Divina Estradiol and Medroxyprogesterone 21 Tablets

BRIEF PRODUCT INFORMATION

1. NAME OF THE MEDICAL PRODUCT

DIVINA tablet

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Active substance:

Each white tablet in DIVINA package, 2 mg estradiol valerate; each blue tablet contains 2 mg of estradiol valerate and 10 mg of medroxyprogesterone acetate.

Excipients:

72 mg in blue tablet and 86.62 mg in white tablet.

For excipients see 6.1.

3. PHARMACEUTICAL FORM

Tablet.

White Tablet: White or almost white, 7 mm diameter, round and convex tablet.

Blue Tablet: Light blue, 7 mm diameter, flat and conical edge tablet.

4. CLINICAL FEATURES

4.1. Therapeutic indications

DIVINA tablets;

For theestrogen deficiency symptoms

treatment of

treatment of osteoporosis in patients who have not tolerated approved medicines for osteoporosis or are contraindicated for osteoporosis - for the.

- Experience is limited in patients over 65 years of age.

DIVINA is not a contraceptive.

4.2. Posology and method of administration

Posology / frequency and duration of administration:

DIVINA; because it is a preparation that mimics the double phase human menstrual cycle; 11 days white tablet, once a day (estrogen phase) and 10 days blue tablet, once a day (combined estrogen and progestin phase) is applied.

After 21 days of treatment, 7 days break is given.

Postmenopausal patients can start treatment immediately, while premenopausal patients are advised to start using DIVINA on day 5 of the cycle.

DIVINA treatment can be started on a suitable day in those who do not receive replacement therapy (HRT) or who are undergoing continuous combined HRT treatment.

In patients who have undergone cyclic or sequential HRT treatment, treatment should be started on the day following completion of the previous cycle.

If the patients forget to take a tablet, the forgotten tablet should not be taken the next day. The bypassed tablet may increase the observation of bleeding and spot bleeding.

The lowest effective dose should be used as soon as possible after the initiation and maintenance of postmenopausal symptoms.

Method of application:

First Day

Control of Blisters on the

Blue Tablets

1. There are small circles showing the days of the week in the top of the printed face of the blister foil. On the first day of the drug, the small circle of that day is drilled. This process is necessary to remember the day when the drug is started.

2. If menstruation is not available, immediately start DIVINA. If available, the first tablet is started on the fifth day of menstruation (fifth day after the onset of the bleeding).

3. The following tablets are taken in the order shown on the printed blister foil. The first day before the white tablet; then use a blue tablet for 10 days and a break of 7 days. Often, during this interruption period, menstruation-like bleeding may be seen.

4. The second box starts the day the first box is started.

5. DIVINA is preferably taken in the evening. If it is forgotten, it is taken the next morning and the treatment is continued with the normal dose on the evening of the same day. If it is forgotten to take both morning and evening, the treatment is continued with the normal dose but there may be a slight bleeding.

6. Bleeding may occur during a 7-day interval.

7. The monitoring card to be found in the box is filled and displayed to the physician at each visit.

Additional information on special populations:

Kidney / Liver failure

• If liver function values, abnormal elevations, cholestatic icter and thromboembolic signs are seen, treatment should be discontinued.

• In renal dysfunction, estrogen should not be used because of negative effect.

Pediatric population:

There is no use in children.

Geriatric population:

Treatment experience in women over 65 years of age is limited.

4.3. Contraindications

- Known, suspected or past breast cancer

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

- Undiagnosed genital bleeding

- Untreated endometrial hyperplasia

- Previous idiopathic or available venous thromboembolism [deep venous thrombosis (DVT), pulmonary embolism ]

- Active or recent arterial thromboembolic disease (eg, angina, myocardial infarction)

- Known thrombophilic disorders (protein C, protein S or antithrombin deficiency, see section 4.4)

- Acute and chronic liver diseases, ikter due to pregnancy and hepatosis, Dubin Johnson and Rotor's diseases

- known hypersensitivity to any of the active substances or excipients

- Porphyria

- Pregnancy

- Cerebrovascular disorders

- Sickle cell anemia

- Pregnancy herpes

- Increased otosclerosis in pregnancy

- Endometriosis.

4.4. Special warnings and precautions for use

Hormone replacement therapy should only be initiated if the quality of life is adversely affected and after the careful assessment of the benefit / risk ratio.

Early menopause experience is limited.

A personal and family medical history should be obtained before starting HRT or resuming treatment. This information, contraindications and precautions should guide the physical examination (including the pelvis and the breast).

Medical evaluation / monitoring

During the treatment, the frequency and nature of the hysterical controls are determined by the patient. Patients should be informed about the changes they should notice in the breasts to the doctor or nurse (see Breast count). According to individual clinical requirements, investigations, including mammography, should be performed in accordance with valid methods.

requiring close supervision:

ConditionsIt should be taken into account that during DIVINA treatment the following conditions may recur or may flare:

- Leiomyoma (endometriosis)

- risk factor or history of thromboembolic disorder

- Estrogen-dependent tumor risk factor, eg first-degree relative breast cancer

- Hypertension

- Liver disorders ( eg adenoma)

- diabetes mellitus with or without vascular involvement

- cholelithiasis

- migraine or (severe) headache

- systemic lupus erythematosus

- history of endometrial hyperplasia

- epilepsy

- asthma

- otosclerosis Conditions

requiring immediate discontinuation

of the treatment :

- jaundice or deterioration in liver function

- significant increase in blood pressure

- new onset migraine type headache

- pregnancy

Endometrial hyperplasia and cancer:

- estrogen alone in women with uterus The risk of endometrial hyperplasia and carcinoma increases with prolonged use. In estrogen users alone, the risk of endometrial cancer increases by 2-12 times, depending on the dose of estrogen and the duration of treatment, compared to non-users (see section 4.8). After terminating the treatment, this risk may remain increased for at least 10 years.

- The addition of progesterone or continuous combined estrogen-progesterone therapy for at least 12 days in a month or a 28-day period in non-hysterectomy women reduces the increased risk associated with HRT alone, including estrogen.

- At the beginning of the treatment, bleeding and spot bleeding may occur. If an intermediate bleeding or puncture bleeding occurs after a period of treatment or if the treatment persists after discontinuation, endometrial biopsy should be investigated in order to eliminate the risk of endometrial cancer.

Breast Cancer

All evidence suggests that there is an increased risk of breast cancer due to the duration of HRT uptake even in women receiving HRT with combined estrogen-progesterone or estrogen alone.Combined estrogen-progesterone treatment

- In a randomized placebo-controlled study (WHI) and in epidemiological studies, women who had combined combined estrogen-progesterone combinations as HRTs were consistent with an increased risk of breast cancer in approximately 3 years.

Estrogen treatment alone

- In the WHI study, an increase in the risk of breast cancer was not observed in women who underwent estrogen treatment alone. Much of the observational studies reported a small increase in breast cancer significantly lower than the results found in the combination of estrogen progesterone (see section 4.8).This increased risk is evident within a few years, but returns to baseline within a few years (up to 5 years) after discontinuing treatment.

HRT, especially with estrogen progesterone combined therapy, increases the density of mammographic images in a way that adversely affects the radiological diagnosis of breast cancer.Venous thromboembolism

- HRT is associated with a 1.3-3 fold increase in the risk of developing venous thromboembolism (VTE), such as deep venous thrombosis or pulmonary embolism.

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

- Generally defined risk factors for venous thromboembolism, estrogen use, advanced age, major surgery, prolonged inactivity, obesity (BMI> 30 kg / m2), pregnancy / postpartum period and systemic lupus erythematosus. There is no consensus on the possible role of varicose veins in venous thromboembolism.

- In all postoperative patients, extreme care should be taken to apply prophylactic methods to prevent venous thromboembolism after surgery. In cases where prolonged immobility may occur after surgery, it is possible to temporarily discontinue the treatment before 4-6 weeks, and treatment should not be initiated until the patient moves.

- In women with a history of VTE who have no history of VTE but who have a history of thrombosis in their first-degree relatives, a careful post-consultation screening may be recommended (only a certain part of thrombophilic disorders are determined by screening).

If family members have a thrombotic thrombophilic disorder, or if the disorder is severe (eg antithrombin, protein S, protein C deficiencies, or a combination of these), HRT is contraindicated.

- Women receiving chronic anticoagulant therapy should undergo a careful assessment of the benefit-risk of HRT treatment.

- If venous thromboembolism develops following treatment, treatment should be terminated. If patients observe potential thromboembolic symptoms (pain in the leg, swelling in the chest, sudden pain in the chest), they should consult their physician immediately.

Coronary artery disease (CAD)

- In randomized clinical trials, there is no evidence for a sustained combination of estrogen-progesterone or estrogen alone in women with or without CAD and protection from myocardial infarction.Combined estrogen-progesterone treatment Combined estrogen-progesterone The relative risk of CAD increases slightly during HRT use. Since the initial absolute risk of CAD is highly dependent on age, the number of CAD extragaries due to the use of estrogen-progesterone in healthy women close to menopause is very low and increases with age.Estrogen-alone trials Randomized controlled trials have not found an increase in the risk of CAD in women with hysterectomy using estrogen alone.

Stroke

- Combined estrogen-progesterone treatment and estrogen alone treatment increased the risk of ischemic stroke by 1.5 times. Relative risk does not change with age or duration following menopause. However, since the risk of onset is highly dependent on age, the risk for all women using HRT increases with age (see section 4.8).

Ovarian cancer

Ovarian cancer is much less than breast cancer. He found a relationship between the use of HRT products containing estrogen only for prolonged (at least 5-10 years) and a slight increase in risk of ovarian cancer. Some studies, including the WHI study, suggest that there may be a similar or slightly lower risk of long-term combined HRT use.

Other conditions:

Estrogens can cause fluid retention, so patients with heart or renal dysfunction should be observed carefully. Patients with end-stage renal disease should be closely monitored because the circulating levels of active substances in DIVINA are expected to increase.

Women with hypertriglyceridemia should be closely monitored during HRT. Because in this case, excessive triglyceride elevation of estrogen therapy, which is a rare cause of pancreatitis, has been reported.Estrogens increase thyroid-binding globulin (TBG), which increases the circulating total thyroid hormone measured by protein-dependent iodide (PBI), T4 levels (by colon- or radio-immunoassay) or T3 levels (by radio-immunoassay). The uptake of T3 in the resin is reduced, which describes the elevation of TBG. Free T4 and free T3 concentrations do not change. Other binding proteins, such as corticoid binding globulin (CBG), sex hormone binding globulin (SHBG), are also elevated in the serum, increasing the levels of corticosteroids and sex steroids in the circulation, respectively. Free or biologically active hormone concentrations do not change. Other plasma proteins may increase (angiotensinogen / renin substrate, alpha-I-antitrypsin, ceruloplasmin).Smoking increases the risk of thrombosis.

In patients with epilepsy, asthma, hypertension, heart and kidney dysfunction, endocrine disorders such as diabetes and hyperthyroidism, edema and migraine-related symptoms, and depression, estrogen may have negative effects.There is no clear evidence of improvement in cognitive function. In the WHI study, there is evidence of an increased risk of dementia in women who start on continuous combined conjugated estrogen and medroxyprogesterone acetate after age 65. It is not known whether these findings will be applied to younger postmenopausal women or other HRT products.

A blue tablet contains 72.00 mg Lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactose deficiency or glucose-galactose malabsorption should not use this drug.

One white tablet contains 86.62 mg Lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactose deficiency or glucose-galactose malabsorption should not use this drug.

4.5. Interactions with other medicinal products and other forms of interaction Themetabolism of estrogen and progesterone may be increased in combination with drugs known to specifically stimulate cytochrome P450, such as anticonvulsants (phenobarbital, phenytoin, carbamazepine) and antibiotics (rifampicin).It may affect the coagulation tests with thyroid and liver function tests.Although known as potent inhibitors, ritonavir and nelfinavirin exhibit inducing properties when used in combination with steroid hormones. Herbal preparations containing St John's wort (Yellowwort = Hypericum perforatum) can induce the metabolism of estrogens and progestagens.Clinically, an increase in the metabolism of estrogens and progestagens can lead to a decrease in effect and a change in the profile of uterine bleeding.

4.6. Pregnancy and lactation

General recommendation Pregnancy category is X.

Women with childbearing potential Contraception There is no use for contraceptive purposes. In most of the epidemiological studies to date; Involuntary fetal exposure with estrodiol valerate and medroxyprogesterone acetate has led to teratogenic or phytotoxic effect. The potential risk for humans is unknown.DIVINA is contraindicated during pregnancy (see section 4.3).Pregnancy should not be used during pregnancy. If pregnancy occurs during the use of DIVINA, treatment should be discontinued immediately.

There is inadequate / limited knowledge that estradiol valerate and medroxyprogesterone acetate arehuman or animal milk. It cannot be ruled out that there is a risk for the child in the breast due to the physicochemical and pharmacological / toxicological data available to remove estrodiol valerate and medroxyprogesterone acetate. DİVİNA should not be used during lactation.

Fertility No effects on fertility / reproductive ability have been reported in humans. Reproductive toxicity was observed in animal studies. The potential risk in humans is unknown.

4.7. Effects on ability toeffects on the ability to drive and use machines Nodrive and use machines have been observed.