ESTROFEM 2 mg Tablets

Contents of the leaflet

1. PATIENT INFORMATION LEAFLET
2. PACKAGE LEAFLET: INFORMATION FOR THE USER
3. Estrofem, 2 mg, coated tablets
   1. Read the package leaflet carefully before taking the medicine, as it contains important information for you.
   2. Table of contents of the package leaflet
4. What is Estrofem and what is it used for
5. Important information before taking Estrofem
   1. Medical history and regular medical examinations
   2. When not to take Estrofem
   3. Warnings and precautions
   4. HRT and cancer
   5. Excessive thickening of the lining of the uterus (endometrial hyperplasia) and cancer of the lining of the uterus (endometrial cancer)
   6. Unexpected bleeding
   7. Breast cancer
   8. You should regularly examine your breasts. You should contact your doctor if you notice any changes in your breasts, such as:
   9. Ovarian cancer
   10. Effect of HRT on the heart and blood vessels
   11. Blood clots in the veins (venous thromboembolism)
   12. Coronary artery disease (heart attack)
   13. Stroke
   14. Other conditions
   15. Estrofem and other medicines
   16. HRT may affect the action of other medicines:
   17. Estrofem with food and drink
   18. Pregnancy and breastfeeding
   19. Driving and using machines
   20. Estrofem contains lactose monohydrate
   21. Estrofem contains sodium
   22. Laboratory tests
6. How to take Estrofem
   1. Take one tablet daily, at the same time each day.
   2. Taking a higher dose of Estrofem than recommended
   3. Missing a dose of Estrofem
   4. Stopping Estrofem treatment
   5. If surgery is planned
7. Possible side effects
   1. Hypersensitivity and/or allergic reactions (uncommon side effects - may occur in less than 1 in 100 women)
   2. Common (may occur in less than 1 in 10 women)
   3. Uncommon (may occur in less than 1 in 100 women)
   4. Rare (may occur in less than 1 in 10,000 women)
   5. Other side effects after taking estrogens
   6. Reporting side effects
8. How to store Estrofem
9. Contents of the pack and other information
   1. What Estrofem contains
   2. What Estrofem looks like and contents of the pack
   3. Marketing authorization holder and manufacturer
   4. For more detailed information, please contact the local representative of the marketing authorization holder:
   5. Date of last revision of the leaflet:
   6. Other sources of information
   7. INSTRUCTIONS FOR THE USER
   8. How to use the calendar pack
10. Setting the day indicator
11. Removing the first tablet
12. Subsequent tablets
    1. The transparent part can only be turned after the tablet has been removed from the blister.

PATIENT INFORMATION LEAFLET

PACKAGE LEAFLET: INFORMATION FOR THE USER

Estrofem, 2 mg, coated tablets

Estradiol

Read the package leaflet carefully before taking the medicine, as it contains important information for you.

• You should keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If you experience any side effects, including those not listed in this leaflet, please inform your doctor or pharmacist. See section 4.

Table of contents of the package leaflet

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

1. What is Estrofem and what is it used for

Estrofem is a medicine used for hormone replacement therapy (HRT). The medicine contains the female hormone - estradiol. Estrofem is indicated for use in postmenopausal women, particularly in women who have had their uterus removed (after a hysterectomy) and therefore do not need to take combined estrogen-progestogen therapy.

Estrofem is used to:

relieve symptoms occurring after menopause

During menopause, the level of estrogen produced by the body decreases, which can cause symptoms such as hot flashes on the face, neck, and chest. Estrofem helps to alleviate these symptoms. Estrofem should only be prescribed to a patient if these symptoms seriously disrupt daily life.

Experience in treating women over 65 years of age is limited.

2. Important information before taking Estrofem

Medical history and regular medical examinations

Taking HRT involves risks that should be considered when a patient decides to start or continue hormone replacement therapy.

Experience in treating women with premature menopause (due to ovarian failure or surgery) is limited. If a patient is experiencing premature menopause, the risk associated with HRT may be different. You should talk to your doctor.

Before starting (or restarting) HRT, the doctor should take a medical history, including a family history. The doctor will decide whether to perform tests, including a breast examination and/or a gynecological examination, if necessary.

If a patient decides to take Estrofem, she should regularly visit her doctor for check-ups (at least once a year). During these check-ups, she should discuss with her doctor the benefits and risks of taking Estrofem.

The patient should regularly undergo mammography examinations as recommended by her doctor.

When not to take Estrofem

If any of the following conditions occur or if you have any doubts, you musttell your doctorbefore taking Estrofem.

Do not start taking Estrofem if:

• you are allergicto estradiolor any of the other ingredients of this medicine (listed in section 6. "Contents of the pack and other information");
• you have been diagnosedwith, suspectedof having, or have had breast cancer;
• you have been diagnosedwith, suspectedof having, or have had an estrogen-dependent tumor, such as endometrial cancer (cancer of the lining of the uterus);
• you have unusual vaginal bleedingthat has not been diagnosed by a doctor;
• you have excessive thickening of the lining of the uterus(endometrial hyperplasia) and it is not being treated;
• you have been diagnosedwith or have had blood clots in the veins(venous thromboembolism), in the veins of the legs (deep vein thrombosis) or in the lungs (pulmonary embolism);
• you have blood clotting disorders(a disorder with a tendency to form blood clots, such as protein C, protein S, or antithrombin deficiency);
• you have had or have arterial diseases caused by blood clots(thromboembolic disorders), such as ischemic heart disease, heart attack;
• you have had or have liver disease, and liver function tests have not returned to normal;
• you have a rare, hereditary blood disease - porphyria.

If any of the above conditions occur for the first time while taking Estrofem, you should stop taking it and consult your doctor.

Warnings and precautions

Before starting Estrofem, you should discuss it with your doctor or pharmacist. Before starting treatment, you should inform your doctor about any current or past diseases, as they may recur or worsen while taking Estrofem. In these cases, your doctor may decide that you need to be closely monitored:

• uterine fibroids (fibroids),
• endometriosis or excessive thickening of the lining of the uterus (endometrial hyperplasia) in your medical history,
• factors that increase the risk of blood clots (see "Blood clots in the veins (venous thromboembolism)"),
• factors that increase the risk of estrogen-dependent tumors (breast cancer in your mother, sister, or grandmother),
• high blood pressure,
• liver disease, such as liver tumor (benign tumor),
• diabetes,
• gallstones,
• migraine or severe headaches,
• systemic lupus erythematosus (an autoimmune disease),
• epilepsy,
• asthma,
• otosclerosis (a disease of the ear that leads to gradual hearing loss),
• high levels of fats in the blood (triglycerides),
• fluid retention in the body due to heart or kidney failure,
• hereditary and acquired angioedema.

If the following diseases occur while taking HRT, it is recommended to stop taking Estrofem immediately and consult a doctor:

• if any of the conditions listed in the "When not to take Estrofem" section occur;
• if the skin or whites of the eyes turn yellow (jaundice) or liver function is impaired;
• if you experience facial, tongue, and/or throat swelling, and/or difficulty swallowing or hives, along with difficulty breathing, which may indicate angioedema;
• if you experience a significant increase in blood pressure (symptoms of high blood pressure may include headache, fatigue, dizziness);
• if you experience a migraine headache;
• if you become pregnant;
• if you experience signs of a blood clot, such as:
• painful swelling and redness of the legs,
• sudden chest pain,
• breathing difficulties (shortness of breath). For more information, see "Blood clots in the veins (venous thromboembolism)".

Note:Estrofem is not a contraceptive. If it has been less than 12 months since your last menstrual period or you are under 50 years old, you may need to use an additional method of contraception. You should talk to your doctor.

HRT and cancer

Excessive thickening of the lining of the uterus (endometrial hyperplasia) and cancer of the lining of the uterus (endometrial cancer)

Taking only estrogens in HRT increases the risk of excessive thickening of the lining of the uterus (endometrial hyperplasia) and cancer of the lining of the uterus (endometrial cancer).

Taking a progestogen in combination with estrogen for at least 12 days of each 28-day cycle protects against this additional risk, so your doctor may prescribe a progestogen in addition to Estrofem if you have a uterus. However, if you have had a hysterectomy (uterus removal), you should discuss with your doctor whether taking this medicine without combining it with a progestogen is safe.

Comparison

In women who have a uterus and do not take HRT, endometrial cancer is diagnosed in approximately 5 out of 1000 women between the ages of 50 and 65.

Depending on the duration of treatment and the dose of estrogens taken, in women between the ages of 50 and 65 who have a uterus and take only estrogens in HRT, endometrial cancer is diagnosed in 10 to 60 out of 1000 women (i.e., an additional 5 to 55 cases).

Unexpected bleeding

While taking Estrofem, you will experience monthly bleeding (so-called withdrawal bleeding). However, if you experience unexpected bleeding or spotting between monthly bleedings, which:

• lasts longer than the first 6 months,
• occurs after taking Estrofem for more than 6 months,
• continues after stopping HRT, you should contact your doctor as soon as possible.

Breast cancer

Data confirm that taking hormone replacement therapy (HRT) in the form of a combination of estrogen and progestogen or only estrogen increases the risk of breast cancer. The additional risk depends on how long you take HRT. This additional risk becomes apparent after 3 years of HRT. After stopping HRT, the additional risk will decrease over time, but the risk may persist for 10 years or more if HRT lasted more than 5 years.

Comparison

In women between the ages of 50 and 54 who do not take HRT, breast cancer is diagnosed in approximately 13 to 17 out of 1000 women over a 5-year period.

In women aged 50 who start a 5-year estrogen-only HRT, the number of cases will be 16-17 out of 1000 patients (i.e., 0 to 3 additional cases).

In women aged 50 who start a 5-year estrogen-progestogen HRT, the number of cases will be 21 out of 1000 patients (i.e., 4 to 8 additional cases).

In women between the ages of 50 and 59 who do not take HRT, breast cancer is diagnosed in approximately 27 out of 1000 women over a 10-year period.

In women aged 50 who start a 10-year estrogen-only HRT, the number of cases will be 34 out of 1000 patients (i.e., 7 additional cases).

In women aged 50 who start a 10-year estrogen-progestogen HRT, the number of cases will be 48 out of 1000 patients (i.e., 21 additional cases).

You should regularly examine your breasts. You should contact your doctor if you notice any changes in your breasts, such as:

• wrinkling of the skin,
• changes in the nipple,
• lumps that can be seen or felt.

In addition, it is recommended to participate in offered breast cancer screening programs.

It is important to inform the nurse or medical staff performing the X-ray examination that you are taking hormone replacement therapy, as this medicine may increase breast density, which can affect the results of the mammogram. Not all lumps can be detected during a mammogram in areas with increased breast density.

Ovarian cancer

Ovarian cancer is rare - much rarer than breast cancer. Taking HRT that includes 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 take HRT, ovarian cancer is diagnosed over a 5-year period in approximately 2 out of 2000 women.

In women who have taken HRT for 5 years, ovarian cancer occurs in approximately 3 out of 2000 women taking it (i.e., approximately 1 additional case).

Effect of HRT on the heart and blood vessels

Blood clots in the veins (venous thromboembolism)

The risk of developing venous thromboembolismis 1.3 to 3 times higher in women taking HRT compared to those not taking it, especially in the first year of treatment.

Blood clots can be life-threatening and if they move to the lungs, they can cause chest pain, shortness of breath, fainting, and even death.

In patients with a diagnosed tendency to form blood clots, there is a higher risk of venous thromboembolism, and taking HRT may increase this risk. In these patients, HRT is contraindicated.

The risk of blood clots in the veins is higher if you are older and if you have any of the following factors. You should inform your doctor if:

• you are unable to walk for a long time due to extensive surgery, injury, or illness (see also section 3. "If surgery is planned");
• you are obese (body mass index - BMI > 30 kg/m2);
• you have had thromboembolic disorders in the past that required taking medicines to prevent blood clots (anticoagulants);
• you or anyone in your close family has had blood clots in the past in the legs, lungs, or other organs;
• you are pregnant or in the postpartum period;
• you have systemic lupus erythematosus;
• you have been diagnosed with cancer.

Symptoms of a blood clot, see "If the following diseases occur while taking HRT, it is recommended to stop taking Estrofem immediately and consult a doctor".

Comparison

In women between the ages of 50 and 59 who do not take HRT, the estimated number of cases of blood clots in the veins over 5 years is 4 to 7 out of 1000 women.

In women between the ages of 50 and 59 who take estrogen-progestogen HRT, the number of cases of blood clots in the veins over 5 years will be 9 to 12 out of 1000 women (i.e., 5 additional cases).

In women between the ages of 50 and 59 with a uterus removed who take only estrogen HRT, the number of cases of blood clots in the veins over 5 years will be 5 to 8 out of 1000 women (i.e., 1 additional case).

Coronary artery disease (heart attack)

There is no evidence that HRT helps prevent heart attacks. In women over 60 years old who take estrogen-progestogen HRT, there is a slightly higher risk of developing coronary artery disease compared to women who do not take HRT.

In women with a uterus removed who take only estrogen HRT, there is no increased risk of developing coronary artery disease.

Stroke

The risk of stroke is approximately 1.5 times higher in women taking HRT compared to those not taking it.

The number of additional cases of stroke caused by HRT increases with age.

Comparison

In women between the ages of 50 and 59 who do not take HRT, stroke occurs in approximately 8 out of 1000 women over 5 years.

In women between the ages of 50 and 59 who take HRT, the number of cases of stroke over 5 years will be 11 out of 1000 women (i.e., 3 additional cases).

Other conditions

HRT does not improve cognitive function (perception, attention, memory). The risk of memory loss may be slightly higher in women who start taking HRT at an age over 65.

You should consult your doctor.

Estrofem and other medicines

Some medicines may affect the effectiveness of Estrofem. This may lead to irregular bleeding. These include:

• •antiepileptic drugs(e.g., phenobarbital, phenytoin, and carbamazepine),
• •antituberculosis drugs(e.g., rifampicin, rifabutin),
• •HIV drugs(e.g., nevirapine, efavirenz, ritonavir, and nelfinavir),
• •herbal preparations containing St. John's Wort(Hypericum perforatum).

HRT may affect the action of other medicines:

• antiepileptic drug (lamotrigine), which may cause an increase in seizure frequency;
• drugs used to treat hepatitis C (e.g., the combination of ombitasvir/paritaprevir/ritonavir with dasabuvir, or without dasabuvir, as well as the combination of glecaprevir/pibrentasvir) may cause an increase in liver function test results (increase in ALT enzyme activity) in women taking combined hormonal contraceptives containing ethinyl estradiol. Estrofem contains estradiol, not ethinyl estradiol. It is not known whether taking Estrofem with this combination of hepatitis C drugs may cause an increase in ALT enzyme activity.

Tell your doctor or pharmacistabout all medicines you are taking, or have recently taken, and about any medicines you plan to take (e.g., over-the-counter medicines, herbal medicines, or other natural products). Your doctor will advise you on this.

Estrofem with food and drink

Tablets can be taken with or without food and drink.

Pregnancy and breastfeeding

Estrofem is intended for use in postmenopausal women only.

If pregnancy is detected while taking Estrofem, treatment should be stopped immediately and your doctor consulted.

Taking Estrofem is not recommended during breastfeeding.

Driving and using machines

The effect of Estrofem on the ability to drive and use machines is not known.

Estrofem contains lactose monohydrate

If you have been diagnosed with intolerance to some sugars, you should consult your doctor before taking Estrofem.

Estrofem contains sodium

Estrofem contains less than 1 mmol of sodium (23 mg) per tablet, which means the medicine is considered "sodium-free".

Laboratory tests

If a blood test is necessary, you should inform your doctor or laboratory staff that you are taking Estrofem, as this medicine may affect the results of some tests.

3. How to take Estrofem

This medicine should always be taken exactly as directed by your doctor. If you are unsure, consult your doctor or pharmacist.

In women with a uterus removed who are not taking other hormone replacement therapy, Estrofem can be started on any day.

Take one tablet daily, at the same time each day.

After taking all 28 tablets from the calendar pack, treatment should be continued by starting the next pack without a break.

Instructions for using the calendar pack can be found at the end of this leaflet, in the section titled "INSTRUCTIONS FOR THE USER".

Your doctor will prescribe the lowest possible dose for you to take for the shortest time necessary to relieve your symptoms. If you think the dose of Estrofem is too high or too low, you should consult your doctor.

Women with a uterus removed will not be advised by their doctor to take an additional progestogen (another female hormone) unless endometriosis (the presence of uterine lining tissue outside the uterus) has been diagnosed.

If you are currently taking other HRT medicines, you should ask your doctor or pharmacist when you can start taking Estrofem.

If bleeding or spotting occurs during the cycle, it is not a cause for concern, especially in the initial months of HRT (for more information, see also section 2. "HRT and cancer", "Excessive thickening of the lining of the uterus (endometrial hyperplasia) and cancer of the lining of the uterus (endometrial cancer)").

Taking a higher dose of Estrofem than recommended

If you take more Estrofem than you should, consult your doctor or pharmacist.

Overdose of Estrofem may cause nausea or vomiting.

Missing a dose of Estrofem

If you forget to take a tablet at the usual time, you should take it within the next 12 hours. If more than 12 hours have passed, do not take the missed dose, but take the next dose at the usual time the next day. Do not take a double dose to make up for a missed dose. Missing a dose may increase the likelihood of bleeding and spotting during the cycle, if you have a uterus.

Stopping Estrofem treatment

If you want to stop taking Estrofem, you should consult your doctor, who will explain the consequences of stopping treatment and discuss other possible forms of therapy.

If you have any further questions about taking this medicine, you should consult your doctor or pharmacist.

If surgery is planned

If you are scheduled to have surgery, you should tell the surgeon that you are taking Estrofem.

It may be necessary to stop taking Estrofem 4 to 6 weeks before surgery to minimize the risk of blood clots (see section 2. "Blood clots in the veins (venous thromboembolism)"). Before restarting Estrofem, you should consult your doctor.

4. Possible side effects

Like all medicines, Estrofem can cause side effects, although not everybody gets them.

Women taking HRT are at a higher risk of developing the following diseases compared to women not taking HRT:

• breast cancer;
• excessive thickening or cancer of the lining of the uterus (endometrial hyperplasia or cancer);
• ovarian cancer;
• blood clots in the veins of the legs or lungs (venous thromboembolism);
• coronary artery disease;
• stroke;
• possibly cognitive impairment (perception, attention, memory), if HRT is started at an age over 65.

For more information, see section 2. "Important information before taking Estrofem".

Hypersensitivity and/or allergic reactions (uncommon side effects - may occur in less than 1 in 100 women)

Although hypersensitivity is an uncommon side effect, it can occur. Symptoms of hypersensitivity and/or allergic reactions may include one or more of the following:

hives, itching, swelling, difficulty breathing, low blood pressure (pale and cold skin, rapid heartbeat), dizziness, sweating, which can be signs of an anaphylactic reaction and/or anaphylactic shock. If you experience any of these symptoms, you muststop taking Estrofem and seek medical attention immediately.

Common (may occur in less than 1 in 10 women)

• depression,
• headache,
• abdominal pain,
• nausea,
• leg cramps,
• breast pain, tenderness, or enlargement,
• peripheral edema (fluid retention),
• weight gain.

Uncommon (may occur in less than 1 in 100 women)

• vision disturbances,
• venous thrombosis,
• heartburn (indigestion),
• vomiting,
• bloating and/or gas,
• gallstones,
• rash or hives.

Rare (may occur in less than 1 in 10,000 women)

• generalized allergic reactions (e.g., anaphylactic reaction, anaphylactic shock),
• irregular vaginal bleeding*,
• worsening of migraine,
• stroke,
• dizziness,
• diarrhea,
• hair loss (alopecia),
• increased blood pressure. *in women with a uterus

Other side effects after taking estrogens

• heart attack, congestive heart failure,
• venous thromboembolism, e.g., deep vein thrombosis of the legs or pelvis and pulmonary embolism,
• gallbladder disease,
• skin and subcutaneous tissue disorders:
• skin discoloration, especially on the face or neck, known as "pregnancy spots" (chloasma),
• red, painful lumps (erythema nodosum),
• rash, including rash with blisters and peeling skin (erythema multiforme),
• purpura,
• itching,
• vaginal fungal infection,
• estrogen-dependent benign and malignant tumors, e.g., endometrial cancer,

endometrial hyperplasia or uterine fibroids*,

• insomnia,
• epilepsy,
• libido disorders,
• worsening of asthma,
• possibly dementia. *in women with a uterus

Reporting side effects

If you experience any side effects, including those not listed in this leaflet, you should inform your doctor or pharmacist, or nurse. Side effects can be reported directly to the Department of Drug Safety of the Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products:

Al. Jerozolimskie 181C, 02-222 Warsaw, tel.: 22 49-21-301, fax: 22 49-21-309, website: https://smz.ezdrowie.gov.pl.

Side effects can also be reported to the marketing authorization holder.

By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Estrofem

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date stated on the label and carton after "EXP". The expiry date refers to the last day of that month.

Store at a temperature not exceeding 25°C. Do not store in a refrigerator.

Store in the original package.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Contents of the pack and other information

What Estrofem contains

• The active substance is estradiol 2 mg (in the form of estradiol hemihydrate).
• The other ingredients are: lactose monohydrate, corn starch, hydroxypropyl cellulose, talc, and magnesium stearate.
• The ingredients of the tablet coating are: hypromellose, talc, titanium dioxide (E171), macrogol 400, indigo carmine (E132).

What Estrofem looks like and contents of the pack

The coated tablets are blue, round, 6 mm in diameter, and have the inscription NOVO 280 on one side.

Available pack sizes:

• 28 coated tablets

Marketing authorization holder and manufacturer

Novo Nordisk A/S

Novo Allé

2880 Bagsværd, Denmark

For more detailed information, please contact the local representative of the marketing authorization holder:

Novo Nordisk Pharma Sp. z o.o.

Tel.: 22 444 49 00

Fax: 22 444 49 01

Date of last revision of the leaflet:

Other sources of information

Detailed information about this medicine can be found on the website of the Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products: www.urpl.gov.pl.

INSTRUCTIONS FOR THE USER

How to use the calendar pack

1. Setting the day indicator

Turn the inner dial so that the day of the week you start treatment is opposite the hole in the outer part.

2. Removing the first tablet

Break off the blister cover and remove the first tablet.

3. Subsequent tablets

The next day, turn the transparent part one place clockwise, i.e., in the direction indicated by the arrow. Remove the next tablet. Remember to take one tablet daily.

The transparent part can only be turned after the tablet has been removed from the blister.