Estrofem mite

Package leaflet: Information for the user

Estrofem mite, 1 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. 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 any not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of the leaflet

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

1. What Estrofem mite is and what it is used for

Estrofem mite is a medicine used in hormone replacement therapy (HRT). The medicine contains the female hormone estradiol. Estrofem mite 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 mite is used to:
relieve symptoms occurring after menopause
During menopause, the level of estrogens produced in a woman's body decreases, which may lead to symptoms such as hot flushes affecting the face, neck, and chest ("hot flashes"). Estrofem mite helps to relieve these symptoms. Estrofem mite 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 mite

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 discuss this with your doctor.
Before starting (or restarting) HRT, your doctor should take a full medical and family history. Your doctor will decide whether examinations are necessary, including breast examination and (or) gynaecological examination, if needed. If you decide to use Estrofem mite, 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 mite. You should undergo regular mammograms as recommended by your doctor.

When not to use Estrofem mite
If any of the conditions listed below apply, or if you have any doubts, you must inform your doctor before using Estrofem mite.
Do not start using Estrofem mite 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");
• breast cancer has been diagnosed, suspected, or occurred in the past;
• an estrogen-dependent tumour has been diagnosed, suspected, or occurred in the past, such as cancer of the lining of the womb (endometrial cancer);
• you have unexplained vaginal bleeding not diagnosed by a doctor;
• you have excessive growth of the lining of the womb (endometrial hyperplasia) that has not been treated;
• you have or have had 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 predisposing to thrombosis, such as protein C deficiency, protein S deficiency, or antithrombin deficiency);
• you have or have had arterial blood clotting disorders (thromboembolic disease), such as ischaemic heart disease or myocardial infarction;
• you have or have had liver disease, and liver function tests have not returned to normal;
• you have porphyria, a rare inherited blood disorder.

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

Warnings and precautions
Before starting Estrofem mite, discuss this with your doctor or pharmacist.
You should inform your doctor if you currently have or have had any of the following conditions, as they may recur or worsen during treatment with Estrofem mite. In such cases, your doctor may decide that you require particularly close monitoring:

• uterine fibroids (leiomyomas),
• endometriosis or a history of excessive growth of the lining of the womb (endometrial hyperplasia),
• factors increasing the risk of thromboembolic disorders (see "Blood clots in the veins (venous thromboembolic disease)"),
• factors increasing the risk of estrogen-dependent tumours (e.g. history of 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 mite and contact your doctor:

• if any of the conditions listed under "When not to use Estrofem mite" occur;
• if you develop yellowing of the skin or whites of the eyes (jaundice) or liver function abnormalities;
• if you develop swelling of the face, tongue and (or) throat, and (or) difficulty swallowing, or hives with breathing difficulties, indicating angioedema;
• if you develop a significant increase in blood pressure (symptoms may include headache, fatigue, dizziness);
• if you develop a migraine-type headache;
• if pregnancy is diagnosed;
• if you experience signs of blood clots 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 mite is not a contraceptive. If less than 12 months have passed since your last menstrual period, or if you are under 50 years of age, you may need to use an additional method of contraception. Please discuss this with your doctor.

HRT and cancer

Excessive growth of the lining of the womb (endometrial hyperplasia) and cancer of the lining of the womb (endometrial cancer)
Taking estrogen-only HRT increases the risk of excessive growth of the lining of the womb (endometrial hyperplasia) and cancer of the lining of the womb (endometrial cancer).
Taking a progestogen together with estrogen 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 estrogen for women who still have a uterus. However, if you have had a hysterectomy (removal of the womb), discuss with your doctor whether taking this medicine without a progestogen is safe.

Comparison
Among women who have a uterus and do not use HRT, an average of 5 out of 1,000 will be diagnosed with endometrial cancer between the ages of 50 and 65.
Depending on the duration of treatment and the dose of estrogen used, among women aged 50 to 65 who have a uterus and take estrogen-only HRT, 10 to 60 out of 1,000 will be diagnosed with endometrial cancer (i.e. an additional 5 to 55 cases).

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

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

Breast cancer
Evidence confirms that taking hormone replacement therapy (HRT), either as a combination of estrogen and progestogen or estrogen alone, increases the risk of breast cancer. The additional risk depends on how long HRT is used. 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 more if HRT was used for over 5 years.

Comparison
Among women aged 50 to 54 not using HRT, breast cancer will be diagnosed in an average of 13 to 17 out of 1,000 women over 5 years.
Among women aged 50 starting 5 years of estrogen-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 starting 5 years of estrogen-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 not using HRT, breast cancer will be diagnosed in an average of 27 out of 1,000 women over 10 years.
Among women aged 50 starting 10 years of estrogen-only HRT, the number of cases will be 34 per 1,000 women (i.e. 7 additional cases).
Among women aged 50 starting 10 years of estrogen-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 breast cancer screening programmes is recommended. It is important to inform the nurse or radiographer performing the mammogram that you are taking hormone replacement therapy, as this medicine may increase breast density, which could affect the mammogram result. Not all lumps may be detected during a mammogram in areas of increased breast density.

Ovarian cancer
Ovarian cancer is rare—much rarer than breast cancer. Taking HRT, whether estrogen-only or combined estrogen-progestogen, is associated with a slightly increased risk of ovarian cancer.
The risk of ovarian cancer depends on age. For example, among women aged 50 to 54 not using HRT, ovarian cancer will be diagnosed in about 2 out of 2,000 women over 5 years.
Among women who have used HRT for 5 years, it will occur in about 3 out of 2,000 women (i.e. about 1 additional case).

Effect 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 and, if they travel to the lungs, may cause chest pain, shortness of breath, fainting, or even death.
Women with diagnosed thrombophilia have a higher risk of venous thromboembolic disease, and HRT may further increase this risk. HRT is contraindicated in such patients.
The risk of venous blood clots is higher if you are older or have any of the following risk 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 previous thromboembolic events 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 mite and contact your doctor".

Comparison
Among women aged 50 to 59 not using HRT, the number of venous blood clot cases over 5 years is estimated at 4 to 7 per 1,000 women.
Among women aged 50 to 59 using estrogen-progestogen HRT, the number of venous blood clot cases over 5 years is 9 to 12 per 1,000 women (i.e. 5 additional cases).
Among women aged 50 to 59 with a hysterectomy using estrogen-only HRT, the number of venous blood clot cases over 5 years is 5 to 8 per 1,000 women (i.e. 1 additional case).

Coronary heart disease (heart attack)
There is no evidence that HRT helps prevent heart attacks. In women over 60 using estrogen-progestogen HRT, there is a slightly increased tendency to develop coronary heart disease compared to non-users.
In women with a hysterectomy taking estrogen-only HRT, there is no increased risk of coronary heart disease.

Ischaemic stroke
The risk of ischaemic stroke is approximately 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, stroke will occur in an average of 8 out of 1,000 women 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 mite and other medicines
Some medicines may affect the effectiveness of Estrofem mite, which may lead to irregular bleeding. These include:

• antiepileptic drugs (e.g. phenobarbital, phenytoin, carbamazepine),
• antituberculosis drugs (e.g. rifampicin, rifabutin),
• HIV medications (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 lead to increased seizure frequency;
• medications used for hepatitis C virus (HCV) infection (e.g. 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 mite contains estradiol, not ethinylestradiol. It is unknown whether using Estrofem mite together with these HCV combination treatments may cause increased AlAT liver enzyme activity.

You must inform your doctor or pharmacist about all medicines you are currently taking or have recently taken, as well as any medicines you plan to take (e.g. over-the-counter drugs, herbal remedies, or other natural products). Your doctor will advise you accordingly.

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

Pregnancy and breastfeeding
Estrofem mite is intended for use only in postmenopausal women.
If pregnancy occurs while taking Estrofem mite, treatment must be stopped immediately and you should contact your doctor.
Estrofem mite is not recommended during breastfeeding.

Driving and operating machinery
The effect of Estrofem mite on the ability to drive or operate machinery is unknown.

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

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

3. How to use Estrofem mite

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

In women who have had their uterus removed and who are not receiving any other hormonal treatment, treatment with Estrofem mite may be started on any day.

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

After taking all 28 tablets from the calendar pack, treatment should be continued 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 “USER INSTRUCTIONS”.

Your doctor will prescribe the lowest effective dose for the shortest duration necessary to relieve your symptoms. If you feel that the dose of medicine you are taking is too high or too low, you should consult your doctor.

In women who have had their uterus removed, your doctor will not usually prescribe additional progestogen (another female hormone), unless endometriosis (presence of endometrial tissue outside the uterine cavity) has been diagnosed.

If you are currently taking other hormone replacement therapy (HRT) medicines, ask your doctor or pharmacist when you should start taking Estrofem mite.

If breakthrough bleeding or spotting occurs during the cycle, this is not usually a cause for concern, especially during the first few months of HRT (for further information, see section 2. “HRT and cancer”, “Endometrial hyperplasia and endometrial cancer”).

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

Missing a dose of Estrofem mite
If you forget to take a tablet at your usual time, take it as soon as possible within the next 12 hours. If more than 12 hours have passed, do not take the missed tablet; instead, take the next tablet at your 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, especially if you still have your uterus.

Stopping Estrofem mite
If you wish to stop taking Estrofem mite, you should inform your doctor, who can explain the consequences of stopping treatment and discuss alternative therapies.

If you have any further questions about how to use 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 mite. It may be necessary to stop taking Estrofem mite 4 to 6 weeks before surgery to minimize the risk of blood clots (see section 2. “Venous thromboembolism (venous thrombosis)”). Before restarting Estrofem mite, consult your doctor.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone experiences them.
In women using hormone replacement therapy (HRT), there is an increased risk of developing the following conditions,
compared to women not using HRT:

• breast cancer;
• excessive growth 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 thromboembolic disease);
• coronary heart disease;
• stroke;
• possibly cognitive decline (perception, attention, memory), if HRT is initiated after the age of 65.

For further information, see section 2. "Important information before taking
Estrofem mite".
Hypersensitivity and (or) allergy (uncommon adverse reaction – may occur in no more than 1 in 100 women)
Although hypersensitivity is an uncommon adverse reaction, it may occur. Symptoms of
hypersensitivity and (or) allergy may include one or more of the following:
urticaria, itching, swelling, difficulty breathing, 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 mite
and seek immediate medical advice.
Common (may occur in no 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 no more than 1 in 100 women)

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

Very rare (may occur in no 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 reactions following use of estrogens

• 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 "chloasma" (melasma),
  • red, tender nodules (erythema nodosum),
  • rash, including erythematous-edematous ring-shaped lesions (erythema multiforme),
  • vasculitis,
  • 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 reactions
If any adverse reactions occur, including any not listed in this leaflet, inform your doctor, pharmacist, or nurse. Adverse reactions can be reported directly to the Department of Monitoring Adverse Reactions of Medicinal Products, 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 reactions can also be reported to the marketing authorization holder.
Reporting adverse reactions helps to provide more information on the safety of the medicine.

5. How to store Estrofem mite

Keep the medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and outer packaging following "Expiry date". The expiry date refers to the last day of the stated month.
Store at a temperature not exceeding 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. Such measures help protect the environment.

6. Contents of the pack and other information

What Estrofem mite contains

• The active substance is estradiol 1 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), propylene glycol, and iron oxide red (E172).

What Estrofem mite looks like and contents of the pack
The coated tablets are red, round, 6 mm in diameter, and have the imprint NOVO 282 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.

PATIENT LEAFLET

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 by one position clockwise, i.e. in the direction indicated by the arrow. Remove the next tablet. Remember to take one tablet per day.
The transparent part can only be rotated after the tablet located in the opening has been removed.