Package leaflet: Information for the user

Warning! Keep the leaflet. Information on the immediate packaging is in a foreign language.
Ovestin (Synapause-E)
2 mg, tablets
Estriol
Ovestin and Synapause-E are different trade names for the same medicine.
Please read this leaflet carefully before using the medicine, as it contains
important information for the patient.

Keep this leaflet so that you can read it again if necessary.
If you have any doubts, consult your doctor or pharmacist.
This medicine has been prescribed for a specific individual. Do not pass it on to others. The medicine may harm another person, even if their symptoms are the same.
If you experience any adverse effects, including any adverse effects not listed in this leaflet, inform your doctor, pharmacist, or nurse. See section 4.

Leaflet contents:

What Ovestin is and what it is used for
Important information before taking Ovestin
How to take Ovestin
Possible side effects
How to store Ovestin
Contents of the pack and other information

1. What Ovestin is and what it is used for

Ovestin is used as part of hormone replacement therapy (HRT). The medicine contains the female sex hormone estriol (an estrogen). Ovestin is used in postmenopausal women, at least 12 months after the natural cessation of menstruation.

Ovestin is used to relieve postmenopausal symptoms.

During menopause, the amount of estrogen produced by a woman's body gradually decreases. If the ovaries have been surgically removed before menopause (a procedure called oophorectomy), estrogen production decreases very rapidly.

In many cases, reduced estrogen levels lead to menopausal symptoms such as hot flushes or night sweats. Estrogen deficiency may also cause vaginal dryness and increased sensitivity of the vaginal walls, resulting in painful sexual intercourse, inflammation, and intense vaginal itching. Estrogen deficiency may also lead to urinary incontinence and recurrent urinary bladder infections.

Ovestin relieves symptoms occurring after menopause. Improvement may not become noticeable until after several days or even weeks. Ovestin is prescribed by a doctor only when symptoms seriously interfere with the patient's daily life.

In addition to the above-mentioned use of Ovestin tablets, this medicine may also be used in the following cases:

Treatment of certain forms of infertility
Acceleration of postoperative wound healing in postmenopausal women who have undergone vaginal surgery
Accurate assessment of cervical smears in women during the postmenopausal period.

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2. Important information before using Ovestin

Medical history and regular check-ups
Hormone replacement therapy (HRT) carries risks that should be considered when deciding whether to start or continue treatment.
Experience with treating women who have premature menopause (due to ovarian failure or surgical removal) is limited. In women with premature menopause, the risks associated with HRT may differ. Always consult your doctor.
Before starting (or resuming) HRT, your doctor will take a detailed medical and family history. Your doctor may also decide to perform a physical examination, including, if necessary, a breast examination and/or a gynecological examination via the vagina.
After starting treatment with Ovestin, you should have regular check-ups with your doctor (at least once a year). During these visits, discuss with your doctor the benefits and risks of continuing treatment with Ovestin.
You should have regular breast examinations as recommended by your doctor.

When not to use Ovestin:
Do not use Ovestin if any of the following situations apply to you. If in doubt, consult your doctor before using Ovestin.

When not to use Ovestin:

if you are allergic to estriol or any of the other ingredients of this medicine (listed in section 6).
if you currently have or have ever had breast cancer, or if breast cancer is suspected.
if you have an estrogen-dependent tumour, for example cancer of the endometrium (the lining of the womb), or if such a tumour is suspected.
if you have vaginal bleeding of unknown cause.
if you have untreated excessive thickening of the lining of the womb (endometrial hyperplasia).
if you currently have or have ever had blood clots in the blood vessels (venous thromboembolism), for example in the veins of the legs (deep vein thrombosis) or in the blood vessels of the lungs (pulmonary embolism).
if you have blood clotting disorders (such as protein C deficiency, protein S deficiency or antithrombin deficiency).
if you currently have or have recently had arterial diseases caused by blood clots, such as: heart attack, stroke or angina pectoris.
if you currently have or have ever had liver disease, and liver function test results have not returned to normal.
if you have a rare inherited blood disorder called "porphyria".
if you have rare inherited conditions such as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

If any of the above medical conditions occur for the first time while using Ovestin, stop treatment immediately and contact your doctor without delay.

Warnings and precautions
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Before starting treatment, inform your doctor if any of the following conditions are currently present or have ever occurred in the past, as these symptoms may return or worsen during treatment with Ovestin. If this happens, you should have more frequent check-ups:

uterine fibroids (leiomyoma)
endometriosis (growth of endometrial tissue outside the uterus) or previous excessive growth of the lining of the womb (endometrial hyperplasia)
increased risk of blood clots [see section "Blood clots in the veins (venous thromboembolism)"]
increased risk of developing an estrogen-dependent tumour (e.g. breast cancer in mother, sister or grandmother)
high blood pressure
liver disorders, such as benign liver tumours
diabetes with or without vascular complications
gallstones
migraine or severe headaches
autoimmune disease affecting multiple internal organs (systemic lupus erythematosus - SLE, a chronic connective tissue disease with skin changes throughout the body)
epilepsy
asthma
otosclerosis (a disease affecting the ear bones and causing hearing loss)
fluid retention associated with heart or kidney disease.

Inform your doctor if you have hepatitis C and are being treated with medications such as: ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin. Concurrent use of these drugs with certain estrogen-containing medicines may increase liver function test results (elevated liver enzyme ALT activity); the risk of this occurring with Ovestin is currently unknown.
Inform your doctor if you notice any changes in your condition while using Ovestin.
Stop using Ovestin and contact your doctor immediately
if any of the following conditions occur while using HRT:

any of the conditions listed in section "When not to use Ovestin"
yellowing of the skin or whites of the eyes (jaundice), which may be a sign of liver disease
a significant increase in blood pressure (which may present as headache, fatigue, dizziness)
first occurrence of migraine-type headaches
pregnancy
symptoms indicating the formation of blood clots, such as:
- painful swelling and redness of the legs
- sudden chest pain
- breathing difficulties. More information is provided in the section "Blood clots in the veins (venous thromboembolism)".

Note: Ovestin 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 should use contraception to avoid pregnancy. Consult your doctor.

HRT and cancer

Excessive thickening of the lining of the womb (endometrial hyperplasia) and cancer of the lining of the womb (endometrial cancer)
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Using estrogen-only HRT increases the risk of excessive thickening of the lining of the womb (endometrial hyperplasia) and cancer of the endometrium. This additional risk can be prevented by taking a progestagen-containing medicine together with estrogen for at least 12 days of each 28-day menstrual cycle. Therefore, if you still have your uterus, your doctor will prescribe a progestagen separately. If you have had your womb surgically removed (hysterectomy), discuss with your doctor whether it is safe for you to take this medicine without a progestagen.

Among women with an intact uterus who do not use HRT, endometrial cancer is diagnosed in an average of 5 out of 1,000 women aged 50 to 65 years.

Among women aged 50 to 65 years 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 dose and duration of treatment. One epidemiological study showed that long-term oral use of low-dose estriol may increase the risk of endometrial cancer. This risk increases with the duration of treatment and disappears within one year after stopping therapy. Cancers diagnosed in women using estriol were less clinically advanced than in women not using estriol.

To reduce the risk of endometrial stimulation, do not use a dose higher than the maximum daily dose, and the maximum daily dose should not be used for longer than a few weeks.

Your doctor may perform periodic monitoring of the uterus or alternatively prescribe additional progestagen for long-term use.

Irregular bleeding or spotting may occur during the first few months of HRT.
However, if bleeding or spotting:

persists beyond the first few months,
occurs after a period of HRT use,
continues after stopping HRT, contact your doctor, who will decide whether further investigations are needed.

Breast cancer
Evidence confirms that using hormone replacement therapy (HRT), either combined estrogen-progestagen therapy or estrogen-only therapy, increases the risk of breast cancer. This additional risk depends on the duration of HRT use and becomes apparent after 3 years of treatment. After stopping HRT, the additional risk gradually decreases, but may persist for 10 years or longer if HRT was used for more than 5 years.

Comparison
Breast cancer will be diagnosed within 5 years in an average of 13 to 17 out of 1,000 women aged 50 to 54 years who do not use HRT.
For women aged 50 who start a 5-year course of estrogen-only HRT, the number of cases will be 16–17 per 1,000 women (i.e. 0 to 3 additional cases).
For women aged 50 who start a 5-year course of estrogen-progestagen HRT, breast cancer will be diagnosed in 21 out of 1,000 women (i.e. 4–8 additional cases).
For women aged 50 to 59 years who do not use HRT, breast cancer will be diagnosed in an average of 27 out of 1,000 women within 10 years.
For women aged 50 who start a 10-year course of estrogen-only HRT, the number of cases will be 34 per 1,000 women (i.e. 7 additional cases).
For women aged 50 who start a 10-year course of estrogen-progestagen HRT, the number of cases will be 48 per 1,000 women (i.e. 21 additional cases).
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You should have regular breast examinations and contact your doctor if you notice any changes, such as:

skin indentation or retraction
changes in the nipple
any visible or palpable lumps or thickening.

It is not known whether using Ovestin carries the same increased risk of breast cancer as other HRT medicines. Women concerned about the risk of breast cancer should discuss the benefits and risks of such therapy with their doctor.

Ovarian cancer
Ovarian cancer is rare – much rarer than breast cancer. Using HRT containing only estrogens or a combination of estrogens and progestagens is associated with a slightly increased risk of ovarian cancer.
The risk of ovarian cancer depends on age. For example, in women aged 50 to 54 years who do not use HRT, ovarian cancer will be diagnosed within 5 years in about 2 out of 2,000 women. In 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).
It is not known whether using Ovestin carries the same increased risk as other HRT medicines.

Effects of HRT on the heart or circulation

Blood clots in the veins (venous thromboembolism)
The risk of blood clots in the veins is about 1.3 to 3 times higher in women using HRT than in those who do not, especially during the first year of treatment. Venous thromboembolism can be severe. If a clot travels to the lungs, it may cause chest pain, shortness of breath, fainting or even death.
The likelihood of developing venous blood clots increases with age and in the following situations. If any of the situations listed below apply to you, inform your doctor:

prolonged immobility due to major surgery, injury or illness (see also section 3 "Need for surgery")
significant overweight (body mass index above 30 kg/m²)
blood clotting disorders requiring long-term anticoagulant therapy
history of venous thrombosis in legs, lungs or another organ in a close relative
systemic lupus erythematosus
cancer.

Symptoms of thrombosis are described in the section "When to stop using Ovestin and contact your doctor immediately".
Comparison
In women over 50 years of age who do not use HRT, venous thromboembolism is expected in an average of 4 to 7 out of 1,000 women within 5 years. In women of the same age taking estrogen-progestagen HRT, the number of such cases will be 9 to 12 per 1,000 women within 5 years (i.e. 5 additional cases).
In women over 50 years of age who have had their womb removed and who have used estrogen-only HRT for more than 5 years, the number of cases will be 5 to 8 per 1,000 women (i.e. 1 additional case).
It is not known whether using Ovestin carries the same increased risk as other HRT medicines.
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Heart disease (heart attack)
There is no evidence that HRT prevents heart attacks.
The likelihood of developing heart disease is slightly higher in women over 60 years of age using estrogen-progestagen HRT compared to those not using such therapy.
In women who have had their womb removed and who use only estrogens as part of HRT, the risk of heart disease is not increased.

Stroke
The risk of stroke is about 1.5 times higher in women using HRT than in those who do not. The number of additional stroke cases associated with HRT use increases with age.
Comparison
It is estimated that in women over 50 years of age not using HRT, stroke will occur in an average of 8 out of 1,000 women within 5 years, whereas in women of the same age using HRT, the rate is 11 cases per 1,000 women within 5 years (i.e. 3 additional cases).

Other disorders
HRT will not prevent memory loss. Some evidence suggests a higher risk of memory loss in women who start HRT after the age of 65. Consult your doctor about this.

Ovestin and other medicines
Some medicines may affect the effectiveness of Ovestin, and Ovestin may affect the effectiveness of other medicines, potentially leading to irregular bleeding. These include:

antiepileptic drugs (such as: phenobarbital, phenytoin and carbamazepine)
medicines used to treat tuberculosis (such as: rifampicin, rifabutin)
medicines used in HIV infection (such as: nevirapine, efavirenz, ritonavir and nelfinavir)
herbal products containing St. John's wort (Hypericum perforatum)

Tell your doctor or pharmacist about all medicines you are currently taking or have recently taken, including those obtained without a prescription, herbal products and other natural supplements.

Laboratory tests
If you need to have blood tests, inform your doctor or laboratory staff that you are using Ovestin, as it may affect the results of certain tests.

Ovestin with food and drink
Food and drink do not affect the effectiveness of Ovestin therapy.

Pregnancy and breastfeeding
Ovestin is intended for use only in postmenopausal women. If you become pregnant, stop using Ovestin and contact your doctor.
Women who are breastfeeding should consult their doctor before using Ovestin.

Driving and operating machinery
Using Ovestin should not affect your ability to drive or operate machinery. However, individual responses to the medicine may vary.

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

3. How to use Ovestin

This medicine should always be used exactly as directed by your doctor or pharmacist. If in doubt,
please consult your doctor or pharmacist.
For symptoms associated with menopause, the usual dose is generally 4–8 mg per day during the
first weeks of treatment; thereafter, the daily dose should be gradually reduced, for example to a
maintenance dose of 1–2 mg per day.
For the treatment of certain forms of infertility, the usual dose is generally 1–2 mg per day during
days 6 to 15 of the menstrual cycle. The optimal dose may vary between individual patients.
To improve wound healing in postmenopausal women undergoing vaginal procedures, the usual
dose is 4–8 mg per day for 2 weeks before the procedure and 1–2 mg per day for 2 weeks after
the procedure.
To facilitate the interpretation of cervical smear test results in postmenopausal women, the usual
dose is 2–4 mg per day for 7 days in the week preceding the smear test.
The score line on the tablet is intended only to assist in breaking the tablet for easier swallowing.
Tablets should be taken with a sufficient amount of water or another liquid. The medicine should
be taken regularly every day at the same time. Doses should not be divided.
Your doctor will aim to prescribe the lowest possible dose, which should be taken for the shortest
duration necessary to relieve your symptoms.
If you feel that the effect of Ovestin is too strong or too weak, consult your doctor.
Use of a higher than recommended dose of Ovestin
If you take more than the recommended dose, contact your doctor or pharmacist immediately.
Taking more than the recommended dose of Ovestin is not life-threatening or dangerous to health.
Nevertheless, you should inform your doctor. Symptoms of overdose are usually nausea and vomiting;
in women, vaginal bleeding may also occur after a few days.
Missed dose of Ovestin
Do not take a double dose to make up for a missed tablet.
If you miss a dose, take the tablet as soon as possible, provided that the gap since the missed dose
is no longer than 12 hours. If the gap is longer than 12 hours, skip the missed tablet and continue
taking the tablets according to your regular schedule.
Need for surgery
Patients scheduled for surgery should inform their surgeon that they are taking Ovestin. It may be
necessary to stop taking the medicine approximately 4 to 6 weeks before surgery to reduce the risk
of blood clots (see section 2 "Blood clots in the veins"). Please consult your doctor about when you
can restart taking Ovestin.
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If you have any further questions about the use of this medicine, please consult your doctor or
pharmacist.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them.
In women using HRT, the following diseases occur more frequently than in women who do not use such therapy:

breast cancer
abnormal growth or cancer of the lining of the womb (endometrial hyperplasia or cancer)
ovarian cancer
presence of blood clots in the veins of the legs or lungs (venous thromboembolic disease)
heart disease
stroke
possible memory loss if HRT is started after the age of 65.

For more information about adverse effects, see section 2.
Depending on the doses used and the patient's sensitivity, the following adverse effects may occur:

swelling and increased tenderness of the breasts
slight vaginal bleeding
increased vaginal discharge
nausea
fluid retention, usually manifesting as swelling of the ankles or feet
flu-like symptoms

In most patients, these symptoms usually disappear after the first weeks of treatment.
The following adverse effects have been reported during use of other medicines in hormone replacement therapy:

inflammation of the gallbladder
various skin disorders
- skin pigmentation changes, especially on the face or neck (chloasma)
- painful red nodules on the skin (erythema nodosum)
- rash with target-shaped red lesions or erosions (erythema multiforme)

Reporting of adverse effects
If any adverse effects occur, including any not listed in this leaflet, inform your doctor, pharmacist, or nurse. Adverse effects can be reported directly to the Department of 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
Reporting adverse effects helps to provide more information on the safety of the medicine.
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5. How to store Ovestin

Keep this medicine out of the sight and reach of children.
Store below 30°C. Keep in the original packaging to protect from light and moisture.
Do not use this medicine after the expiry date stated on the container. The expiry date refers to the last day of the stated month.
Medicines must 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 Ovestin contains

The active substance in Ovestin is estriol. Each tablet contains 2 mg of estriol.
Other ingredients: colloidal anhydrous silica, magnesium stearate, potato starch, povidone, lactose monohydrate.

What Ovestin looks like and contents of the pack
White, round, flat tablets with bevelled edges and a score line. Each tablet is embossed on one side
with the code DG above the score line and the number 8 below the score line. The pack contains 30 tablets.
For further information, please contact the Marketing Authorisation Holder or the Parallel Importer.
Marketing Authorisation Holder in the Netherlands, the country of export:
Aspen Pharma Trading Limited, 3016 Lake Drive, Citywest Business Campus, Dublin 24, Ireland
Manufacturer:
Cyndea Pharma, Polígono Industrial Emiliano Revilla Sanz, Avendia de Ágreda, 31 42110 Ólvega
(Soria), Spain
Parallel Importer:
Delfarma Sp. z o.o., ul. Św. Teresy od Dzieciątka Jezus 111, 91-222 Łódź, Poland
Repackaged in:
Delfarma Sp. z o.o., ul. Św. Teresy od Dzieciątka Jezus 111, 91-222 Łódź, Poland
Marketing Authorisation number in the Netherlands, the country of export: RVG 09970
Parallel Import Authorisation Number: 238/23
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