Medicinal Products

DUOVA 1 mg / 5 mg

Generic drug of the therapeutic class: Gynecology
active ingredients: Estradiol, Medroxyprogesterone
laboratory: Orion Corporation

Compressed
Box of 1 Plate of 28
All forms

Indication

Hormone replacement therapy (HRT) symptoms of estrogen deficiency in women without hysterectomized menopause for more than three years.

Prevention of postmenopausal osteoporosis in women with an increased risk of osteoporotic fracture who have an intolerance or a contraindication to other treatments indicated for the prevention of osteoporosis (see sections Warnings and precautions for use and Pharmacodynamic properties ).

The experience of this treatment in women over 65 is limited.

Dosage DUOVA 1 mg / 5 mg Tablet Box of 1 Plate of 28

DUOVA is a continuous combined hormone replacement therapy (HRT) in which estrogen and progestin are given daily without interruption.

Dosage: one tablet per day, orally, without free interval. The tablet should be taken at about the same time of the day.

It is recommended to start treatment with a tablet of DUOVA 1 mg / 2.5 mg. The dosage can then be adjusted individually depending on the clinical response.

The 2.5 mg dose of medroxyprogesterone acetate is usually sufficient to prevent intercurrent bleeding. In case of occurrence and persistence of these bleeds and after elimination of an endometrial abnormality, the dose may be increased to 5 mg (DUOVA 1 mg / 5 mg).

If the 1 mg dose of estradiol valerate is not sufficient to correct the symptoms of estrogen deficiency, the dose may be increased to 2 mg (DUOVA 2 mg / 5 mg).

In postmenopausal women with amenorrhea who do not take HRT as well as relays for continuous combined HRT, treatment with DUOVA can be started any day. In relay of a cyclic HRT, treatment with DUOVA should be started one week after the end of the cycle.

The effect of estrogen on bone mineral density is dose-dependent. Therefore, the effect of 1 mg estradiol valerate may be less than that of 2 mg (see section 5.1 Pharmacodynamic properties ).

If the patient has forgotten to take a tablet, the forgotten tablet should be discarded. Forgetting a tablet can lead to intercurrent bleeding and spotting.

To start or continue treatment for the indication of postmenopausal symptoms, the minimum effective dose should be used for the shortest possible duration (see Warnings and Precautions ).

Against indications

· Known or suspected breast cancer or history of breast cancer

· Known or suspected estrogen-dependent malignant neoplasms (eg, endometrial cancer);

· Undiagnosed genital haemorrhage;

· Untreated endometrial hyperplasia;

· History of venous thromboembolic accident or evolving venous thromboembolic event (deep vein thrombosis, pulmonary embolism);

· Known thrombophilic disorders (eg deficiency of protein C, protein S or antithrombin) (see Warnings and precautions for use )

· Recent or evolving arterial thromboembolic stroke (eg, angina, myocardial infarction);

· Acute liver disease or history of liver disease, until hepatic tests are normalized;

Hypersensitivity to any of the active ingredients or to any of the excipients;

· Porphyria.

Duova side effects

The most commonly reported adverse event in clinical trials with DUOVA was breast tenderness, occurring in 10.6% of treated women.

Adverse reactions reported in clinical trials with DUOVA are presented in the table below:

Class of organ systems

Common side effects ( ³ 1/100, <1/10)

Uncommon side effects

( 1/1000, <1/100)

Rare side effects ( ³ 1/10 000,

<1/1000)

Not known (can not be estimated from the available data)

Benign, malignant and unspecified neoplasms (including cysts and polyps)

Breast cancer, endometrial cancer

Psychiatric disorders

Changes in mood (anxiety, depression), changes in libido

Nervous system disorders

headaches

Dizziness, migraines

Vascular disorders

Elevation of blood pressure

Venous thromboembolic accidents

Pulmonary embolism

Gastrointestinal disorders

Nausea, abdominal pain

Dyspepsia, vomiting, flatulence, biliary disorders / cholelithiasis

Skin and subcutaneous tissue disorders

Alopecia, hirsutism, rash, pruritus

Disorders of reproductive organs and breasts

Uterine bleeding, increased volume of uterine fibroids, breast tenderness, breast hypertrophy

Vaginal candidiasis

Endometrial hyperplasia

Musculoskeletal and connective tissue disorders

Cramps of the lower limbs

General conditions and anomalies at the administration site

Weight gain / loss, edema

Breast cancer

· A 2-fold increase in breast cancer risk has been reported in women who have taken a combined oral contraceptive regimen for more than 5 years.

· The increased risk for users of estrogen alone is significantly lower compared to users of combined hormonal combinations.

· The level of risk is dependent on the duration of treatment (see Warnings and Precautions ).

· The results of the largest randomized placebo-controlled trial (WHI study) and the largest epidemiological study (MWS) are presented below.

Study Million Women Study - Estimated additional risk of breast cancer over 5 years of treatment.

Age (years)

Number of additional cases per 1000 women not using HRT over 5 years *

Relative Risk #

Number of additional cases per 1000 users of HRT over 5 years (95% CI)

Estrogen alone

50-65

9-12

1.2

1-2 (0-3)

Estroprogestative Association

50-65

9-12

1.7

6 (5-7)

# Overall relative risk. The relative risk is not constant but increases with the duration of the treatment.

Note: Since the baseline incidence of breast cancer varies from country to country in the EU, the number of additional breast cancer cases will vary proportionally.

* Derived from basic incidence rates in developed countries

WHI study in USA - Additional breast cancer risk over 5 years of treatment

Age (years)

Incidence for 1000 women in the placebo arm over 5 years

Relative Risk (95% CI)

Number of additional cases per 1000 users of HRT over 5 years (95% CI)

Estrogen alone (equine conjugated estrogens)

50-79

21

0.8 (0.7 - 1.0)

-4 (-6 - 0) *

Estro-Progestational Association (EEC + MPA) #

50-79

14

1.2 (1.0 - 1.5)

+4 (0 - 9)

# When the analysis was limited to women who did not use HRT before the study, no increase in risk was observed during the first 5 years of treatment: after 5 years, the risk was higher than in non-users.

* WHI study in hysterectomized women who have not shown an increased risk of breast cancer.

Endometrial cancer

The risk of endometrial cancer is about 5 per 1000 women with intact uterus and not using HRT.

In women with intact uteri, the use of estrogen-only HRT is not recommended because of the increased risk of endometrial cancer (see Warnings and Precautions section). employment ).

In epidemiological studies, the increased risk of endometrial cancer was dependent on the duration of treatment with estrogen alone and the dose of estrogen and ranged between 5 and 55 additional cases diagnosed per 1, 000 elderly women. 50 to 65 years old.

Adding a progestin to treatment with estrogen alone for at least 12 days per cycle helps to prevent increased risk. In the MWS study, the use for 5 years of combined HRT (sequential or continuous) did not increase the risk of endometrial cancer (RR = 1.0 (0.8 - 1.2) ).

Ovarian cancer

Prolonged administration of estrogen-only HRT or HRT was associated with a slight increase in the risk of ovarian cancer. In the Million Women Study, 1 additional case for 2, 500 users appeared after 5 years.

Risk of venous thromboembolism

HRT is associated with a 1.3 to 3-fold increase in the relative risk of a venous thromboembolic event, ie, deep vein thrombosis or pulmonary embolism. The probability of occurrence of such an event is higher during the first year of use of HRT (see Warnings and Precautions section ). The results of the WHI studies are presented:

WHI studies - Additional risk of venous thromboembolism over 5 years of treatment

Age (years)

Impact

for 1000 women in the placebo arm over 5 years

Relative risk (95% CI)

Number of additional cases per 1, 000 HRT users

Estrogen alone orally *

50-59

7

1.2 (0.6-2.4)

1 (-3 - 10)

Oral Estroprogestative Association

50-59

4

2.3 (1.2 - 4.3)

5 (1 - 13)

* Study in hysterectomized women

Risk of coronary heart disease

The risk of coronary heart disease is slightly increased in users of hormone replacement therapy over the age of 60 (see Warnings and precautions for use section ).

Risk of ischemic stroke

The use of estrogen alone or estrogen / progestin-only HRT is associated with up to 1.5-fold increase in the relative risk of ischemic stroke. The risk of haemorrhagic stroke is not increased when using HRT.

This relative risk does not depend on age or duration of treatment, but because the baseline risk is highly age-dependent, the overall risk of stroke in women using HRT increases with age (see section on caution and precautions for use ).

Combined WHI Studies - Additional Stroke Risk * Over 5 Years of Treatment

Age (years)

Incidence for 1000 women in the placebo arm over 5 years

Relative risk (95% CI)

Number of additional cases per 1, 000 HRT users over 5 years

50-59

8

1.3 (1.1 1.6)

3 (1-5)

* There is no distinction between ischemic and haemorrhagic stroke.

The following side effects are reported with estrogen-progestin therapy (class effects):

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

· Dementia likely beyond the age of 65 (see Warnings and precautions for use section ).

· Pancreatitis (see Warnings and Precautions section ).

Ovarian cancer (see Warnings and precautions for use section ).

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