Medicinal Products

ACTIVELLE 1 mg / 0.5 mg

Generic drug of the therapeutic class: Gynecology
active ingredients: Estradiol, Norethisterone
laboratory: Novo Nordisk

Coated tablet
Box of 1 daily dispenser of 28
All forms

Indication

Hormone replacement therapy (HRT) symptoms of estrogen deficiency in postmenopausal women whose last menstrual period goes back more than a year.

Prevention of postmenopausal osteoporosis in women with an increased risk of osteoporotic fracture and intolerance or contraindication to other treatments indicated for the prevention of osteoporosis.

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

Dosage ACTIVELLE 1 mg / 0.5 mg Film-coated tablet Box of 1 daily dispenser of 28

ACTIVELLE is a continuous combined hormone replacement therapy product designed for use in women with intact uteri. A tablet should be taken orally once a day without interruption, preferably at the same time of day.

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

A switch to a more strongly dosed combined product may be indicated if after three months of treatment the expected relief of symptoms is insufficient.

In women with amenorrhea who are not on hormone replacement therapy (HRT) or in women who have previously taken another combined combined hormone replacement therapy, treatment with ACTIVELLE can be started any day. In women previously treated with sequential HRT, treatment should begin immediately after the end of withdrawal bleeding.

If the patient has forgotten to take a tablet, it should be taken as soon as possible within 12 hours of the usual time of day. If more than 12 hours have elapsed, the tablet should be discarded. Forgetting a dose may promote the occurrence of bleeding and spotting.

Against indications

· Known or suspected breast cancer or history of breast cancer

· Known or suspected estrogen-dependent malignancies or history of estrogen-dependent malignancies (eg, endometrial cancer);

· Undiagnosed genital haemorrhage;

· Untreated endometrial hyperplasia;

· History of venous thromboembolism or evolving venous thromboembolism (deep vein thrombosis, pulmonary embolism);

· Known thrombophilic disorders (eg, protein C, protein S or antithrombin deficiency, see Warnings and Precautions section );

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

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

· Known hypersensitivity to any of the active ingredients or to any of the excipients;

· Porphyria.

Activelle side effects

Clinical experience

The most common side effects reported in clinical trials with ACTIVELLE are vaginal bleeding and breast pain / tension, reported in approximately 10 to 20% of patients. Vaginal bleeding usually occurs in the first few months of treatment. Breast pain usually occurs after a few months of treatment. Side effects observed in randomized clinical trials, which were higher in patients treated with ACTIVELLE compared to placebo and considered likely to be related to treatment, are presented below.

System

Very common side effects

≥ 1/10

Common side effects

≥ 1/100; <1/10

Uncommon side effects

≥ 1/1000;

<1/100

Rare side effects

≥ 1/10 000;

<1/1000

Infections and infestations

Genital candidiasis or vaginitis, see also "Disorders of the reproductive organs and breast"

Immune system disorders

Hypersensitivity, see also "Skin and subcutaneous tissue disorders"

Metabolism and nutrition disorders

Fluid retention, see also "General disorders and administration site conditions"

Psychiatric disorders

Depression or worsening of depression

Nervousness

Nervous system disorders

Headache, migraine or worsening of migraine

Vascular disorders

Superficial thrombophlebitis

Deep vein thromboembolic disease, pulmonary embolism

Gastrointestinal disorders

nausea

Abdominal pain, discomfort or abdominal swelling.

Flatulence or bloating

Skin and subcutaneous tissue disorders

Alopecia, Hirsutism

Acne

Pruritus or hives

Musculoskeletal and systemic disorders

Back pain

Cramps in the lower limbs

Disorders of reproductive organs and breast

Pain or breast tension

Vaginal haemorrhage

Breast edema or breast hypertrophy Appearance, recurrence or aggravation of uterine fibroids

General disorders and administration site conditions

Peripheral edema

Inefficient drug

investigations

Weight gain

Post-marketing experience

In addition to the previously mentioned events, the side effects reported below have been reported spontaneously and are believed to be attributable to ACTIVELLE. The frequency of these spontaneous adverse effects is very rare (<1 / 10, 000 or indeterminate frequency (can not be estimated from the available data)). Postmarketing reports of adverse reactions are likely to be underestimated, particularly for well-known adverse effects. The frequencies presented must therefore be interpreted in this context:

· Benign and malignant tumors (including cysts and polyps): endometrial cancer

· Immune system disorders: generalized hypersensitivity reactions (eg, anaphylactic reaction / shock)

· Psychiatric conditions: insomnia, anxiety, increased or decreased libido

· Nervous system disorders: dizziness, stroke

· Eye disorders: visual disturbances

· Cardiac disorders: myocardial infarction

· Vascular disorders: worsening of hypertension

· Gastrointestinal disorders: dyspepsia, vomiting

· Hepatobiliary disorders: Gallbladder disease, cholelithiasis, aggravation of cholelithiasis, recurrence of cholelithiasis

· Skin and subcutaneous tissue disorders: seborrhea, exanthema, angioneurotic edema

· Disorders of reproductive organs and breast: endometrial hyperplasia, vulvovaginal pruritus

· Investigations: weight loss, increased blood pressure

Other undesirable effects have been reported in the literature when administering estrogen / progestogen treatment:

· Cutaneous and subcutaneous disorders: alopecia, chloasma, erythema multiforme, erythema nodosum, vascular purpura

· Likely dementia after age 65 (for more information see section Warnings and Precautions ).

Breast cancer risk

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

· The increase in risk is significantly lower among users of estrogen alone compared to users of combined hormonal supplementation.

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

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

Study "Million Women Study" - Estimation of the additional risk of breast cancer over 5 years of treatment

Age (years)

Number of additional cases per 1, 000 women not using HRT over 5 years * 2

Relative risk #

Number of additional cases per 1, 000 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 use

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

WHI Studies in the United States: Additional Breast Cancer Risk Over 5 Years of Treatment

Age (years)

Incidence per 1, 000 women

in the placebo arm over 5 years

Relative risk (95% CI)

Number of additional cases per 1, 000 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) * 3

Estrogen and Progestin 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 among non-users.

2 * Based on basic incidence rates in developed countries

3 * WHI study in hysterectomized women, not showing increased risk of breast cancer

Risk of endometrial cancer

The risk of endometrial cancer is approximately 5 per 1, 000 women with intact uteri who do not use HRT.

In women with an intact uterus, the use of estrogen-only HRT is not recommended as it increases the risk of endometrial cancer (see Warnings and Precautions section ).

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 estrogen alone for at least 12 days per cycle helps prevent this increased risk. In the Million Women Study, 5-year use of combined HRT (sequential or continuous) did not increase the risk of endometrial cancer (RR 1.0 (0.8- 1.2)).

Risk of ovarian cancer

Long-term use of estrogen-only HRT and estrogen / progestin combination therapy has been associated with a small increase in ovarian cancer risk. 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)

Incidence per 1, 000 women in the placebo arm over 5 years

Relative risk (95% CI)

Number of additional cases per 1, 000 HRT users

Estrogen alone orally * 4

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)

4 * 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 risk of stroke * 5 over 5 years of treatment

Age (years)

Incidence per 1, 000 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)

5 * There is no distinction between ischemic and haemorrhagic stroke.

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