Medicinal Products

DERMESTRIL SEPTEM 25 micrograms / 24 hours

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

Transdermal patch
Case of 4
All forms

Indication

Hormone Replacement Therapy (HRT) symptoms of estrogen deficiency in postmenopausal women whose last menstrual period is at least 6 months old.

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

Dosage DERMESTRIL SEPTEM 25 micrograms / 24 hours Transdermal patch Case of 4

Dosage

DERMESTRIL SEPTEM is an estrogen transdermal patch alone, applied to the skin once a week to ensure a continuous supply of estradiol to the body; thus, each used device is removed after 7 days and replaced by a new one.

Three dosages of DERMESTRIL SEPTEM are available: DERMESTRILSEPTEM 25, 50 and 75.

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 ).

Treatment usually starts with DERMESTRILSEPTEM 25 micrograms / 24 hours, transdermal patch.

If after 1 to 2 months of treatment with DERMESTRIL SEPTEM 25 micrograms / 24 hours, transdermal patch, applied once a week, the symptoms of estrogen deficiency have not decreased, a higher dosage of DERMESTRILSEPTEM may be used.

If any side effects or symptoms of overdose occur (eg feeling of breast tenderness and / or bleeding), the dosage should be reduced.

In non-hysterectomized women, a progestin (approved in addition to estrogen therapy) should be added at least 12 to 14 days per month / 28-day cycle to prevent the development of estrogen-induced endometrial hyperplasia. (see section Warnings and precautions for use ).

In women who have undergone hysterectomy, it is not recommended to combine a progestin with estrogen replacement therapy, except for a history of endometriosis.

Two treatment regimens can be used:

· A) Cyclic: DERMESTRILSEPTEM is administered cyclically, usually 21 days of treatment followed by an interval of 7 days without treatment. The progestin is usually given for 12 to 14 days of the cycle. Haemorrhage deprivation may occur after stopping the progestin.

· B) Continuous sequential: DERMESTRIL SEPTEM is administered continuously. The progestin is added sequentially, usually for 12 to 14 days (or more) of each 28-day cycle. This pattern may be indicated in cases where the symptoms of estrogen deficiency manifest themselves strongly again during the free interval. Haemorrhage of deprivation may occur when the progestin is stopped.

If it is a prescription in a woman who does not take HRT, treatment with DERMESTRILSEPTEM can be started at any time.

If it is a relay of cyclic or sequential estrogen / progestin treatment, the current treatment cycle must be completed before starting treatment with DERMESTRILSEPTEM. The right time to start treatment with DERMESTRILSEPTEM is the first day of withdrawal bleeding.

If it is a relay of an estrogen / progestin-based combination therapy, treatment with DERMESTRILSEPTEM can begin directly.

Administration mode

Apply DERMESTRIL SEPTEM on the skin at the hips, upper buttocks, lumbar or abdominal area. Press firmly all over the surface and around the edges to ensure maximum adhesion.

The level of estradiol released by the device depends on the absorption capacity of the skin. Thus, the application site influencing the release of estradiol, the application to another cutaneous region located higher than the recommended regions is not recommended.

At the application site, the skin must be clean, dry, non-greasy, without redness or irritation. Body locations with severe skin folds or being subject to friction during movement should be avoided.

DERMESTRILSEPTEM should not be applied on or near breasts.

The transdermal patch should not be applied 2 times in a row.

If the transdermal patch is properly applied, it will adhere to the skin for a whole week without any problem. In case of premature detachment, use a new patch that will be removed on the date originally planned. The initial regimen will then be resumed.

If the device is not changed on the originally scheduled date, it should be replaced as soon as possible and then changed again according to the original regimen.

Forgetting a device can promote the occurrence of bleeding and spotting.

It is possible to shower or bathe while keeping the transdermal patch. However, it can come off in case of hot bath or sauna. In this case, it must be replaced with a new transdermal patch (as indicated above). The sauna will be programmed preferably the day of change of the transdermal device.

Against indications

· Known hypersensitivity to estradiol or any of the excipients;

· 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 (such as antithrombin III deficiency, protein C or protein S deficiency, see Warnings and Precautions section );

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

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

· Porphyria.

Side effects Dermestril Septem

In clinical trials, approximately 10 to 17% of patients treated with DERMESTRIL SEPTEM 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 effects observed with DERMESTRIL SEPTEM and other THS containing 17β-estradiol.

Common side effects

(> 1/100, <1/10)

Uncommon side effects

(> 1/1000, <1/100)

Rare side effects (> 1/10 000, <1/1000)

Psychiatric disorders

Depression.

Central nervous system disorders

Irritability, headache.

Migraine, dizziness.

Changes in libido, worsening of epilepsy.

Vascular disorders

Increased blood pressure.

Venous thromboembolic accidents

Gastrointestinal disorders

Nausea, abdominal cramps, meteorism.

Vomiting.

Hepatobiliary disorders

Disturbed or abnormal liver function tests.

Skin and subcutaneous tissue disorders (1)

Contact dermatitis, reversible post-inflammatory pigmentation, pruritus and generalized exanthema.

Disorders of reproductive organs and breast

Mammary tension, painful breasts, metrorrhagia, vaginal secretions modification, endometrial hyperplasia.

General disorders

Fluid retention with edema, feeling of heavy legs, weight gain or weight loss.

Alterations in glucose tolerance and blood coagulation.

Eye irritation in contact lens wearers, anaphylactic reactions (sometimes in patients with allergic reactions in their anamnesis).

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

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 ).

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

17

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 or estrogen / progesterone 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 below.

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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