family history,

obesity (body mass index> 30kg / m2) and systemic lupus erythematosus.VTE

no common opinion about the possible role of varicose veins in the development of

There is.

Patients with a history of VTE or known thrombophilic statusa high risk for VTE

carry. HRT can increase this risk. The history of personal and family thromboembolic events or

recurrent spontaneous abortionswellto rule out a thrombophilic predisposition

<span s