SYNTHESIS |
VIDAL pharmacotherapeutic classification:Gynecology - Obstetrics : Non-contraceptive estroprogestogens : Menopause - Hormone substitution : Estroprogestogens ( Oral route )
ATC classification:GENITO-URINARY SYSTEM AND SEX HORMONES : SEX HORMONES AND MODULATORS OF GENITAL FUNCTION - PROGESTATIVES AND ESTROGENS IN ASSOCIATION : PROGESTATIVES AND ESTROGENS IN FIXED ASSOCIATION ( NORETHISTERONE AND ESTROGEN )
Excipients:
corn starch , copovidone , magnesium stearate
excipient and film coating: talc
film coating: hypromellose , triacetin
Excipients with known effect :
NTE without threshold dose: lactose monohydrate
SHAPES AND PRESENTATIONS |
COMPOSITION |
| p cp | |
| Estradiol (as estradiol hemihydrate) | 1mg |
| Norethisterone acetate | 0.5mg |
Film-coating: hypromellose, triacetin, talc.
Excipient with known effect: lactose monohydrate (37.0 mg/tablet).
| DC | DIRECTIONS |
- Hormone replacement therapy (HRT) for symptoms of estrogen deficiency in postmenopausal women whose last menstrual period dates back more than a year.
- Prevention of post-menopausal osteoporosis in women at increased risk of osteoporotic fractures and with intolerance or contraindication to other treatments indicated for the prevention of osteoporosis.
| DC | WARNINGS AND PRECAUTIONS FOR USE |
In the indication for the treatment of menopausal symptoms, HRT should only be started if the disorders are perceived by the patient as impairing her quality of life. In any case, a reassessment of the benefit/risk ratio must be carried out at least once a year. HRT can be continued as long as the benefit outweighs the risk.
Evidence regarding the risks associated with the use of HRT in women going through early menopause is limited. However, due to the low absolute risk in younger women, the benefit/risk ratio may be more favorable in these women than in older women.
- Clinical examination and monitoring:
- Before starting or restarting HRT, it is essential to carry out a complete clinical and gynecological examination (including the collection of personal and family medical history), taking into account the contraindications and precautions for use. Throughout the duration of the treatment, regular examinations are recommended, their nature and frequency being adapted to each patient. Women should be informed of the type of breast abnormalities that may occur under treatment; these abnormalities must be reported to the attending physician or nurse (see “Breast cancer” paragraph below). The examinations, including the appropriate imaging tools, for example a mammogram, must be carried out according to the recommendations in force, and adapted to each patient.
- Conditions requiring monitoring:
- If any of the following conditions occur, have occurred previously and/or have worsened during pregnancy or previous hormone therapy, the patient should be closely monitored. The following conditions may come back or get worse during treatment with Activelle, in particular:
- Leiomyoma (uterine fibroid) or endometriosis.
- Thromboembolic risk factors (see below).
- Risk factors for estrogen-dependent tumours, for example: 1 st degree of heredity for breast cancer.
- High blood pressure.
- Liver disorders (eg hepatic adenoma).
- Diabetes with or without vascular involvement.
- Cholelithiasis.
- Migraine or headache (severe).
- Systemic lupus erythematosus.
- History of endometrial hyperplasia (see below).
- Epilepsy.
- Asthma.
- Otosclerosis.
- Immediate discontinuation of treatment:
- Treatment should be stopped if a contraindication occurs or in the following cases:
- Jaundice or impaired liver function.
- Significant increase in blood pressure.
- Unusual migraine-like headache.
- Pregnancy.
- Endometrial hyperplasia and carcinoma:
- In women with an intact uterus, the risk of endometrial hyperplasia and carcinoma is increased with prolonged administration of estrogens alone. An increased risk of endometrial cancer has been reported in users of estrogen alone compared to non-users, from 2 to 12 times depending on the duration of treatment and the dose of estrogen ( see Adverse effects ). After stopping treatment, the risk may remain elevated for at least 10 years.
- In women without hysterectomy, the addition of a progestogen for at least 12 days per month over a 28-day cycle or the initiation of a continuous estrogen-progestogen combination prevents the increased risk associated with treatment with progestins. estrogens alone.
- Metrorrhagia and spotting may occur during the first months of treatment. If these events persist after the first months of treatment, begin some time after the start of treatment, or if they persist after stopping treatment, their cause should be investigated. This approach may require an endometrial biopsy to exclude malignancy.
- Breast cancer :
- The available data show an increased risk of breast cancer in women taking estrogen-progestogen treatment or in those taking estrogen-only HRT, this risk being dependent on the duration of treatment.
- The randomized controlled trial versus placebo Women's Health Initiative Study (WHI) and a meta-analysis of prospective epidemiological studies confirm an increased risk of occurrence of breast cancer in women treated with combined estrogen-progestogen HRT. This increased risk becomes significant after about 3 (1-4) years of use ( see Adverse effects ).
- The results of a large meta-analysis showed that after stopping treatment, the additional risk decreases over time and the length of time it takes for it to return to normal depends on how long you take HRT. When HRT has been followed for more than 5 years, the risk may persist for 10 years or more.
- HRT, particularly combined estrogen-progestogen therapy, increases breast density on mammography, which could interfere with the diagnosis of breast cancer.
- Ovarian cancer:
- Ovarian cancer is much rarer than breast cancer. Epidemiological data from a large meta-analysis suggest a small increased risk in women taking estrogen-alone HRT or a combination of estrogens and progestins, which appears within five years of starting use of the product and gradually decreases after discontinuation of treatment. Other studies, including the Women's Health Initiative (WHI) trial, suggest that a similar or slightly lower risk may be associated with combined HRT use ( see Adverse effects ).
- Venous thromboembolism:
- HRT is associated with a 1.3 to 3 times higher risk of occurrence of venous thromboembolism (VTE), for example deep vein thrombosis or pulmonary embolism. The probability of occurrence of such an event is higher during the first year of HRT use ( see Adverse effects ).
- Patients with a known thrombophilic state have an increased risk of VTE and taking HRT may increase this risk. HRT is therefore contraindicated in these patients ( see Contraindications ).
- Generally, the recognized risk factors for VTE are: estrogen use, advanced age, major surgery, prolonged immobilization, obesity (BMI > 30 kg/m 2 ), pregnancy/postpartum, systemic lupus erythematosus (SLE) and cancer. On the other hand, there is no consensus on the possible role of varicose veins on the risk of venous thromboembolism.
- As in all patients in the postoperative period, prophylactic measures should be applied to prevent VTE after surgery. If prolonged immobilization is to follow scheduled surgery, temporary discontinuation of HRT, 4 to 6 weeks before surgery, is recommended. Treatment should not be reintroduced until the patient has regained full mobility.
- In women with no personal history of VTE, but having a first-degree relative with a history of VTE at a young age, screening may be offered after carefully presenting its limitations (only certain thrombophilic abnormalities are identified by screening).
- If a thrombophilic abnormality is identified, associated with VTE in family members, or if the deficiency is “severe” (for example: deficiency in antithrombin, protein S or protein C, or combination of deficiencies), HRT is contraindicated.
- In women on chronic anticoagulant therapy, the benefit/risk ratio of using HRT should be carefully assessed.
- If VTE develops after initiation of treatment, treatment should be discontinued. Patients should be instructed to contact their doctor immediately if they develop symptoms suggestive of a thromboembolic event (eg painful swelling of a leg, sudden chest pain, dyspnoea).
- Coronary disease :
- Randomized controlled trials have not shown any protection against myocardial infarction in women with or without coronary artery disease and taking an estrogen-progestogen combination or estrogen-only HRT.
- The relative risk of coronary artery disease when using an estrogen-progestogen combination is slightly increased. Because the baseline absolute risk of coronary heart disease is strongly age-dependent, the number of excess cases of coronary heart disease associated with estrogen-progestogen combination use is very low in healthy women approaching menopause. , but increases with age.
- Ischemic stroke:
- The use of an estrogen-progestogen combination or estrogen-only therapy is associated with an increased risk of ischemic stroke by up to 1.5 times. The relative risk does not change with age or duration of menopause. However, because the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women taking HRT increases with age ( see Adverse effects ).
- Other pathologies:
- Since estrogen can cause fluid retention, patients with renal or cardiac abnormality should be closely monitored.
- Women with pre-existing hypertriglyceridaemia should be closely monitored during estrogen replacement therapy or during hormone replacement therapy because rare cases of significant increase in plasma triglyceride levels leading to pancreatitis have been observed under estrogen therapy.
- During treatment with estrogens, an increase in plasma levels of TBG (thyroid-binding globulin) is observed, leading to an increase in plasma levels of total thyroid hormones measured by PBI (protein-bound iodine) of total T4 ( measured on a column or by RIA [radio-immunoassay]) and total T3 (measured by RIA). The binding of T3 to the resin is reduced, reflecting the increase in TBG. The concentrations of the free fractions of T4 and T3 remain unchanged. Serum levels of other binding proteins such as CBG (corticoid-binding globulin) and SHBG (sex hormone-binding globulin) may be increased resulting in increased circulating levels of corticosteroids and sex steroids, respectively. The concentrations of the free or biologically active fractions of the hormones remain unchanged. Other plasma proteins may also be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin and ceruloplasmin).
- Using HRT does not improve cognitive function. Data suggest that the risk of probable dementia is increased in women starting continuous estrogen-progestogen therapy or estrogen-only HRT after age 65.
- Activelle contains lactose monohydrate. This medicine should not be used in patients with galactose intolerance, Lapp lactase deficiency or glucose or galactose malabsorption syndrome (rare hereditary diseases).
| DC | FERTILITY / PREGNANCY / BREASTFEEDING |
Activelle is not indicated during pregnancy.
Discovery of pregnancy during treatment with Activelle requires immediate discontinuation of treatment.
Clinical data on a limited number of exposed pregnancies reveal adverse effects of norethisterone on the foetus. At doses higher than those usually contained in oral contraceptives and HRT, cases of masculinization of female fetuses have been observed.
To date, most epidemiological studies have not demonstrated any teratogenic or foetotoxic effect in pregnant women inadvertently exposed to estrogen-progestogen combinations.
Feeding with milk :
Activelle is not indicated during lactation.
Fertility:No data is available.
| DC | DRIVING AND USING MACHINES |
| DC | OVERDOSAGE |
Overdose may be manifested by nausea and vomiting. Treatment should be symptomatic.
| PP | PRECLINICAL SAFETY |
The acute toxicity of estrogens is low. Due to an important difference between animal species and between animals and humans, data from preclinical studies cannot be fully applied to the use of estrogens in humans.
Estradiol and estradiol valerate possess an embryotoxic effect at relatively low doses in experimental animal models; malformations of the urogenital system and feminizations of male fetuses have been observed.
Norethisterone, like other progestins, caused virilization of female fetuses of rats and monkeys. Embryotoxic effects have been observed with the administration of high doses of norethisterone.
Non-clinical data from conventional studies of safety pharmacology, repeated dose toxicology, genotoxicity, carcinogenicity, and reproduction and development functions, reveal no special hazard for humans other than those already cited in the other sections of the SPC.
| DP | STORAGE CONDITIONS |
- The duration of the conversation :
- 3 years.
Store at a temperature not exceeding 25°C. Do not put in the refigerator. Store the daily dispenser in the outer packaging, protected from light.
| DP | HANDLING/DISPOSAL PROCEDURES |
Any unused medication or waste should be disposed of in accordance with applicable regulations.
PRESCRIPTION/ISSUE/CARE |
| MA | 3400934879944 (1998, RCP rev 25.11.2020). |
| Price : | 6.25 euros (dispenser of 28 tablets). |
| 65% Sec Remb. Collect. | |