Medicinal Products

DELIDOSE 1 mg

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

Transdermal gel
Box of 28 sachets-dose
All forms

Indication

Substitute Hormonal Therapy (HRT) of estrogen deficiency symptoms in postmenopausal women.

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

Dosage DELIDOSE 1 mg Transdermal Gel Box of 28 Sachets-dose

Dosage

DELIDOSE is a gel for cutaneous application. DELIDOSE can be used in continuous or batch treatment (cyclically).

The usual starting dose is 1.0 mg estradiol (1.0 g gel) per day, but the initial dose may be adjusted according to the severity of the clinical symptoms.

After 2 to 3 cycles of treatment, the dosage may be adjusted depending on the clinical response. It must be between 0.5 and 1.5 mg of estradiol per day (ie between 0.5 and 1.5 g of gel per day).

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 ).

In non-hysterectomized patients, it is recommended to add a progestogen to DELIDOSE at least 12 to 14 days per month / per 28-day cycle to prevent the development of estrogen-induced endometrial hyperplasia (see also section 4.4). Warnings and precautions for use ).

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

In women who do not take HRT, as well as in a continuous combined HRT relay, DELIDOSE treatment can be started on any day. In relaying a continuous sequential THS, the treatment must be started the day after the end of the last previous treatment cycle.

If the patient has forgotten to apply a dose, the missed dose should be applied as soon as possible within 12 hours of the usual time of application. Beyond 12 hours, the dose will not be applied and treatment will continue normally by applying the dose the following day. Forgetting a dose may encourage the occurrence of spotting and bleeding.

There is no relevant indication for the use of DELIDOSE in children.

Administration mode

Apply on clean and dry skin.

DELIDOSE is applied once a day, alternately on the lower abdomen or on the right or left thigh. The application surface must be 1 to 2 times the surface of a hand.

DELIDOSE should not be applied to breasts, face or irritated skin.

After application, let the gel dry for a few minutes and do not put the skin in contact with water for one hour. Avoid any contact of the gel with the eyes. Wash hands after application.

Against indications

· 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 events or evolving venous thromboembolic events (deep vein thrombosis, pulmonary embolism);

· Known thrombophilic diseases (eg deficiencies of protein C, protein S or antithrombin deficiency, see Warnings and precautions for use );

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

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

Hypersensitivity to any of the active ingredients or to any of the excipients listed in the Composition section;

· Porphyria.

Delidose side effects

During the first few months of treatment, occasional bleeding, spotting and tenderness or swelling of the breasts may occur. These effects are usually temporary and disappear after treatment.

Adverse reactions reported, particularly in three phase III clinical studies (n = 611 exposed women), were included in the table below when considered as at least potentially related to 50 μg / day or 100 μg / day of estradiol, respectively, following dermal application.

The table below presents the adverse effects that occurred in clinical studies and those reported after marketing. In general, these adverse effects are expected in 76% of patients. Adverse events that occurred in more than 10% of patients in clinical trials included application site reactions and breast pain.

Adverse reactions according to the class of organ systems, associated with transdermal estradiol treatment, are shown below.

Class of organ systems

Common side effects (≥1 / 100, <1/10)

Uncommon side effects

(≥ 1/1000, <1/100)

Rare side effects

(≥1 / 10, 000, <1/1000)

Adverse reactions observed post-marketing, with an indefinite frequency (can not be estimated from the available data)

Benign, malignant and unspecified neoplasms (including cysts and polyps)

Benign neoplasm of the breast, benign neoplasm of the endometrium

Uterine fibroids

Immune system disorders

Exacerbation of hereditary angioedema

Metabolism and nutrition disorders

Edema, weight gain

Increased feeling of hunger hypercholesterolemia 1

Psychiatric disorders

Depression, nervousness, lethargy

Anxiety, insomnia, apathy, emotional lability, difficulty concentrating, changes in libido and mood euphoria 1,

stirring 1

Central nervous system disorders

Headache, vertigo

Migraine,

paresthesia,

tremor

Eye disorders

Abnormal vision 1, dry eye 1

Heart conditions

palpitations

Vascular disorders

Hot flashes

Hypertension,

superficial phlebitis 1, purpura 1

Venous thromboembolic accidents

Ischemic stroke 1

Respiratory, thoracic and mediastinal disorders

Dyspnoea 1, rhinitis 1

Gastrointestinal disorders

Nausea, vomiting, stomach cramps, flatulence

Constipation, dyspepsia 1, diarrhea 1, rectal disorders 1

Abdominal pain, bloating (abdominal distension),

Hepatobiliary disorders

Alteration of liver function and biliary secretions

Cholestatic jaundice

Skin and subcutaneous tissue disorders

Acne, alopecia, dry skin disorders in the nails 1, cutaneous nodule, hirsutism 1

Exanthema

Contact dermatitis, eczema, cutaneous 1

Musculoskeletal tissue disorders

Disorders of the joints, cramps

Affections of the kidneys and urinary system

Micturition disorders (frequency or increased urgency),

urinary incontinence 1, cystitis 1, urine discoloration 1, hematuria 1

Disorders of reproductive organs and breasts

Irregular bleeding or spotting, vaginal discharge, vulvar or vaginal disorders, menstrual tension / breast pain

Breast swelling, breast tenderness, endometrial hyperplasia, uterine disorders 1

General and application site conditions

Skin irritation, pruritus at application site, pain, excessive sweating

Tired,

abnormal laboratory tests 1, asthenia 1, fever 1, influenza-like illness 1, malaise 1

1 ) These are unique cases reported in clinical studies. Since these studies were conducted on a small population (n = 611), it is not possible to determine if these effects are infrequent or rare.

Other adverse effects reported following estrogen-progestin therapy:

· Benign and malignant estrogen-dependent tumors, eg endometrial cancer.

· Venous thromboembolic disease (deep vein thrombosis of the pelvis or lower extremities, pulmonary embolism), more common in women on HRT than non-users. For more information, see Contraindications section "Contraindications" and section Warnings and precautions for use "Special warnings and precautions for use".

· Myocardial infarction and stroke.

· Biliary disorders.

· Skin and subcutaneous tissue disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura.

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

Breast cancer risk

· In women taking combined estrogen-progestin for more than 5 years, an increased risk of being diagnosed with breast cancer increased by 2 times has been reported.

· In women taking estrogen alone, the risk is significantly less than in estrogen-progestogen combination therapy.

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

· The results of a large randomized placebo-controlled study (WHI study) as well as a large epidemiological study (MWS) are presented in the tables below:

Million Women Study- Estimated Additional Risk of Breast Cancer After 5 Years of Taking

age range

(Years)

Additional cases per 1000 women who have never taken HRT over a period of more than 5 years * 2

Percentage of risk with a

95% confidence index (CI) #

Additional cases per 1000 women who took HRT over a period of more than 5 years (95% CI)

THS by estrogen alone

50-65

9-12

1.2

1-2 (0-3)

Estrogen-progestin combined HRT

50-65

9-12

1.7

6 (5-7)

#General risk report. The risk ratio is not constant but it will increase with the duration of use.

Note: Since the incidence of breast cancer differs by country in the European Union, the number of additional cancer cases may vary proportionally.

2 * based on incidence rates in developed countries.

American Studies WHI - Additional risk of breast cancer after 5 years of taking

age range

(Years)

Incidence for 1000 women on placebo

over 5 years

Percentage of risk with an index

95% confidence interval

Additional cases per 1000 women who took HRT over a period of more than 5 years (95% CI)

THS by estrogen alone (ECE equine conjugated estrogens)

50-79

21

0.8 (0.7 - 1.0)

-4 (-6 - 0) * 3

Estrogen-Progestin Combined HRT (ECE + Medroxyprogesterone Acetate) ‡

50-79

17

1.2 (1.0 - 1.5)

+4 (0 - 9)

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

‡ When the analysis was restricted to women who did not use HRT prior to the study, there was no apparent increase in risk during the first 5 years of treatment. After 5 years, the risk has increased compared to non-users.

Risk of endometrial cancer

Menopausal women not hysterectomized:

The risk of endometrial cancer is approximately 5 per 1000 women who are not hysterectomized and do not use HRT.

In non-hysterectomized women, 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, according to duration of use and dose of estrogen alone, the increase in the risk of endometrial cancer varies from 5 to 55 new cases diagnosed in 1000 women, whose age is understood between 50 and 65 years old.

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

Ovarian cancer

Long-term use of estrogen alone and combined (estrogen-progestin) HRT is associated with a slight increase in the risk of ovarian cancer. In the MWS study, 5 years of HRT result in 1 new case for 2500 users.

Risk of venous thromboembolic accident

HRT is associated with a 1.3 to 3 increase in the relative risk of developing a venous thromboembolic event, such as deep vein thrombosis or pulmonary embolism.

The occurrence of such an event is more likely during the first year of hormonal treatment (see Warnings and Precautions ).

The results of the WHI studies are presented in the table below:

WHI Studies - Additional Risk of Venous Thromboembolic Events After Use for More Than 5 Years

Age range (years)

Incidence per 1000 women on placebo over 5 years

Percentage of risk with a 95% confidence index (CI)

Additional cases for 1000 HRT users over 5 years

Oral THS by estrogen alone * 4

50-59

7

1.2 (0.6-2.4)

1 (-3-10)

Oral combined HRT estrogen-progestin

50-59

4

2, 3 (1, 2-4, 3)

5 (1-13)

4 * study in the hysterectomized woman.

Risk of coronary heart disease

· The risk of coronary heart disease is slightly increased in users of estrogen-progestogen combined HRT over 60 years of age (see Warnings and Precautions section ).

Risk of stroke

· The use of estrogen alone and combined (estrogen-progestin) therapy is associated with a 1.5-fold increase in the relative risk of ischemic stroke. The risk of haemorrhagic stroke is not increased during the use of HRT.

· Relative risk does not depend on age and duration of use, but since the absolute risk (baseline) is highly age-dependent, the overall risk of an accident for women who use HRT will increase with age, see Warnings and Precautions section .

Combined WHI Studies - Additional Risk of Stroke * 5 after more than 5 years of taking

Age range (years)

Incidence per 1000 women on placebo over 5 years

Percentage of risk with 95% CI

Additional cases for 1000 users of HRT over 5 years

50-59

8

1.3 (1.1-1.6)

3 (1 - 5)

5 * No difference was found between ischemic and hemorrhagic stroke.

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. Healthcare 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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