ESTREVA 0.1 % Gel

Contents of the leaflet

1. Package Leaflet: Information for the Patient
2. Warning! Keep the leaflet! Information on the immediate packaging in a foreign language.
   1. You should carefully read the contents of the leaflet before using the medicine, as it contains important information for the patient.
   2. Table of Contents of the Leaflet:
3. What is Estreva and what is it used for
4. Important information before using Estreva
   1. When not to use Estreva:
   2. Warnings and precautions
   3. HRT and malignant tumors
   4. Endometrial hyperplasia and endometrial cancer
   5. Breast cancer
   6. Ovarian cancer
   7. Effect of HRT on the heart and circulation
   8. Vein thrombosis (thrombophlebitis)
   9. Coronary heart disease
   10. Stroke
   11. Other conditions
   12. Children
   13. Estreva and other medicines
   14. Pregnancy and breastfeeding
   15. Driving and using machines
   16. Important information about some of the ingredients of Estreva
5. How to use Estreva
   1. Dosage
   2. How to apply Estreva gel, 0.1%?
   3. Use of a higher than recommended dose of Estreva
   4. Missed application of Estreva
   5. Stopping the use of Estreva
6. Possible side effects
   1. Reporting side effects
7. How to store Estreva
8. Contents of the pack and other information
   1. What Estreva contains
   2. What Estreva looks like and contents of the pack
   3. Marketing authorization holder in Portugal, the country of export:
   4. Manufacturer:
   5. Parallel importer:
   6. Repackaged by:
   7. Parallel import authorization number: 178/23
   8. Date of leaflet approval: 30.08.2023

Package Leaflet: Information for the Patient

Warning! Keep the leaflet! Information on the immediate packaging in a foreign language.

Estreva,0.1%, gel
Estradiol

You should carefully read the contents of the leaflet before using the medicine, as it contains important information for the patient.

• You should keep this leaflet so that you can read it again if you need to.
• If you have any doubts, you should consult a doctor or pharmacist.
• This medicine has been prescribed specifically for you. Do not pass it on to others. The medicine may harm another person, even if their symptoms are the same.
• If the patient experiences any side effects, including any side effects not listed in this leaflet, they should tell their doctor or pharmacist. See section 4.

Table of Contents of the Leaflet:

• 1. What is Estreva and what is it used for
• 2. Important information before using Estreva
• 3. How to use Estreva
• 4. Possible side effects
• 5. How to store Estreva
• 6. Contents of the pack and other information

1. What is Estreva and what is it used for

The medicine contains synthetic 17β-estradiol, which is chemically and biologically identical to endogenous human estradiol. Estradiol belongs to the group of sex hormones - estrogens.
Estreva is used in hormone replacement therapy (HRT) for the treatment of estrogen deficiency symptoms in postmenopausal women.
There is only limited experience with the use of the preparation in women over 65 years of age.

2. Important information before using Estreva

When not to use Estreva:

• if the patient is allergicto estradiolor any of the other ingredients of this medicine (listed in section 6);
• if the patient currently has or has had breast canceror if there is a suspicion of it;
• if the patient has malignant estrogen-dependent tumors, such as endometrial cancer (endometrium) or if there is a suspicion of it;
• if there are unexplained vaginal bleeding;
• if there is untreated endometrial hyperplasia;
• if the patient has or has had venous thromboembolic disease(deep vein thrombosis, pulmonary embolism);
• if the patient has blood coagulation disorders(such as protein C, protein S, or antithrombin deficiency);
• if the patient has or has recently had a disease caused by arterial thrombosis, such as myocardial infarction, stroke, or angina pectoris;
• if the patient has or has had liver diseaseand liver function tests have not returned to normal;
• if the patient has a rare inherited blood disease called porphyria.

If any of the above factors occur for the first time during the use of Estreva, the use of the medicine should be stopped immediately and the doctor should be contacted without delay.

Warnings and precautions

Before starting to use Estreva, you should discuss it with your doctor or pharmacist.
Special precautions
HRT should only be used to treat menopausal symptoms that negatively affect the quality of life.
The patient should have a check-up at regular intervals (at least once a year).
If the patient notices any changes in the breasts during treatment, they should inform their doctor without delay.
Women with an intact uterus for at least 12 days of the cycle should also take a progestogen.
If any of the diseases listed below have been diagnosed, occurred in the past, or worsened during pregnancy or previous hormonal treatment, the patient should be kept under close supervision. It should be considered that these diseases may recur or worsen during treatment with Estreva; in particular, the following should be mentioned:

• uterine fibroids
• endometriosis or previous cases of endometrial hyperplasia
• thromboembolic disorders or the presence of risk factors for their occurrence (see below)
• risk factors for estrogen-dependent tumors, such as first-degree relatives with breast cancer
• hypertension
• liver function disorders (e.g., liver tumors)
• diabetes, with or without vascular complications
• gallstones
• migraine or severe headaches
• systemic lupus erythematosus
• epilepsy
• asthma
• otosclerosis (a disease of the ear leading to deafness)
• hereditary and acquired angioedema.

The doctor will decide to stop the treatment if contraindications occur, as well as in the following situations:

• jaundice or liver function disorders
• significant increase in blood pressure
• new migraine headache
• pregnancy
• swelling of the face, tongue, and/or throat, and/or difficulty swallowing or hives, in combination with difficulty breathing, suggesting angioedema.

HRT and malignant tumors

Endometrial hyperplasia and endometrial cancer

The use of estrogen-only HRT increases the risk of endometrial hyperplasia and endometrial cancer. The additional use of a progestogen for at least 12 days in each 28-day cycle protects the patient from this increased risk. The doctor will prescribe a progestogen separately if the patient has an intact uterus. If the uterus has been removed (hysterectomy), it should be discussed with the doctor whether the use of this medicine without a progestogen is safe.
In the case of women with an intact uterus who do not use HRT, endometrial cancer is diagnosed in an average of 5 out of 1,000 women between the ages of 50 and 65. In women between the ages of 50 and 65 with an intact uterus who use estrogen-only HRT, endometrial cancer is diagnosed in 10-60 out of 1,000 women (i.e., 5 to 55 additional cases), depending on the dose and duration of treatment.

Breast cancer

Data confirm that taking hormone replacement therapy (HRT) in the form of a combination of estrogen and progestogen or estrogen alone increases the risk of breast cancer. The additional risk depends on how long the patient uses HRT. This additional risk becomes apparent after 3 years of HRT use. After stopping HRT, the additional risk will decrease over time, but the risk may persist for 10 years or longer if HRT lasted more than 5 years.
Comparison
In the case of women between the ages of 50 and 54 who do not use HRT, breast cancer is diagnosed in an average of 13 to 17 out of 1,000 women over a period of 5 years.
In the case of women aged 50 who start 5-year estrogen-only HRT, the number of cases will be 16-17 out of 1,000 patients (i.e., 0 to 3 additional cases).
In the case of women aged 50 who start 5-year estrogen-progestogen HRT, the number of cases will be 21 out of 1,000 patients (i.e., 4 to 8 additional cases).
In the case of women between the ages of 50 and 59 who do not use HRT, breast cancer is diagnosed in an average of 27 out of 1,000 women over a period of 10 years.
In the case of women aged 50 who start 10-year estrogen-only HRT, the number of cases will be 34 out of 1,000 patients (i.e., 7 additional cases).
In the case of women aged 50 who start 10-year estrogen-progestogen HRT, the number of cases will be 48 out of 1,000 patients (i.e., 21 additional cases).

• Regular breast examinations should be performed. You should contact your doctor if you notice any changes such as:
• wrinkles of the skin,
• changes in the nipple area,
• any visible or palpable thickening.

Ovarian cancer

Ovarian cancer is rare - much rarer than breast cancer.
The use of HRT containing only estrogens or a combination of estrogens and progestogens is associated with a slightly increased risk of ovarian cancer.
The risk of ovarian cancer depends on age. For example, in women between the ages of 50 and 54 who do not use HRT, ovarian cancer is diagnosed over a period of 5 years in approximately 2 out of 2,000 women. In women who have taken HRT for 5 years, it occurs in approximately 3 out of 2,000 users (i.e., approximately 1 additional case).

Effect of HRT on the heart and circulation

Vein thrombosis (thrombophlebitis)

The risk of vein thrombosisis about 1.3 to 3 times higher in women using HRT, especially in the first year of treatment, than in women who do not use it. If a thrombus enters the lungs, it can cause chest pain, shortness of breath, fainting, or even death.
The likelihood of vein thrombosis increases with age and depends on the presence of the following factors. You should inform your doctor if any of the following situations occur:

• the patient is unable to walk for a long time due to extensive surgery, injury, or illness (see also section 3 "If surgery is necessary"),
• the patient is obese (Body Mass Index, BMI >30 kg/m2),
• the patient has blood coagulation disorders and requires long-term treatment with anticoagulant medication,
• if any close relatives have had a thrombus in the lower limb, lung, or other organ,
• the patient is pregnant and/or postpartum,
• the patient has systemic lupus erythematosus (SLE),
• the patient has cancer.

Comparison
In the case of women between the ages of 50 and 59 who do not use HRT, vein thrombosis occurs in approximately 4-7 out of 1,000 women over a period of 5 years. In women between the ages of 50 and 59 who have used combined estrogen-progestogen HRT for more than 5 years, vein thrombosis occurs in 9-12 out of 1,000 women (i.e., 5 additional cases). In the case of women between the ages of 50 and 59 with a removed uterus who have used estrogen-only HRT for 5 years, vein thrombosis occurs in 5-8 out of 1,000 women (i.e., 1 additional case).

Coronary heart disease

There is no scientific evidence to confirm that HRT can prevent myocardial infarction. Women over 60 years of age who use combined estrogen-progestogen HRT are slightly more likely to develop heart disease than women who do not use HRT.
In the case of women who have had a hysterectomy and use estrogen-only therapy, there is no increased risk of heart disease.

Stroke

The risk of ischemic stroke is about 1.5 times higher in people using HRT than in those who do not use it. The number of additional stroke cases due to HRT use increases with age.
Comparison
In the case of women between the ages of 50 and 59 who do not use HRT, ischemic stroke occurs in approximately 8 out of 1,000 women over a period of 5 years. In women between the ages of 50 and 59 who use HRT, ischemic stroke occurs in 11 out of 1,000 women over a period of 5 years (i.e., 3 additional cases).

Other conditions

Estrogens can cause fluid retention in the body, so patients with heart or kidney disorders should be closely monitored. This is especially true for patients with end-stage renal failure, as they can expect an increase in the concentration of the active substance of Estreva.
Women with previously diagnosed hypertriglyceridemia should be closely monitored during estrogen use, as rare cases of significant triglyceride elevation leading to pancreatitis have been reported.
Estrogens increase the amount of thyroid-binding globulin (TBG), leading to an increase in the total amount of circulating thyroxine. The uptake of T3 by the resin is decreased, reflecting the increased TBG concentration. The concentrations of free T4 and free T3 remain unchanged. The concentrations of other binding proteins in the blood may also increase, such as corticosteroid-binding globulin or sex hormone-binding globulin, leading to an increase in the concentration of circulating corticosteroids and sex hormones, respectively. The free and biologically active concentrations of hormones remain unchanged. There may also be an increase in the concentration of other blood proteins (substrate for the angiotensinogen/renin system, alpha-1 antitrypsin, ceruloplasmin).
HRT does not improve cognitive function (memory loss, perception disorders, attention). There is evidence of an increased risk of dementia in women who start HRT at an age over 65.

Children

Estradiol in the form of a spray or gel can be accidentally transferred from the patient's skin to other people. You should not allow other people, especially children, to come into contact with the area of skin where the spray or gel has been applied, and if necessary, cover it with clothing.
If a child comes into contact with the area of skin where estradiol has been applied, the child's skin should be washed with soap and water as soon as possible. Due to the transfer of estradiol, small children may exhibit unexpected signs of sexual maturation (e.g., breast budding). In most cases, these symptoms disappear when the child is no longer exposed to estradiol in the form of a spray or gel.
If a child who may have been accidentally exposed to estradiol in the form of a spray or gel shows any signs or symptoms of maturation (breast development or other sexual changes), you should contact a doctor.

Estreva and other medicines

You should tell your doctor about all medicines you are currently taking or have recently taken, as well as any medicines you plan to take.
This applies to the following medicines:

• medicines used to treat epilepsy(such as phenobarbital, phenytoin, and carbamazepine),
• medicines used to treat tuberculosis(such as rifampicin, rifabutin),
• medicines used to treat HIV infection(such as nevirapine, efavirenz, ritonavir, and nelfinavir),
• herbal preparations containing St. John's Wort(Hypericum perforatum).

Some medicines may affect the action of Estreva. This may lead to irregular bleeding. This applies to the following medicines:

• medicines used to treat hepatitis C(such as a treatment regimen using ombitasvir/paritaprevir/ritonavir with or without dasabuvir, as well as a treatment regimen using glecaprevir/pibrentasvir) may cause an increase in liver function test parameters in the blood (increased ALT enzyme activity) in women using combined hormonal contraceptives containing ethinyl estradiol. Estreva contains estradiol instead of ethinyl estradiol. It is not known whether increased ALT enzyme activity may occur during the use of Estreva with such a hepatitis C treatment regimen. The doctor will provide the patient with appropriate instructions.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or plan to have a child, you should consult your doctor or pharmacist before using this medicine.
Estreva should not be used during pregnancy and breastfeeding.
If you become pregnant during treatment, you should stop the treatment and consult your doctor immediately.
Unintentional use of the medicine during pregnancy is not a reason to terminate it.
Before using the medicine, please consult your doctor or pharmacist.

Driving and using machines

No studies have been conducted on the effect of Estreva on the ability to drive and use machines.

Important information about some of the ingredients of Estreva

Estreva contains propylene glycol, which may cause skin irritation.

3. How to use Estreva

This medicine should always be used as directed by your doctor. If you have any doubts, you should consult your doctor or pharmacist.
Do not allow other people to touch the area of skin where the spray or gel has been applied until it has dried, and if necessary, cover it with clothing.

Dosage

Each press of the dosing pump (a dose of the medicine) delivers 0.5 g of gel.
The average dose is 1.5 g of gel, i.e., 3 doses of the medicine once a day for 24 to 28 days.
With the recommended daily dose of 1.5 g, a 50 g container is sufficient for a month.
The gel should be applied once a day, in the morning or evening, preferably after a bath.
The dose can be adjusted to individual needs.
Individual daily doses may range from 0.5 g to 3 g of gel.
When starting and continuing treatment for menopausal symptoms, the minimum effective dose should be used for the shortest possible period.
Women with an intact uterus should take a progestogen for at least 12 to 14 days of the cycle in combination with Estreva to avoid estrogen-induced endometrial hyperplasia.
It is not recommended to add a progestogen when treating women who have had a hysterectomy, unless endometriosis has been previously diagnosed.
Two therapeutic regimens can be used:

• 1) Cyclical: Estreva is used for 24 to 28 days, followed by a 2 to 7-day break. In women with an intact uterus, a progestogen should be administered for at least the last 12 days of estrogen treatment. Withdrawal bleeding may occur during the period without medication.
• 2) Continuous: Estreva is used continuously, without breaks. In women with an intact uterus, a progestogen should be administered for at least 12 days per month. Withdrawal bleeding may occur during the period without progestogen. Continuous treatment can be recommended in cases where severe estrogen deficiency symptoms occur during the period without Estreva.

How to apply Estreva gel, 0.1%?

1/ Remove the cap.
2/ Holding the container with one hand, place the other hand under the tip of the pump and press the pump to obtain a dose of gel. When using it for the first time, it may be necessary to press the pump several times to start the device and obtain the first dose of gel. This dose may not have the correct volume and should be discarded.
3/ Allow the tip of the pump to return to its original position between presses.
The application surface of the gel should be approximately equal to the surface of two palms. The patient applies the gel to clean, dry, and intact skin on the abdomen, thighs, arms, or shoulders, preferably after a bath in the morning or evening. The gel should not be applied to the breast skin or mucous membranes. You should avoid contact with the eyes. You do not need to rub the medicine into the skin, but you should leave it on for about 2 minutes before putting on clothes.
The gel does not stain clothes. After applying the gel, you should wash your hands.

Use of a higher than recommended dose of Estreva

In the event of using a higher than recommended dose of Estreva, the following may occur: nausea, vomiting, and withdrawal bleeding.

Missed application of Estreva

If the patient forgets to apply the gel on a given day, they should apply it as soon as possible and continue treatment with the recommended dose.
You should not use a double dose to make up for a missed dose.
If the gel is not applied for several days, irregular bleeding or spotting may occur.

Stopping the use of Estreva

After stopping therapy, menopausal symptoms may recur.
If you have any further doubts about the use of this medicine, you should consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, Estreva can cause side effects, although not everybody gets them.
Common side effects: (≥1/100 to <1>Uncommon side effects: (≥1/1000 to <1>Rare side effects: (≥1/10,000 to <1>

Reporting side effects

If you experience any side effects, including any side effects not listed in this leaflet, you should tell your doctor or pharmacist. Side effects can be reported directly to the Department of Drug Safety Monitoring of the Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products, Al. Jerozolimskie 181C, 02-222 Warsaw, tel.: +48 22 49 21 301, fax: +48 22 49 21 309, website: https://smz.ezdrowie.gov.pl.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Estreva

The medicine should be stored out of sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging. The expiry date refers to the last day of the month stated.
There are no special precautions for storage.
Do not use this medicine if you notice any signs of deterioration.
Medicines should not be disposed of via wastewater or household waste. You should ask your pharmacist how to dispose of medicines that are no longer needed. This will help protect the environment.

6. Contents of the pack and other information

What Estreva contains

The active substance of Estreva is estradiol. 1 g of gel contains 1.0325 mg of estradiol hemihydrate, which corresponds to 1.0000 mg of anhydrous estradiol.
Each dose delivers 0.5 g of gel, i.e., 0.5 mg of estradiol (as 0.516 mg of estradiol hemihydrate).
The excipients are: ethanol, purified water, propylene glycol, diethylene glycol monoethyl ether, carbomer, tromethamine, disodium edetate.

What Estreva looks like and contents of the pack

Estreva is a transparent and odorless gel.
The packaging contains a bottle with 50 g of gel.
For more detailed information, please contact the marketing authorization holder or parallel importer.

Marketing authorization holder in Portugal, the country of export:

Theramex Ireland Limited
3 Floor, Kilmore House
Park Lane, Spencer Dock
D01 YE64 Dublin 1
Ireland

Manufacturer:

Delpharm Drogenbos SA, Groot Bijgaardenstraat 128, B-1620 Drogenbos, Belgium
Teva Pharmaceuticals Europe B.V., Swensweg 5, 2031 GA Haarlem, Netherlands

Parallel importer:

InPharm Sp. z o.o.
ul. Strumykowa 28/11
03-138 Warsaw

Repackaged by:

InPharm Sp. z o.o. Services sp. k.
ul. Chełmżyńska 249
04-458 Warsaw
Marketing authorization number in Portugal, the country of export:2902880

Parallel import authorization number: 178/23

Date of leaflet approval: 30.08.2023

[Information about the trademark]