Ovestin

Patient Information Leaflet

Keep this leaflet! The information on the immediate packaging is in a foreign language.
Ovestin (Synapause-E), 0.5 mg, globules
Estriol
Ovestin and Synapause-E are different trade names for the same medicine.

Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet so that you can read it again if necessary.
• If you have any further questions, please consult 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 as yours.
• If you experience any adverse reactions, including those not listed in this leaflet, inform your doctor or pharmacist. See section 4.

Table of contents:

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

1. What Ovestin is and what it is used for

Ovestin belongs to a group of medicines known as local estrogen replacement therapy (ERT) for vaginal use. 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 menopausal symptoms affecting the vagina, such as dryness or irritation. In medical terminology, this condition is known as "atrophic vaginitis." It is caused by decreased estrogen levels in the body and occurs naturally after menopause.

If the ovaries have been surgically removed before menopause (a procedure called oophorectomy), estrogen production decreases rapidly.

Estrogen deficiency may lead to vaginal dryness and increased sensitivity of the vaginal walls, resulting in painful sexual intercourse, inflammation, and intense vaginal itching. Estrogen deficiency may also cause urinary incontinence and recurrent urinary tract infections. These symptoms often improve with estrogen-containing medications. Noticeable improvement usually occurs within a few days or weeks after starting treatment.

Ovestin works by replacing the estrogen normally produced by a woman's ovaries. The medicine is administered vaginally, so the hormone is released exactly where it is needed. This may help relieve vaginal discomfort.

Improvement may become noticeable only after several days or even weeks.

In addition to the indications described above, Ovestin may also be used:

• to accelerate healing of wounds following vaginal surgery
• to improve the assessment of cervical smears in postmenopausal women.

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 of ovaries) 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 history, including family medical conditions. The doctor may also decide to perform a physical examination, including, if necessary, a breast examination and/or a vaginal gynecological examination.
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 Ovestin treatment.
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 apply to you. If you are unsure, consult your doctor before using Ovestin.

Do not use Ovestin:

• if you are allergic to estriol or any of the other ingredients of this medicine (listed in section 6 “Contents of the pack and other information”).
• if you currently have or have had breast cancer in the past, or if breast cancer is suspected.
• if you currently have or suspect an estrogen-dependent tumor, such as endometrial cancer (cancer of the lining of the womb), or if such a tumor 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 had blood clots in blood vessels (venous thromboembolism), for example in the veins of the legs (deep vein thrombosis) or in 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: myocardial infarction, stroke, or angina pectoris.
• if you currently have or have had liver disease in the past and liver function test results have not returned to normal.
• if you have a rare inherited blood disorder called "porphyria".

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

Warnings and Precautions
Before starting treatment, inform your doctor if you currently have or have ever had any of the following conditions, as 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 a history of excessive growth of the endometrial lining (endometrial hyperplasia)
• increased risk of blood clots [see section “Blood clots in veins (venous thromboembolism)”]
• increased risk of estrogen-dependent cancer (e.g., breast cancer in mother, sister, or grandmother)
• hypertension
• liver disorders, such as benign liver tumor
• diabetes with or without vascular complications
• gallstones
• migraine or severe headaches
• systemic autoimmune disease affecting multiple organs (systemic lupus erythematosus - SLE; chronic connective tissue disease with skin lesions throughout the body)
• epilepsy
• asthma
• otosclerosis (a disease affecting the ear bones and causing hearing loss)
• fluid retention associated with heart or kidney disease
• hereditary or acquired angioedema.

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.
Tell 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 symptoms occur during HRT:

• any of the conditions listed under “When not to use Ovestin”
• yellowing of the skin or whites of the eyes (jaundice), which may indicate liver disease
• swelling of the face, tongue, and/or throat and/or difficulty swallowing or hives combined with breathing difficulties, suggesting angioedema
• significantly increased blood pressure (possible symptoms include: headache, fatigue, dizziness)
• first occurrence of migraine-type headaches
• pregnancy
• symptoms suggesting blood clot formation, such as:
  • painful swelling and redness in the legs
  • sudden chest pain
  • difficulty breathing
    More information is provided in the section “Blood clots in 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, additional contraception may be necessary. Consult your doctor.

HRT and Cancer

Excessive thickening of the uterine lining (endometrial hyperplasia) and cancer of the uterine lining (endometrial cancer)
Long-term use of estrogen-only HRT in tablet form may increase the risk of developing cancer of the uterine lining (endometrium).
It is not certain whether a similar risk exists with repeated or long-term use (longer than one year) of Ovestin. However, Ovestin has been shown to be absorbed into the bloodstream only to a very small extent, and therefore adding a progestogen is not necessary.
Bleeding or spotting is usually not a cause for concern, but you should consult your doctor, as it may be a sign of endometrial thickening.
To prevent endometrial stimulation, do not exceed the maximum dose or use it for longer than a few weeks (maximum 4 weeks).

The risks described below apply to HRT medicines that enter the bloodstream. Ovestin, however, is applied locally in the vagina and is absorbed into the bloodstream only in very small amounts. It is less likely that the conditions listed below will worsen or recur during treatment with Ovestin, but if you have any doubts, consult your doctor.

Breast Cancer
Data indicate that using Ovestin does not increase the risk of breast cancer in women who have never had it before. It is unknown whether Ovestin can be safely used in women who have had breast cancer.
You should regularly examine your breasts and see your doctor if you notice any changes, such as:

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

Screening mammograms are also recommended, as advised by your doctor.

Ovarian Cancer
Ovarian cancer is rare—much rarer than breast cancer. Estrogen-only HRT 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 who do not use HRT, ovarian cancer will be diagnosed within 5 years in about 2 out of 2000 women. Among women who use HRT for 5 years, ovarian cancer will be diagnosed in about 3 out of 2000 women (i.e., about 1 additional case).

Effects of HRT on the Heart or Circulatory System

Blood Clots in Veins (Venous Thromboembolism)
The risk of blood clots in veins is about 1.3 to 3 times higher in women using HRT than in those not using it, especially during the first year of treatment.
Blood clots can have serious consequences, and 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 following 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 blood clots in legs, lungs, or another organ in a close relative
• systemic lupus erythematosus (SLE; chronic connective tissue disease with skin lesions throughout the body)
• cancer.

Symptoms of thrombosis are listed in the section “When to stop using Ovestin and contact your doctor immediately.”

Comparison
Among women over 50 years of age not using HRT, venous thrombosis is expected to occur in 4 to 7 out of 1000 women over a 5-year period.
Among women over 50 using estrogen-only HRT for more than 5 years, the number of cases will be 5 to 8 per 1000 women (i.e., 1 additional case).

Heart Disease (Myocardial Infarction)
In women using estrogen-only HRT, the risk of developing heart disease is not increased.

Stroke
The risk of stroke is about 1.5 times higher in women using HRT than in those not using it. The number of additional stroke cases associated with HRT use increases with age.

Comparison
Among women over 50 not using HRT, stroke is expected to occur in about 8 out of 1000 women over 5 years. Among women of the same age using HRT, the rate is 11 cases per 1000 women over 5 years (i.e., 3 additional cases).

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

Ovestin and Other Medicines
Tell your doctor or pharmacist about all medicines you are currently taking or have recently taken, including those you plan to take, even if they are available without a prescription, herbal remedies, or other natural products.
Some medicines may affect the action of Ovestin, leading to irregular bleeding. These include:

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

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 treatment with Ovestin.

Pregnancy and Breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant, or are planning to become pregnant, you should consult your doctor or pharmacist before using this medicine.
Ovestin is intended for use only in postmenopausal women. If you become pregnant, stop using Ovestin and contact your doctor.
Women who are breast-feeding should consult their doctor before using Ovestin.

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

3. How to use Ovestin

This medicine should always be used exactly as directed by your doctor or pharmacist. If in doubt,
consult your doctor or pharmacist.
For atrophic changes in the lower urogenital tract, 1 suppository is usually used once daily for the
first few weeks (up to a maximum of 4 weeks), after which the dose is gradually reduced to 1
suppository twice a week.
To improve wound healing in postmenopausal women who have undergone vaginal procedures, 1
suppository is usually used once daily for 2 weeks before the procedure and 1 suppository twice a
week for 2 weeks after the procedure.
To facilitate interpretation of cervical smear results in postmenopausal women, 1 suppository is
usually used every other day during the week preceding the smear test.
The suppository should be inserted deeply into the vagina while lying in a semi-reclining position,
before going to bed for the night. The suppository must not be used rectally.
Your doctor will aim to prescribe the lowest possible dose, to be used 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.
Taking more Ovestin than recommended
If you use more Ovestin than recommended, contact your doctor or pharmacist immediately.
Accidental swallowing of the suppositories does not pose a health or life hazard. Nevertheless, you
should inform your doctor. Symptoms of overdose most commonly include nausea and vomiting. In
women, vaginal bleeding may also occur after a few days.
If you forget to use Ovestin
Do not use a double dose to make up for a forgotten dose.
If you forget to use a dose, take it as soon as possible, unless you notice the omission on the day
when the next dose is due. If the omission is noticed on the day the next suppository is to be used,
skip the missed dose and continue with the next dose according to your regular schedule.
Need for surgery
Patients scheduled for surgery should inform the surgeon that they are using Ovestin. It may be
necessary to discontinue Ovestin approximately 4 to 6 weeks before surgery to reduce the risk of
blood clots (see section 2 "Blood clots in the veins (venous thrombosis)"). Ask your doctor when
you may resume using Ovestin.
If you have any further questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everybody will experience them.
The following conditions are reported more frequently in women using systemic hormone replacement therapy (HRT) – i.e. treatments that enter the bloodstream – than in women not using HRT. These risks are less relevant for locally administered medicines such as Ovestin:

• ovarian cancer
• blood clots in the veins of the legs or lungs (venous thromboembolism)
• stroke
• possible memory loss if HRT is initiated after the age of 65. For more information about these adverse effects, see section 2.

Depending on the dose used and individual patient sensitivity, the following adverse effects may occur:

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

In most patients, these symptoms subside after the first few weeks of treatment.
The following adverse effects have been reported during the use of other HRT medicines:

• inflammation of the gallbladder
• various skin disorders
  • skin discolouration, particularly on the face or neck, known as "melasma" (chloasma)
  • painful red nodules on the skin (erythema nodosum)
  • rash with target-shaped redness or ulceration (erythema multiforme)

Reporting of adverse effects
If any adverse effects occur, including any not listed in this leaflet, inform your doctor or pharmacist. Adverse effects can be reported directly to the Department of Monitoring of Adverse Drug Reactions at the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, Al. Jerozolimskie 181C, 02-222 Warsaw, telephone: +48 22 49 21 301, fax: +48 22 49 21 309, website: https://smz.ezdrowie.gov.pl .
Reporting adverse effects helps to provide more information on the safety of this medicine.

5. How to store the medicine Ovestin

Keep the medicine out of the sight and reach of children.
Store below 25°C. Keep in the original blister pack to protect from light and moisture.
Do not store in the refrigerator. Do not freeze.
Do not use the Ovestin medicine after the expiry date stated on the packaging.
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. This will help protect the environment.

6. Contents of the pack and other information

What Ovestin contains
The active substance in Ovestin is estriol. Each globule contains 0.5 mg of estriol.
The other ingredients are: hard fat (containing stearic acid polyethylene glycol ester and glycerol ricinoleate).

What the medicine looks like and contents of the pack
White, oval globules. Each blister contains 5 vaginal globules. The blisters are contained in a cardboard box.
The pack contains 15 vaginal globules.

For more detailed information, please contact the Marketing Authorisation Holder or Parallel Importer.

Marketing Authorisation Holder in the Netherlands, country of export:
Aspen Pharma Trading Limited
3016 Lake Drive
Citywest Business Campus
Dublin 24, Ireland

Manufacturer:
Unither Industries
Zone Industrielle Le Malcourlet, 17
Avenue des Portes Occitanes
03800 Gannat
France

Parallel Importer:
InPharm Sp. z o.o.
ul. Strumykowa 28/11
03-138 Warsaw
Poland

Repackaged by:
InPharm Sp. z o.o. Services sp. k.
ul. Chełmżyńska 249
04-458 Warsaw
Poland

Marketing Authorisation Number in the Netherlands, country of export: RVG 08978
Parallel Import Licence Number: 10/26