Ovestin

Package leaflet: Information for the user

Warning! Keep this leaflet. The information on the immediate packaging is in a foreign language.
Ovestin (Synapause-E), 1 mg/g, vaginal cream
Estriol
Ovestin and Synapause-E are different brand names for the same medicine.
Please read the entire 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, please 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 not listed in this leaflet, inform your doctor, pharmacist, or nurse. See section 4.

Table of contents:

1. What Ovestin is and what it is used for
2. What you need to know 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 called local estrogen replacement therapy (ERT) for vaginal use. It 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. This condition is medically known as "atrophic vaginitis." It results from decreased estrogen levels in the body and occurs naturally after menopause.

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

Estrogen deficiency may cause vaginal dryness and increased sensitivity of the vaginal walls, leading to painful sexual intercourse, as well as inflammation and intense vaginal itching. Estrogen deficiency may also cause urinary incontinence and recurrent urinary tract infections. These symptoms often improve with estrogen-containing treatments. 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 relieve vaginal discomfort.

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

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

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

2. Important information before using Ovestin

Medical history and regular check-ups
HRT is associated with 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 the 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 diseases. Your doctor may also decide to perform a physical examination, including, if necessary, a breast and/or gynecological vaginal 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 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 apply to you. If in doubt, 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 previously had breast cancer, or if breast cancer is suspected.
• If you have an oestrogen-dependent tumour, for example endometrial cancer (cancer of 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 blood vessels (venous thromboembolism), for example in the blood vessels 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 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 any of the above health conditions occur for the first time while using Ovestin, stop treatment immediately and contact your doctor without delay.

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

• Uterine fibroids (leiomyoma)
• Growth of endometrial tissue outside the uterus (endometriosis), or previous excessive growth of the lining of the womb (endometrial hyperplasia)
• Increased risk of blood clots [see section “Blood clots in veins (venous thromboembolism)”]
• Increased risk of developing oestrogen-dependent cancer (e.g. breast cancer in mother, sister or grandmother)
• Hypertension
• Liver disorders, such as benign liver tumour
• Diabetes with or without vascular complications
• Gallstones
• Migraine or severe headache
• Autoimmune disease affecting multiple internal organs (systemic lupus erythematosus – SLE; chronic connective tissue disease with skin lesions)
• Epilepsy
• Asthma
• Otosclerosis (a disease affecting the ear bones and causing hearing loss)
• Fluid retention due to 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 oestrogen-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 health while using Ovestin.
Stop using Ovestin and contact your doctor immediately if any of the following occur during HRT:

• Any of the conditions listed in the section “When not to use Ovestin”
• Yellowing of the skin or whites of the eyes (jaundice), which may indicate liver disease
• Significant increase in blood pressure (which may cause headache, fatigue, dizziness)
• New onset of migraine-type headaches
• Pregnancy
• Symptoms suggesting blood clots, such as:
  • Painful swelling and redness in the legs
  • Sudden chest pain
  • Breathing difficulties. 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, 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)
Long-term use of oral oestrogen-only HRT 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 (longer than one year) use 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 should not usually be a cause for concern, but you should contact your doctor. It may be a sign of endometrial thickening.
To prevent stimulation of the endometrium, do not exceed the maximum dose or use it for longer than a few weeks (maximum 4 weeks).

The following risks apply to medicines used in hormone replacement therapy (HRT) that enter the bloodstream. However, Ovestin is applied locally via the vagina and is absorbed into the blood in very small amounts. It is less likely that the conditions listed below will worsen or recur during treatment with Ovestin, but if in doubt, consult your doctor.

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

• Dimpling or puckering of the skin
• Changes in the nipples
• Any visible or palpable lumps or nodules.

Additionally, screening mammograms are recommended as advised by your doctor.

Ovarian cancer
Ovarian cancer is rare – significantly rarer than breast cancer. Oestrogen-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 years who do not use HRT, ovarian cancer will be diagnosed in about 2 out of 2000 women over a 5-year period. 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.
Venous thromboembolism can be serious. 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 other organs in a close relative
• Systemic lupus erythematosus
• Cancer.

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

Comparison
In women over 50 years of age not using HRT, about 4 to 7 out of 1000 women can be expected to develop venous thromboembolism over a 5-year period.
In women over 50 years of age who have used oestrogen-only HRT for more than 5 years, the number of cases is 5 to 8 per 1000 women (i.e. 1 additional case).

Heart disease (myocardial infarction)
In women using oestrogen-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
It is estimated that among women over 50 years of age not using HRT, about 8 out of 1000 women will have a stroke over a 5-year period, compared with 11 out of 1000 women using HRT in the same age group over the same period (i.e. 3 additional cases).

Other disorders
HRT does 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
Tell your doctor or pharmacist about all medicines you are currently taking or have recently taken, including medicines you plan to take, even those available without a prescription, herbal remedies or other natural products.
Some medicines may affect the effectiveness of Ovestin, and Ovestin may interfere with the action of other medicines, potentially causing 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 )

Laboratory tests
If blood tests are required, 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 treatment.

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

Driving and using machines
Ovestin is unlikely to affect your ability to drive or operate machinery. However, individual responses to the medicine may vary.

Ovestin cream contains cetyl alcohol and stearyl alcohol.
These may cause local skin reactions (e.g. contact dermatitis).

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 urinary and genital tract, 1 application per day is usually recommended
for the first few weeks (maximum 4 weeks), after which the dose should be gradually reduced
to 1 application twice a week.
To improve wound healing in postmenopausal women undergoing vaginal procedures, 1 application
per day is usually recommended for 2 weeks before the procedure and 1 application twice a week
for 2 weeks after the procedure.
To facilitate interpretation of cervical smear results in postmenopausal women, 1 application every other
day is usually recommended during the week preceding the smear collection.
Ovestin cream should be administered intravaginally using the applicator, preferably before going to
bed.
1 application (applicator filled to the circular mark) contains 0.5 g of cream, corresponding to 0.5 mg of estriol.

1. Remove the cap from the tube, turn it over, and use the sharp end to pierce the seal.
2. Screw the applicator onto the tube. Ensure the plunger is fully inserted into the applicator.

3. Slowly squeeze the cream into the applicator until resistance is felt (the plunger will stop at the point marked by the red ring indicated by arrows in the illustration below).

4. Unscrew the applicator from the tube and replace the cap on the tube.
5. Lie down and insert the applicator tip containing the cream deeply into the vagina.
6. Slowly push the entire cream content into the vagina using the plunger.

7. After use, remove the plunger from the applicator by overcoming the resistance point, and wash both parts thoroughly with warm water and soap. Do not use detergents. After washing, rinse both parts well. DO NOT PLACE THE APPLICATOR IN HOT OR BOILING WATER.
8. The device can be reassembled by inserting the plunger into the applicator, overcoming the resistance point.

After the tube is empty, dispose of the applicator.
Your doctor will aim to prescribe the lowest possible dose for the shortest duration necessary to relieve 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 more than the recommended dose is used, contact your doctor or pharmacist immediately.
Accidental ingestion of the cream does not pose a health or life hazard. However, 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.
Missed dose of Ovestin
Do not use a double dose to make up for a missed dose.
If a dose is missed, take it as soon as possible, unless the next scheduled dose is due the following day. If the missed dose is noticed on the day of the next scheduled application, skip the missed dose and continue with the previously established dosing schedule.
Need for surgery
Patients scheduled for surgery should inform the surgeon that they are using Ovestin. It may be necessary to discontinue the use of this medicine approximately 4 to 6 weeks before surgery to reduce the risk of blood clots (see section 2, "Venous thromboembolism (venous thrombosis)"). Ask your doctor when you can resume using Ovestin.
If you have any further questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although they do not occur in everyone.
The following conditions have been more frequently reported in women using systemic hormone replacement therapy (HRT) delivered via the bloodstream. The risks below are less relevant for locally administered vaginal medicines, such as Ovestin:

• ovarian cancer
• presence of blood clots in the veins of the legs or lungs (venous thromboembolic disease)
• stroke
• possible memory loss when HRT is initiated after the age of 65.

For more information on adverse reactions, see section 2.
Depending on the dosage used and individual patient sensitivity, the following adverse reactions may occur:

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

In most patients, these symptoms resolve after the first few weeks of treatment.
The following adverse reactions have been reported with other medicines used 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 (nodular erythema)
  • rash with target-shaped red lesions or erosions (erythema multiforme).

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 also 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
Phone: 22 49-21-301
Fax: 22 49-21-309
Website: https://smz.ezdrowie.gov.pl
Reporting adverse reactions helps to provide more information on the safety of the medicine.

5. How to store Ovestin

Keep this medicine out of the sight and reach of children.
Store below 25°C. Do not freeze. Keep in the original packaging to protect from light.
Do not use this 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. These measures help protect the environment.

6. Contents of the package and other information

What Ovestin contains

• The active substance in Ovestin vaginal cream is estriol, 1 milligram per 1 gram of cream (0.1%). The other ingredients are: octyldodecanol, cetyl palmitate, glycerol, cetyl alcohol, stearyl alcohol, polysorbate 60, sorbitan stearate, lactic acid, chlorhexidine dihydrochloride, sodium hydroxide and purified water.

What the medicine looks like and contents of the pack
Ovestin cream is a homogeneous, white or almost white mass. Ovestin cream in a quantity of 15 g is contained in an aluminium tube. The carton contains one tube with cream and an applicator marked with the CE conformity symbol.
For further information, contact the responsible party or the 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:
Aspen Bad Oldesloe GmbH, Industriestrasse 32-36, D-23843 Bad Oldesloe, Germany
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, country of export: RVG 08977
Parallel import licence number: 130/22