Estrofem

Package leaflet: Information for the user

Estrofem, 2 mg, coated tablets
Estradiolum
Please read all of this leaflet carefully before taking this medicine, because it contains
important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any further questions, please ask your doctor or pharmacist.
• This medicine has been prescribed for a specific individual. Do not pass it on to others. It may harm them even if their symptoms are the same.
• If you experience any adverse reactions, including any not listed in this leaflet, please inform your doctor or pharmacist. See section 4.

Contents of the leaflet

1. What Estrofem is and what it is used for
2. What you need to know 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 Estrofem is and what it is used for

Estrofem is a medicine used in hormone replacement therapy (HRT). It contains the female hormone estradiol. Estrofem is indicated for use in postmenopausal women, particularly in women who have had their uterus removed (following hysterectomy) and therefore do not require combined oestrogen-progestagen therapy.
Estrofem is used to:
relieve symptoms occurring after menopause
During menopause, the level of oestrogens produced by a woman's body decreases, which may lead to symptoms such as sudden feelings of heat in the face, neck and chest ("hot flushes"). Estrofem helps to relieve these symptoms. Estrofem should only be prescribed when these symptoms seriously impair daily life.
Experience with treatment in women over 65 years of age is limited.

2. Important information before using Estrofem

Medical history and regular medical examinations
Hormone replacement therapy (HRT) carries risks that should be considered when a woman decides to start or continue HRT.
Experience in treating women with premature menopause (due to ovarian failure or surgical intervention) is limited. If a woman experiences premature menopause, the risks associated with HRT may differ. Please consult your doctor.
Before starting (or restarting) HRT, your doctor should take a full medical and family history. Your doctor will decide whether examinations, including breast examination and/or gynaecological examination, are necessary.
If you decide to use Estrofem, you should have regular medical check-ups (at least once a year). During these visits, you should discuss with your doctor the benefits and risks of continuing Estrofem.
You should have regular mammograms as recommended by your doctor.

When not to use Estrofem
Do not use Estrofem if you have any of the conditions listed below, or if you are unsure, tell your doctor before taking Estrofem.

Do not start using Estrofem if:

• you are allergic to estradiol or any of the other ingredients of this medicine (listed in section 6, "Contents of the pack and other information");
• you have been diagnosed with, suspect, or have had breast cancer in the past;
• you have been diagnosed with, suspect, or have had a past oestrogen-dependent tumour, such as cancer of the lining of the womb (endometrial cancer);
• you have abnormal vaginal bleeding that has not been investigated by a doctor;
• you have excessive thickening of the lining of the womb (endometrial hyperplasia) that is untreated;
• you have had or currently have blood clots in the veins (venous thromboembolic disease), including deep vein thrombosis in the legs or pulmonary embolism in the lungs;
• you have blood clotting disorders (a condition that increases the risk of thrombosis, such as protein C, protein S or antithrombin deficiency);
• you currently have or have had in the past arterial blood clotting disorders (thromboembolic disorders), such as ischaemic heart disease, myocardial infarction;
• you currently have or have had in the past liver disease, and liver function tests have not returned to normal;
• you have a rare inherited blood disorder - porphyria.

If any of the above conditions develop for the first time while taking Estrofem, stop taking the medicine immediately and consult your doctor.

Warnings and precautions
Talk to your doctor or pharmacist before starting Estrofem. Inform your doctor if you currently have or have had any of the following conditions in the past, as they may recur or worsen during treatment with Estrofem. In such cases, your doctor may decide you require particularly close monitoring:

• uterine fibroids (leiomyomas),
• endometrial thickening (endometriosis) or excessive thickening of the womb lining (endometrial hyperplasia) in your medical history,
• risk factors for thromboembolic disorders (see "Blood clots in the veins (venous thromboembolic disease)"),
• risk factors for oestrogen-dependent cancers (e.g. breast cancer in mother, sister or grandmother),
• high blood pressure,
• liver disease, e.g. liver adenoma (benign tumour),
• diabetes,
• gallstones,
• migraine or severe headaches,
• systemic lupus erythematosus (an autoimmune disease),
• epilepsy,
• bronchial asthma,
• ear disease leading to progressive hearing loss (otosclerosis),
• high levels of blood fats (triglycerides),
• fluid retention due to heart or kidney failure,
• hereditary or acquired angioedema.

If any of the following conditions occur while taking HRT, you should immediately stop taking Estrofem and contact your doctor:

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

Note: Estrofem is not a contraceptive. If less than 12 months have passed since your last period, or if you are under 50 years of age, you may need to use an additional method of contraception. Please consult your doctor.

HRT and cancer

Excessive thickening of the womb lining (endometrial hyperplasia) and cancer of the womb lining (endometrial cancer)
Taking oestrogen-only HRT increases the risk of excessive thickening of the womb lining (endometrial hyperplasia) and cancer of the womb lining (endometrial cancer).
Taking a progestogen in combination with oestrogen for at least 12 days of each 28-day cycle protects against this additional risk. Therefore, your doctor may prescribe a progestogen in addition to oestrogen if you still have your uterus. However, if you have had a hysterectomy (removal of the uterus), discuss with your doctor whether it is safe to take this medicine without a progestogen.

Comparison
Among women who have not used HRT and still have their uterus, about 5 in 1,000 will be diagnosed with endometrial cancer between the ages of 50 and 65.
Depending on the duration of treatment and dose of oestrogen used, among women aged 50 to 65 who still have their uterus and are taking oestrogen-only HRT, between 10 and 60 women in 1,000 will be diagnosed with endometrial cancer (i.e. an additional 5 to 55 cases).

Unexpected bleeding
While taking Estrofem, you will experience monthly bleeding (withdrawal bleeding). However, if you experience unexpected bleeding or spotting between monthly bleeds that:

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

Breast cancer
Evidence shows that taking hormone replacement therapy (HRT), either oestrogen combined with a progestogen or oestrogen alone, increases the risk of developing breast cancer. The additional risk depends on how long you take HRT. This additional risk becomes apparent after 3 years of HRT use. After stopping HRT, the additional risk gradually decreases, but may persist for 10 years or longer if HRT was taken for more than 5 years.

Comparison
Among women aged 50 to 54 who do not use HRT, an average of 13 to 17 women in 1,000 will be diagnosed with breast cancer over a 5-year period.
Among women aged 50 who start 5 years of oestrogen-only HRT, the number of cases will be 16–17 per 1,000 women (i.e. 0 to 3 additional cases).
Among women aged 50 who start 5 years of oestrogen-progestogen HRT, the number of cases will be 21 per 1,000 women (i.e. 4 to 8 additional cases).
Among women aged 50 to 59 who do not use HRT, an average of 27 women in 1,000 will be diagnosed with breast cancer over a 10-year period.
Among women aged 50 who start 10 years of oestrogen-only HRT, the number of cases will be 34 per 1,000 women (i.e. 7 additional cases).
Among women aged 50 who start 10 years of oestrogen-progestogen HRT, the number of cases will be 48 per 1,000 women (i.e. 21 additional cases).

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

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

Additionally, participation in available mammography screening programmes is recommended. It is important to inform the nurse or radiographer performing the X-ray that you are taking hormone replacement therapy, as this medicine may increase breast density, which may affect the mammogram result. Not all lumps may be detected during mammography in areas of increased breast density.

Ovarian cancer
Ovarian cancer is rare – much rarer than breast cancer. Taking HRT containing oestrogen alone or combined with progestogens is associated with a slightly increased risk of ovarian cancer.
The risk of ovarian cancer increases with age. For example, among women aged 50 to 54 who do not use HRT, about 2 in 2,000 women will be diagnosed with ovarian cancer over a 5-year period.
Among women who have used HRT for 5 years, about 3 in 2,000 women will be diagnosed (i.e. about 1 additional case).

Effects of HRT on the heart and circulation

Blood clots in the veins (venous thromboembolic disease)
The risk of developing venous thromboembolic disease is 1.3 to 3 times higher in women taking HRT compared to non-users, especially during the first year of use.
Blood clots can be life-threatening; if they travel to the lungs, they may cause chest pain, shortness of breath, fainting, or even death.
Women with a diagnosed tendency to thrombosis have a higher risk of venous thromboembolic disease, and HRT may further increase this risk. HRT is contraindicated in such women.

The risk of venous blood clots increases with age and with the presence of any of the following factors. Inform your doctor if:

• you are unable to walk for long periods due to major 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 requiring anticoagulant therapy;
• you or a close family member have had blood clots in the legs, lungs, or other organs in the past;
• you are pregnant or in the postpartum period;
• you have systemic lupus erythematosus;
• you have been diagnosed with cancer.

Symptoms of blood clots: see "If any of the following conditions occur while taking HRT, you should immediately stop taking Estrofem and contact your doctor".

Comparison
Among women aged 50 to 59 not using HRT, the number of venous blood clots over 5 years is estimated at 4 to 7 per 1,000 women.
Among women aged 50 to 59 using oestrogen-progestogen HRT, the number of venous blood clots over 5 years is 9 to 12 per 1,000 women (i.e. 5 additional cases).
Among women aged 50 to 59 who have had a hysterectomy and are using oestrogen-only HRT, the number of venous blood clots over 5 years is 5 to 8 per 1,000 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 using oestrogen-progestogen HRT, there is a slightly increased tendency to develop coronary artery disease compared to non-users.
In women who have had a hysterectomy and are taking oestrogen-only HRT, there is no increased risk of coronary artery disease.

Ischaemic stroke
The risk of ischaemic stroke is about 1.5 times higher in women taking HRT compared to non-users. The number of additional stroke cases due to HRT use increases with age.

Comparison
Among women aged 50 to 59 not using HRT, an average of 8 in 1,000 women will have a stroke over 5 years.
Among women aged 50 to 59 using HRT, the number of stroke cases over 5 years will be 11 per 1,000 women (i.e. 3 additional cases).

Other conditions
HRT does not improve cognitive function (perception, attention, memory). The risk of memory loss may be somewhat higher in women who start HRT after age 65. Consult your doctor.

Estrofem and other medicines
Some medicines may affect the effectiveness of Estrofem, which may lead to irregular bleeding. These include:

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

HRT may affect the action of other medicines:

• the antiepileptic drug lamotrigine, which may increase seizure frequency;
• medicines used in hepatitis C virus (HCV) infection (e.g. the combination regimen of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, or glecaprevir/pibrentasvir) may cause increased liver function test results (increased liver enzyme AlAT activity) in women taking combined hormonal contraceptives containing ethinylestradiol. Estrofem contains estradiol, not ethinylestradiol. It is unknown whether taking Estrofem together with these HCV combination regimens may lead to increased AlAT liver enzyme activity.

Tell your doctor or pharmacist about all medicines you are currently taking, have recently taken, or plan to take (including over-the-counter medicines, herbal remedies, or other natural products). Your doctor will advise you accordingly.

Estrofem with food and drink
Tablets may be taken with or without food and drink.

Pregnancy and breastfeeding
Estrofem is intended for use only in postmenopausal women.
If pregnancy occurs during treatment with Estrofem, stop treatment immediately and contact your doctor.
Estrofem is not recommended during breastfeeding.

Driving and using machines
The effect of Estrofem on the ability to drive and operate machinery is unknown.

Estrofem contains lactose monohydrate
If you have previously been diagnosed with intolerance to certain sugars, consult your doctor before taking this medicine.

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

Laboratory tests
If blood tests are required, inform your doctor or laboratory staff that you are taking Estrofem, as this medicine may affect the results of certain tests.

3. How to use Estrofem

This medicine should always be used exactly as prescribed by your doctor. If in doubt, consult your doctor or pharmacist.
In women who have had a hysterectomy and are not receiving other hormonal treatment, Estrofem may be started on any day.
One tablet should be taken daily at approximately the same time each day.
After taking all 28 tablets from the calendar pack, treatment should continue without interruption by starting the next pack immediately.
Instructions for using the calendar pack are provided at the end of this leaflet, in the section entitled “INSTRUCTIONS FOR THE USER”.
Your doctor will prescribe the lowest possible dose for the shortest possible duration that adequately controls your symptoms. If you feel the dose is too high or too low, consult your doctor.
In women who have had a hysterectomy, your doctor will not usually recommend additional treatment with a progestogen (another female hormone), unless endometriosis (presence of endometrial tissue outside the uterus) has been diagnosed.
If you have previously been taking other hormone replacement therapy (HRT) medicines, ask your doctor or pharmacist when you should start taking Estrofem.
If bleeding or spotting occurs during treatment, this is not usually a cause for concern, especially during the first few months of HRT (for more information, see section 2. “HRT and cancer”, “Endometrial hyperplasia and endometrial cancer”).

Taking more Estrofem than prescribed
If you take more Estrofem than prescribed, contact your doctor or pharmacist immediately.
Overdose of Estrofem may cause nausea or vomiting.

Missed dose of Estrofem
If you forget to take your tablet at the usual time, take it within the next 12 hours. If more than 12 hours have passed, do not take the missed tablet; instead, take the next tablet at the usual time the following day. Do not take a double dose to make up for a missed dose. Missing a dose may increase the likelihood of breakthrough bleeding or spotting during the cycle, particularly if you still have your uterus.

Stopping Estrofem
If you wish to discontinue Estrofem, inform your doctor, who can explain the consequences of stopping treatment and discuss alternative therapies.
If you have any further questions about the use of this medicine, consult your doctor or pharmacist.

If surgery is planned
If you are scheduled for surgery, inform your 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. “Venous thromboembolism (VTE)”). Before restarting Estrofem, consult your doctor.

4. Possible adverse effects

Like any medicine, this medicine can cause adverse effects, although they do not occur in everyone.
In women using hormone replacement therapy (HRT), there is an increased risk of developing the following diseases,
compared to women not using HRT:

• breast cancer;
• overgrowth or cancer of the lining of the womb (endometrial hyperplasia or cancer);
• ovarian cancer;
• blood clots in the veins of the legs or lungs (venous thromboembolic disease);
• coronary heart disease;
• stroke;
• possibly loss of cognitive function (perception, attention, memory), if HRT is initiated at age over 65.

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

Hypersensitivity and (or) allergy (uncommon adverse effect – may occur in not more than 1 in 100 women)
Although hypersensitivity is an uncommon adverse effect, it may occur. Symptoms of hypersensitivity and (or) allergy may include one or more of the following:
urticaria, itching, swelling, breathing difficulties, low blood pressure (pale and cold skin, rapid heartbeat), dizziness, sweating, which may be signs of an anaphylactic reaction and (or) anaphylactic shock. If any of these symptoms occur, you must stop taking Estrofem and seek immediate medical advice.

Common (may occur in not more than 1 in 10 women)

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

Uncommon (may occur in not more than 1 in 100 women)

• visual disturbances,
• venous thrombosis,
• heartburn (dyspepsia),
• vomiting,
• bloating and (or) flatulence,
• gallstones,
• skin rash or urticaria.

Rare (may occur in not more than 1 in 10,000 women)

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

Other adverse effects following estrogen use

• myocardial infarction, congestive heart failure,
• venous thromboembolic disease, e.g. deep vein thrombosis of the lower limbs or pelvis and pulmonary embolism,
• gallbladder disease,
• skin and subcutaneous tissue disorders:
  • skin pigmentation, especially on the face or neck, known as "pregnancy mask" (chloasma),
  • red, tender nodules (nodular erythema),
  • rash, including erythema multiforme lesions in ring-like shapes,
  • vascular purpura,
  • itching,
• fungal vaginal infection,
• estrogen-dependent benign and malignant tumours, e.g. endometrial cancer,

endometrial hyperplasia or enlargement of uterine fibroids*,

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

Reporting of adverse effects
If any adverse effects occur, including any not listed in this leaflet, you should inform your doctor, pharmacist, or nurse. Adverse effects can be reported directly to the Department for Monitoring Adverse Drug Reactions at 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.
Adverse effects can also be reported to the marketing authorisation holder.
Reporting adverse effects helps to provide more information on the safety of the medicine.

5. How to store Estrofem

Keep the medicine out of sight and reach of children.
Do not use this medicine after the expiry date stated on the label and outer packaging following "Expiry". The expiry date refers to the last day of the stated month.
Store below 25 °C. Do not store in the refrigerator.
Keep in the original outer packaging.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This 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: monohydrate lactose, corn starch, hydroxypropylcellulose, talc, and magnesium stearate.
• The ingredients of the tablet coating are: hypromellose, talc, titanium dioxide (E171), polyethylene glycol 400, and indigo carmine (E132).

What Estrofem looks like and contents of the pack
The coated tablets are blue, round, with a diameter of 6 mm, and have the imprint NOVO 280 on one side.

Pack sizes:

• 28 coated tablets

Marketing Authorisation Holder and Manufacturer
Novo Nordisk A/S
Novo Allé
2880 Bagsværd, Denmark

For further information, please contact the local representative of the Marketing Authorisation Holder:
Novo Nordisk Pharma Sp. z o.o.
Tel.: 22 444 49 00
Fax: 22 444 49 01

Other sources of information
Detailed information on this medicinal product is available on the website of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products: www.urpl.gov.pl.

USER INSTRUCTIONS
How to use the calendar pack

1. Setting the day indicator
Rotate the inner disc so that the day of the week on which treatment is started aligns with the opening in the outer part.

2. Removing the first tablet
Break the seal of the opening and remove the first tablet.

3. Subsequent tablets
The next day, rotate the transparent part one position 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 rotated after removing the tablet located in the opening.