ACTIVELLE 1 mg/0,5 Compressed Mg stripped Box of 1 daily Distributer of 28

ACTIVELLE 1 mg/0,5 Compressed Mg stripped Box of 1 daily Distributer of 28
Therapeutic class:   Gynecology
Active ingredients:   Estradiol, Noréthistérone
Statute:   Drug subjected to medical regulation
Rate of refunding S:   65%
Laboratory:   Novo Nordisk

Indications

- Substitute hormonal Treatment (THS) of the symptoms of deficit in estrogenes among women ménopausées since more than one year.
- Prevention of the post-menopausic osteoporosis at the woman having an increased risk of osteoporotic fracture and presenting an intolerance or a counter-indication to the other treatments indicated in the prevention of the osteoporosis.
- The experiment of this treatment among old women of more than 65 years is limited.

Posology

- ACTIVELLE is a product of hormonothérapie substitute combined continues conceived to be used among women who have an intact uterus. A tablet must be taken by oral way once per day without interruption, preferably per same hour of the day.
- To begin or continue a treatment in the indication of the symptoms post-menopausic, the effective minimal amount must be used for the shortest possible length of time (see heading warning statements and precautions for use).
- A passage to a product combined more strongly proportioned can be indicated so after three months of treatment the awaited relief of the symptoms is insufficient.
- Among women presenting an amenorrhoea and not following substitute hormonal treatment (THS) or among women previously having followed another hormonothérapie substitute combined continues, the treatment by ACTIVELLE can be begun any day. Among women previously treated by sequential THS, the treatment must begin just after the end from the bleedings from deprivation.
- If the patient forgot to take a tablet, this one must be thrown. The lapse of memory of an amount can support occurred of bleedings and spottings.

Against indications

- Known Over-sensitiveness with the one of the active ingredient or the one of the excipients;
- Known or suspecté Breast cancer or antecedents of breast cancer;
- Known or suspectées malignant Tumors estrogénodépendantes (example: cancer of the endometer);
- Not diagnosed genital Hemorrhage;
- Hyperplasie endométriale untreated;
- Antecedent of venous accident thrombo-embolic idiopathic or venous accident thrombo-embolic in evolution (major venous thrombosis, pulmonary embolism);
- Recent arterial Accident thrombo-embolic or in evolution (example: angor, myocardial infarction);
- Acute hepatic Affection or antecedents of hepatic affection, until standardization of the hepatic tests;
- Porphyrie.
- Because of the presence of lactose, this drug is contra-indicated in the event of congenital galactosemy, of syndrome of malabsorption of glucose and galactose or of lactase deficit.
- Pregnancy: this drug does not have an indication during the pregnancy. The discovery of a pregnancy during the treatment by ACTIVELLE, compressed stripped imposes the dead halt of the treatment. The data on a limited number of exposed pregnancies reveal undesirable effects of the noréthistérone on the fetus. With amounts higher than those usually contained in the oral contraceptives and the THS, of the cases of masculinisation of fetus females were observed. To date, the majority of the epidemiological studies did not highlight of teratogenic or foetotoxic effect in the expectant mothers exposed inadvertently to therapeutic amounts of estrogenes and progestatifs.
- Breast feeding: this drug does not have an indication during breast feeding.

Undesirable effects

CLINICAL EXPERIMENT:
- The side effects most frequently reported during the clinical trials carried out with ACTIVELLE are vaginal bleedings and pains/tensions mammaires, reported at approximately 10 to 20% of the patients. The vaginal bleedings usually occur in the first months of treatment. The pains mammaires occur in general after a few months of treatment.
- The side effects observed at the time of the randomized clinical studies, whose frequency was higher in the patients treated by ACTIVELLE compared to the placebo and considered as probably related to the treatment, are presented below.
- Infections and infestations:
Frequent > 1/100; < 1/10: Genital Candidose or vaginite, to also see “affections of the reproductive organs and the center”.
- Affections of the immune system:
Not very frequent > 1/1000; < 1/100: Over-sensitiveness, to also see “affections of the skin and subcutaneous fabric”.
- Disorders of the metabolism and the nutrition:
Frequent > 1/100; < 1/10: Hydrous retention to also see “turbid generals and anomalies with the site of administration”.
- Psychiatric Affections:
. Frequent > 1/100; < 1/10: Depression or aggravation of the depression.
. Not very frequent > 1/1000; < 1/100: Nervousness.
- Affections of the nervous system:
Frequent > 1/100; < 1/10: Cephalgia, migraine or aggravation of the migraine.
- Vascular affections:
. Not very frequent > 1/1000; < 1/100: Surface Thrombophlébite.
. Rare > 1/10000; < 1/1000: Major venous thrombo-embolic disease, pulmonary embolism.
- Gastro-intestinal Affections:
. Frequent > 1/100; < 1/10: Nauseas.
. Not very frequent > 1/1000; < 1/100: Abdominal pain, embarrassment or abdominal swelling, flatulence or distension.
- Affections of the skin and subcutaneous fabric:
Not very frequent > 1/1000; < 1/100: Alopécie, hirsutism or acne, prurit or urticaria.
- Musculosquelettic and systemic Affections:
. Frequent > 1/100; < 1/10: Back pains.
. Not very frequent > 1/1000; < 1/100: Cramps with the lower extremities.
- Affections of the reproductive organs and the center:
. Very frequent > 1/10: Pain or tension mammaire, vaginal hemorrhage.
. Frequent > 1/100; < 1/10: Edema mammaire or hypertrophies mammaire, uterine aggravation of fibromes, or reappearance of fibromes uterine or fibroïdes uterine.
- General Disorders and anomalies with the site of administration:
. Frequent > 1/100; < 1/10: Peripheral edema.
. Not very frequent > 1/1000; < 1/100: Inefficiency of the drug.
- Investigations:
Frequent > 1/100; < 1/10: Catch of weight.
BREAST CANCER:
- The results of a great number of epidemiological studies and a randomized study versus placebo, study WHI, show that the total risk of breast cancer increases with the utilization period of the THS among women taking or having recently taken a THS.
- For estrogenes alone, the relative risks (RR) estimated at the conclusion of a new analysis of 51 epidemiological studies (among which more than 80% used a estrogene alone) and MWS are similar, is respectively of 1,35 (IC95%: 1,21-1,49) and of 1,30 (IC95%: 1,21-1,40).
- For estroprogestatives associations, several epidemiological studies showed that the total risk of breast cancer is higher than for estrogenes alone.
- the MWS shows that, compared to the women not having never used a THS, the use of various associations estrogène/progestatif to a cancer risk of the center (RR exposes = 2,00, IC95%: 1,88-2,12) higher than that of estrogenes alone (RR = 1,30, IC95%: 1,21-1,40) or of tibolone (RR = 1,45, IC95%: 1,25-1,68).
- In study WHI, this relative risk is estimated at 1,24 (IC95%: 1,01-1,54) for the whole of the women treated during 5,6 years by an association estrogène/progestatif (the EEC + MPA) compared to those under placebo.
- The absolute risks calculated starting from the results of studies MWS and WHI are presented below:
The MWS, fascinating of account the average incidence of breast cancers in the developed countries, estimates that:
. on 1000 not-users of THS, approximately 32 will develop a breast cancer between 50 and 64 years;
. on 1000 women taking or having recently taken a THS, the number of additional cases would be:
For the users of estrogenes alone:
. Between 0 and 3 cases (better estimate = 1,5) for 5 years of use.
. Between 3 and 7 cases (better estimate = 5) for 10 years of use.
For the users of associations estrogène/progestatif:
. Between 5 and 7 cases (better estimate = 6) for 5 years of use.
. Between 18 and 20 cases (better estimate = 19) for 10 years of use.
- Study WHI estimates that at the end 5,6 years of follow-up of old women from 50 to 79 years, the number of additional cases of ascribable invasive breast cancers to the use of an association estrogène/progestatif (the EEC + MPA) is of 8 cases for 10000 woman-year.
- The calculations carried out starting from the data of the study make it possible to estimate that:
. For 1000 women of the placebo group:
Approximately 16 cases of invasive breast cancers will be diagnosed in 5 years of follow-up.
. For 1000 women using an association estrogène/progestatif (the EEC + MPA), the number of additional cases would be:
Between 0 and 9 (better estimate = 4) for 5 years of use.
- The number of additional cases of breast cancers is practically identical in the users whatever the age of beginning of the treatment (between 45 and 65 years) (see heading warning statements and precautions for use).
CANCER OF THE ENDOMETRE:
- Among not hysterectomized women treated by estrogenes alone, the risk of hyperplasy or cancer of the endometer increases with the duration of treatment.
- According to the data coming from epidemiological studies, the best estimate of the risk between 50 and 65 years is of approximately 5 diagnoses of cancer of the endometer on 1000 women not using a THS.
- Under estrogenes alone, the cancer risk of the endometer is multiplied by 2 to 12 compared to the not-users, according to the period utilization and of the amount of estrogene used. The association of one progestatif with estrogene strongly decreases this risk.
EXPERIMENT POST-MARKETING:
- In addition to the events previously mentioned, the undesirable effects presented hereafter were reported spontaneously and are regarded as probably ascribable with ACTIVELLE.
- The frequency of these spontaneous undesirable effects is very rare (< 1/10000 patients per annum). The collection post-marketing of the undesirable effects is likely to be underestimated particularly with regard to the well-known undesirable effects. The frequencies presented must thus be interpreted in this context:
. benign and malignant tumors (including cysts and polyps): cancer of the endometer;
. psychiatric affections: insomnia, anxiety, increase or reduction in the libido;
. affections of the nervous system: giddinesses;
. ocular affections: eye trouble;
. vascular affections: aggravation of hypertension;
. gastro-intestinal affections: dyspepsia, vomiting;
. affections hépatobiliaires: disease of the gall bladder, biliary lithiasis, biliary aggravation of lithiasis, repeats of a biliary lithiasis;
. affections of the skin and subcutaneous fabric: séborrhée, exanthème, edema angioneurotic;
. affection of the reproductive organs and the center: hyperplasy endométriale, prurit vulvovaginal;
. investigations: weight losses, increase in the blood pressure.
- Other undesirable effects are reported at the time of the administration of a estroprogestatif treatment:
. benign or malignant tumors estrogénodépendantes: cancer of the endometer;
. venous thrombo-embolic disease (pelvic major venous thrombosis or of the lower extremities, pulmonary embolism), more frequent at the women under THS than in the not-users. For additional details, to see headings counter-indications and warning statements and precautions for use;
. myocardial infarction and cerebral vascular accident;
. cutaneous and subcutaneous disorders: chloasma, polymorphic erythema, knotty erythema, will purpura vascular;
. probable insanity (see heading warning statements and precautions for use).