Medicinal Products

DERMESTRIL 100 micrograms / 24 hours

Generic drug of the therapeutic class: Gynecology
active ingredients: Estradiol
laboratory: Rottapharm

Transdermal patch
Box of 8 Sachets of 1
All forms

Indication

Hormone replacement therapy (HRT) symptoms of estrogen deficiency in postmenopausal women, the last menstrual period of which is at least 6 months (for natural menopause).

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

Dosage DERMESTRIL 100 micrograms / 24 hours Transdermal patch Box of 8 Sachets of 1

Apply the patch 2 times a week, that is, repeat the patch every 3 to 4 days.

Three dosages of DERMESTRIL are available: DERMESTRIL 25, 50 and 100 micrograms / 24 hours, transdermal patch.

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 ).

Thus, the usual recommended dosage for starting treatment is a DERMESTRIL 25 microgram / 24 hour device twice a week.

Depending on the clinical course, the dosage should be adapted to individual needs:

· If the dose chosen has not corrected the signs and symptoms of estrogen deficiency, a stronger dosage should be administered.

· Appearance of breast tenderness, bleeding, water retention or bloating (persisting for more than 6 weeks) or irritability usually indicates that the dose is too high and needs to be changed.

DERMESTRIL 100 micrograms / 24 hours can be used according to the therapeutic scheme:

· Cyclic (discontinuous), for 24 to 28 days, followed by a free interval of 2 to 7 days. During this interval, deprivation haemorrhage may occur.

· Continuous, without any period of discontinuation of treatment.

Continuous, noncyclic treatment may be indicated in cases where the symptoms of estrogen deficiency are strongly manifested again during the free interval.

If it is a prescription in a woman who is not taking HRT or a continuous combined HRT relay, treatment can be started any day.

However, if the pretreatment is sequential HRT, the current treatment cycle must be completed before starting treatment with DERMESTRIL 100 micrograms / 24 hours.

In non-hysterectomized women, a progestin should be added at least 12 days per cycle to counter the development of estrogen-induced endometrial hyperplasia. Sequential treatment with progestins should be as follows:

· If DERMESTRIL 100 micrograms / 24 hours is administered cyclically (discontinuous), the progestin will be administered for at least the last 12 days of estradiol therapy. Thus, there will be no hormonal administration during the free interval of each cycle.

· If DERMESTRIL 100 micrograms / 24 hours is administered continuously, it is recommended to take the progestin for at least 12 days per month (continuous sequential).

In both cases, bleeding may occur after discontinuation of progestin therapy.

In hysterectomized women, it is not recommended to combine a progestin unless there is a history of endometriosis.

Administration mode

Once the protective sheet has been removed, the patch should immediately be applied to clean, dry, healthy skin (not irritated or injured), and free from cream, milk or oily products. Choose a location on the abdomen, buttocks or in the lumbar region in a place that does not show any significant wrinkles and is not the seat of sartorial friction.

Since estradiol is degraded by ultraviolet light, the transdermal patch should not be exposed to direct sunlight.

The transdermal patch should not be applied to the breasts . It must not be applied to the same place twice in a row.

It is possible to shower or bathe while keeping the transdermal patch.

In the case of a detachment of the transdermal device (very hot water, sweating, abnormal friction of clothing), it is recommended to replace it on dry skin. If this is not possible, use a new transdermal patch that will be removed on the original date. Then repeat the rate of change of the transdermal patch according to the initial regimen.

If you forget to replace DERMESTRIL 100 micrograms / 24 hours, a new patch should be applied as soon as possible. Then repeat the rate of change of the transdermal patch according to the initial regimen. Forgetting the application of a patch may encourage the recurrence of symptoms and the occurrence of bleeding and spotting.

Against indications

· Known hypersensitivity to the active substance or to any of the excipients listed in the Composition section;

· Known or suspected breast cancer or history of breast cancer;

· Known or suspected estrogen-dependent malignancies (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;

· Porphyria.

Dermestril side effects

More than 700 patients were treated with DERMESTRIL during clinical trials.

In clinical trials, approximately 10 to 17% of patients treated with DERMESTRIL experienced mild and transient systemic adverse events. Mammary tension has been reported in 20 to 35% of patients. Local reactions at the application site, mostly consisting of mild erythema with or without pruritus, occurred in 10 to 25% of patients.

The table below presents the adverse reactions reported in users of hormone replacement therapy (HRT), classified according to the MedDRA system-organ classification. (see also section Warnings and precautions for use Special warnings and precautions for use).

Common side effects

(> 1/100, <1/10)

Uncommon side effects

(> 1/1000, <1/100)

Rare side effects

(> 1/10 000, <1/1000)

Very rare side effects

(<1/10000)

Infections and infestations

vaginitis

Vaginal candidiasis

Immune system disorders

Hypersensitivity reaction

Metabolism and nutrition disorders

Weight gain or weight loss

Decreased tolerance to carbohydrates

Psychiatric disorders

Nervousness, insomnia

Depressed mood

Anxiety

Decreased libido or increased libido

Nervous system disorders

headaches

Dizziness

Migraine

paresthesia

chorea

Eye disorders

Visual disorders

Contact lens intolerance

Heart conditions

palpitations

Gastrointestinal disorders

Abdominal pain,

Nausea, diarrhea

Dyspepsia

bloating

Vomiting

Hepatobiliary disorders

Gallbladder Diseases, Gallstones

Skin and subcutaneous tissue disorders

rash

itching

Skin dryness

Nodular erythema

Skin discoloration

Urticaria

Hirsutism

Alopecia

Acne

Skin necrosis

Skeletal Muscle and Connective Tissue Affections

Back pain

Muscle cramps

myasthenia

Reproductive system and breast disorders

Vaginal / uterine bleeding including mild spotting

Menstrual disorders

Uterine spasms

Endometrial hyperplasia

Breast pain

Breast tension

Dysmenorrhea

Vaginal discharge

Premenstrual type syndrome

Breast hypertrophy

Uterine leiomyomas, paratubular cysts, endocervical polyps

Vascular disorders

Increase in blood pressure

Venous thromboembolism

General disorders and administration site abnormalities

Reaction to the application site (1)

Edema

Tired

investigations

Increased transaminase levels

(1) Skin reactions at the application site are less frequent if the transdermal patch is applied at the upper outer part of the buttocks by changing the application site each time.

The term most appropriate MedDRA is used to describe a certain reaction and its synonym and related states.

Breast cancer risk

· A 2-fold increase in the risk of breast cancer has been reported in women who have taken an estrogen / progestin combination for more than 5 years.

· The increase in risk is significantly lower among users of estrogen alone compared to users of estrogen-progestin combinations.

· 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

non users of 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)

Estro-progestative association

50-65

9-12

1.2

6 (5-7)

* 2 Based on basic incidence rates of developed countries

# 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 one country to another within the EU, the number of additional breast cancer cases varies from country to country within the EU. EU, the number of additional breast cancer cases will vary proportionally.

WHI study in the United States: additional breast cancer risk over 5 years of treatment

Age (years)

Incidence per 1, 000 women

non users of HRT

Over 5 years * 2

Relative risk #

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

Estro-progestative association EEC + MPA §

50-79

17

1.2 (1.0-1.5)

+4 (0-9)

* 3 The WHI study in hysterectomized women who did not show an increased risk of breast cancer

§ 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

Risk of endometrial cancer

Menopausal women not hysterectomized

The risk of endometrial cancer is about 5 per 1000 women with intact uterus and not using 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 depended on the duration of treatment with estrogen alone and the dose of estrogen and ranged from 5 to 55 additional cases diagnosed per 1, 000 elderly women from 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 (sequential or continuous) HRT 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 plus progestin combination therapy has been associated with a small increase in ovarian cancer risk. In the study "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 below:

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

for 1000 users of HRT

Estrogen alone orally * 4

50-59

7

1.2 (0.6-2.4)

1 (-3 - 10)

Estro-progestative oral 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 estrogen-progestin HRT over 60 years of age (see Warnings and Precautions section ).

Risk of ischemic stroke

The use of estrogen-only HRT or estrogen-progestagen combination therapy 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 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 guard and precautions for use )

Combined WHI studies - additional risk of stroke * 5 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

for 1000 users of HRT over 5 years

50-59

8

1.3 (1.1-1.6)

3 (1-5)

* 5 No distinction was made between ischemic and haemorrhagic stroke

Other side effects have been reported with estrogen / progestin therapy:

· Pathology of the gall bladder.

· 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 ).

Reporting of suspected adverse reactions

The reporting of suspected adverse reactions after authorization of the drug is important. It allows continuous monitoring of the benefit / risk ratio of the drug. Health professionals declare any suspected adverse reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (Ansm) and the network of Regional Pharmacovigilance Centers - Website: www.ansm.sante.fr.

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