Package Insert: Information for the User

Ovestinon 1 mg/g Vaginal Cream

Estriol

Read this entire package insert carefully before starting to use this medication,because it contains important information for you.

• Keep this package insert, as you may need to refer to it again.
• If you have any questions, consult your doctor, pharmacist, or nurse.
• This medication has been prescribedonlyfor you and should not be given to others, even if they have the same symptoms as you, as it may harm them.
• If you experience any adverse effects, consult your doctor, pharmacist, or nurse, even if they are not listed in this package insert. See section 4.

Ovestinonbelongs to a group of medicines calledhormone replacement therapy (HRT). It contains the female hormone estriol (estrogen). Ovestinon is used in postmenopausal women who have been at least 12months since their last natural menstrual period.

It is used to relieve menopausal symptoms in the vagina, such as dryness or irritation. In medical terms, this is known as «vaginal atrophy». This is caused by a drop in estrogen levels in the body. This happens naturally after menopause.

If the ovaries are surgically removed (oophorectomy) before menopause, the drop in estrogen production occurs very suddenly.

Estrogen deficiency during menopause can cause the vaginal wall to become thin and dry (vaginal dryness). This can make sex painful and may lead to vaginal irritation and infections. Estrogen deficiency can also lead to symptoms such as urinary incontinence and recurrent cystitis.

Ovestinon acts by replacing the estrogen that is normally produced by the ovaries. It is inserted into the vagina, so the hormone is released where it is needed. This can relieve vaginal discomfort.

It may take several days or even weeks to notice an improvement.

In addition to the uses mentioned earlier, Ovestinon could be used for:

• helping to heal vaginal wounds in postmenopausal women who have undergone vaginal surgery.

helping with cervical smear (Papanicolau) testing in postmenopausal women.

Medical History and Medical Reviews

The use of hormone replacement therapy carries risks that must be taken into account when deciding whether to start treatment or continue taking it.

The experience of treatment in women with premature menopause (due to ovarian failure or surgical intervention) is limited. If you have premature menopause, consult your doctor as the risks of using hormone replacement therapy may be different.

Before starting (or restarting) hormone replacement therapy, your doctor will ask about your medical history and that of your family. Your doctor may decide to perform a physical examination, which may include a breast examination and/or internal examination, if necessary.

Once you have started taking Ovestinon, you should visit your doctor for regular check-ups (at least once a year). In these check-ups, discuss with your doctor the benefits and risks of continuing to take Ovestinon.

Have regular mammograms as recommended by your doctor.

Do Not Use Ovestinon

If you are affected by any of the following situations or have doubts about any of them, consult your doctor before using Ovestinon.

Do not use Ovestinon:

• If you areallergicto estriol or any of the other components of this medication (including those listed in section 6).
• If you have or have hadbreast canceror if you suspect that you may have it.
• If you have acancer sensitive to estrogens, such as endometrial cancer, or if you suspect that you may have it.
• If you have anyunexplained vaginal bleedingorinexplicable.
• If you haveexcessive growth of the tissue that lines the inside of the uterus(endometrial hyperplasia) that is not being treated.
• If you have or have had ablood clot in a vein(thrombosis), in the legs (deep vein thrombosis) or in the lungs (pulmonary embolism).
• If you have ablood clotting disorder(such as protein C deficiency, protein S deficiency, or antithrombin deficiency).
• If you have or have had a recent disease caused by blood clots in the arteries, such asmyocardial infarction,strokeorangina pectoris.
• If you have or have had aliver diseaseand your liver function tests have not returned to normal.
• If you have a rare blood disorder called “porphyria” that is inherited.

If any of the above conditions appear for the first time while taking Ovestinon, stop taking it immediately and consult your doctor immediately.

Warnings and Precautions

Consult your doctor before starting to use Ovestinon if you have had any of the following problems, as they may recur or worsen during treatment with Ovestinon. If so, you should visit your doctor more frequently for medical check-ups:

• fibroids inside the uterus
• growth of the tissue that lines the inside of the uterus outside of it (endometriosis) or history of excessive growth of the uterine lining (endometrial hyperplasia),increased risk of developing blood clots (see “blood clots in a vein (thrombosis)”),
• increased risk of developing a cancer sensitive to estrogens (for example, if your mother, a sister, or grandmother have hadbreast cancer)
• high blood pressure
• liver disease, such as a benign liver tumor,
• diabetes,
• gallstones,
• migraines or severe headaches,
• systemic lupus erythematosus (SLE),
• epilepsy,
• asthma,
• a disease that affects the eardrum and hearing (otosclerosis),
• fluid retention due to heart or kidney problems,
• hereditary and acquired angioedema.

Inform your doctor if you have hepatitis C and are taking the combined medication ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. The combination of these medications with other medications containing estrogens may cause increases in liver function test results (elevations of liver enzymes (ALT)). The risk of this occurring with Ovestinon is currently unknown.

Stop Using Ovestinon and Visit Your Doctor Immediately

If you notice while taking hormone replacement therapy:

• any of the conditions mentioned in the section “Do Not Use Ovestinon”,
• yellowing of the skin or the white of the eyes (jaundice), which may be a sign of liver disease,
• swelling of the face, tongue, or throat and difficulty swallowing or urticaria accompanied by difficulty breathing, which suggests angioedema,
• a significant increase in blood pressure (symptoms may be headache, fatigue, dizziness),

• migraine-like headaches that appear for the first time,
• if you become pregnant,
• if you experience signs of having a blood clot, such as:
• swelling and pain in the legs,
• sudden chest pain,
• difficulty breathing.

For more information, see “blood clots in a vein (thrombosis)”.

Hormone Replacement Therapy and Cancer

Endometrial Hyperplasia and Endometrial Cancer

Taking hormone replacement therapy tablets containing only estrogen for a prolonged period may increase the risk of developing endometrial cancer.

It is not clear if there is a similar risk with Ovestinon used for repeated or long-term treatments (more than one year). However, it has been shown that the absorption of Ovestinon in the blood is very low; therefore, the addition of a progestogen is not necessary.

If you bleed or stain, it is usually nothing to worry about, but you should schedule an appointment to see your doctor. It could be a sign that the endometrium has become thicker.

To avoid endometrial stimulation, do not exceed the maximum daily dose, nor should you use this maximum dose for more than a few weeks (maximum 4 weeks).

The following risks affect hormone replacement therapy (HRT) medications that circulate in the blood. However, Ovestinon is for local treatment in the vagina and its absorption in the blood is very low. It is less likely that the conditions mentioned below will worsen or recur during treatment with Ovestinon, but you should consult your doctor if you are concerned.

Breast Cancer

The available data indicate that using Ovestinon does not increase the risk of breast cancer in women who have not had breast cancer in the past. It is not known if Ovestinon can be used safely in women who have had breast cancer in the past.

Check Your Breasts Regularly. Visit Your Doctor If You Notice Any Changes Such As:

• moles on the skin,
• changes in the nipple,
• any lump that you can see or feel.

Additionally, you are recommended to participate in mammography screening programs when offered.

Ovarian Cancer

Ovarian cancer is rare:much rarer than breast cancer. The use of HRT containing estrogen only has been associated with a slightly increased risk of ovarian cancer.

The risk of ovarian cancer varies with age. For example, in women aged 50-54 who are not taking HRT, approximately 2 women out of 2000 will be diagnosed with ovarian cancer over a 5-year period. For women who have been taking HRT for 5 years, there will be around 3 cases per 2000 users (i.e., around 1 case more).

Effect of Hormone Replacement Therapy on the Heart and Circulation

Blood Clots in a Vein

The risk ofblood clots in veinsis approximately 1.3 to 3 times higher in women using hormone replacement therapy than in those who do not use it, especially during the first year of treatment.

Blood clots can be serious, and if one dislodges and travels to the lungs, it can cause chest pain, shortness of breath, fainting, or even death.

The likelihood of having a blood clot in the veins increases with age and if you have any of the following situations. Inform your doctor if you apply any of these situations:

• you cannot walk for a long period of time due to a major surgical intervention, injury, or illness (see also section3 “If you need to undergo a surgical intervention”),
• you havesignificant obesity (BMI>30kg/m2),
• you havea blood clotting disorder that requires long-term treatment with a medication to prevent blood clots,
• if a close relative has had a blood clot in a vein, lung, or other organ,
• you have systemic lupus erythematosus (SLE),
• you have cancer.

To know the signs of the presence of a blood clot, see the section “Stop Using Ovestinon and Visit Your Doctor Immediately”.

Comparison

An average of 4 to 7 out of 1,000 women in the 50-year-old age group who are not on hormone replacement therapy, over a 5-year period, may have a blood clot in a vein.
In women in the 50-year-old age group who have followed hormone replacement therapy with estrogen only for more than 5years, there will be 5 to 8cases per 1,000users (i.e., 1case more).

Cardiovascular Disease (Myocardial Infarction)

Women taking only estrogen do not have an increased risk of developing cardiovascular disease.

Stroke

The risk of stroke is around 1.5 times higher in women using hormone replacement therapy than in those who do not use it. The number of additional cases of stroke due to the use of hormone replacement therapy increases with age.

Comparison

An average of 8 out of 1,000women in the 50-year-old age group who are not on hormone replacement therapy, over a 5-year period, may have a stroke. In women in the same age group who have been on hormone replacement therapy for more than 5years, there will be 11cases per 1,000users (i.e., 3cases more).

Other Warnings

Hormone replacement therapy does not prevent memory loss. There is some indication of a higher risk of memory loss in women who start using hormone replacement therapy after the age of 65years. Consult your doctor.

Note: Ovestinon is not a contraceptive and should not be used as such. If you have had your last menstrual period less than 12months ago or are less than 50years old, you may still need to use a contraceptive method to avoid becoming pregnant. Consult your doctor.

Other Medications and Ovestinon

Inform your doctor or pharmacist if you are using, have used recently, or may need to use any other medication, even those purchased without a prescription, herbal or other natural products.

Some medications may interfere with the effect of Ovestinon, or Ovestinon may interfere with the effect of other medications. This could produce irregular bleeding. This occurs with the following medications:

• Medications forepilepsy(such as phenobarbital, phenytoin, and carbamazepine).
• Medications fortuberculosis(such as rifampicin, rifabutin).
• Medications forHIV infection(such as nevirapine, efavirenz, ritonavir, and nelfinavir).
• Herbal products containingSt. John's Wort(Hypericum Perforatum).

Inform your doctor if you have hepatitis C and are taking the combined medication ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. The combination of these medications with other medications containing estrogens may cause increases in liver function test results (elevations of liver enzymes (ALT)). The risk of this occurring with Ovestinon is currently unknown.

Use of Ovestinon with Food and Beverages

You can eat and drink normally during treatment with Ovestinon.

Pregnancy, Lactation, and Fertility

If you are pregnant or breastfeeding, or if you think you may be pregnant, consult your doctor or pharmacist before using this medication.

Ovestinon should only be used by postmenopausal women. If you become pregnant, stop taking Ovestinon and contact your doctor.

If you are breastfeeding, consult your doctor before using Ovestinon, as it is excreted in breast milk.

Driving and Operating Machinery

Ovestinon is not expected to affect your ability to drive a vehicle or operate machinery. However, individual responses to the medication may vary.

Laboratory Tests

If you need to have a blood test, inform your doctor or the laboratory staff that you are using Ovestinon, as this medication may affect the results of some tests.

Important Information About Some Components of Ovestinon

This medication may cause local skin reactions (such as contact dermatitis) because it contains cetyl alcohol and stearic alcohol.

Follow exactly the administration instructions of this medication as indicated by your doctor or pharmacist. In case of doubt, consult your doctor or pharmacist again.

Never exceed the dose prescribed by your doctor.

The recommended dose for vaginal discomfort is a daily application during the first weeks (maximum 4 weeks) and then the dose is gradually reduced, for example, to one application twice a week.

For improving wound healing in postmenopausal women undergoing vaginal surgery, the usual dose is 1 application daily for 2 weeks before surgery and subsequently 1 application twice a week for 2 weeks after surgery.

To help evaluate vaginal smears in postmenopausal women, the usual dose is 1 application daily each day of the week before the test.

Your doctor may interrupt treatment every 2-3 months for a period of 4 weeks to assess whether it is necessary to continue.

For other situations, a different dose may be prescribed.

Instructions for correct administration of the preparation

Use the applicator to apply the cream to the vagina. It is recommended to do so before going to bed.

One application (filled applicator up to the mark) contains 0.5 g of Ovestin cream, which contains 0.5 mg of estriol.

1) Remove the cap, invert the plug, and use the pointed end to open the tube's seal.

2) Screw the applicator onto the tube. Make sure the plunger is fully inserted into the cylinder.

3) Tighten the tube slowly so that enough cream penetrates the applicator to fill it up to the mark (red mark, see the dates in the lower drawing).

4) Unscrew the applicator and re-cap the tube.

5) To apply the cream, lie down and insert the end of the applicator deeply into the vagina

6) Push the plunger slowly until the applicator is empty.

7) After use, remove the plunger from the cylinder by passing the resistance point and wash it, along with the applicator, in warm soapy water, rinsing thoroughly afterwards. Do not use detergents. Rinse thoroughly afterwards.

DO NOT PUT THE APLICATOR IN HOT WATER OR BOILING WATER.

8) The applicator can be reassembled by inserting the plunger completely into the cylinder, passing the resistance point.

Discard the applicator once the tube is empty.

The maximum dose (1 application per day) should not be used for more than 2-3 weeks.

Your doctor will try to prescribe the lowest dose to treat your symptoms for the shortest time necessary. If you feel that the effect of Ovestin is too strong or too weak, inform your doctor.

If you use more Ovestin than you should

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicological Information Service, phone 91 562 04 20, indicating the medication and the amount ingested.

If someone ingests some cream, consult a doctor.The symptoms that may appear are nausea and vomiting; in women and girls, it may also cause vaginal bleeding after a few days.

If you forgot to use Ovestin

Do not use a double dose to compensate for the missed doses.

If you forget to administer a dose, do it when you remember, unless you realize the same day that it is time for the next dose. In this case, do not administer it and simply apply the dose of that day in the usual way.

If you need to undergo surgery

If you are to undergo surgery, inform the surgeon that you are using Ovestin. You may need to stop using Ovestin for 4 to 6 weeks before the operation to reduce the risk of a blood clot (see section 2, Blood clots in a vein). Ask your doctor when you can start using Ovestin again.

If you have any other doubts about the use of this medication, ask your doctor or pharmacist.

Like all medications, this medication may cause side effects, although not everyone will experience them.

Compared to women who do not use hormone replacement therapy, the following diseases have been reported more frequently in women using hormone replacement therapy that circulates in the blood..These risks affect fewer treatments administered vaginally, such as Ovestinon:

•ovarian cancer,

•blood clots in the veins of the legs or lungs (venous thromboembolism),

•stroke,

•probable memory loss if hormone replacement therapy is started after the age of 65.

See section 2 for more information on these side effects.

Depending on the dose and patient sensitivity, Ovestinon may cause side effects such as:

• swelling and increased sensitivity in the breasts.
• mild vaginal bleeding,
• increased vaginal discharge,
• nausea,
• fluid retention in tissues, usually marked by swollen ankles or feet,
• local irritation or pruritus,

And with unknown frequency:

• pseudogripal symptoms.

Most patients experience these side effects disappearing after the first few weeks of treatment.

The following side effects have been reported associated with other hormone replacement therapies.

• gallbladder diseases,
• various skin disorders:

- skin pigmentation, especiallyon the face or neck, known as "pregnancy spots" (melasma),

-painful and reddish nodules on the skin (erythema nodosum),

- skin rash with lesions or papules in the shape of a target (erythema multiforme).

Reporting side effects:

If you experience any type of side effect, consult your doctor, pharmacist, or nurse, even if it is a possible side effect that does not appear in this prospectus. You can also report them directly through the Spanish System for the Pharmacovigilance of Medicines for Human Use:https://www.notificaram.es. By reporting side effects, you can contribute to providing more information on the safety of this medication.

Keep this medication out of the sight and reach of children.

Do not use this medicationafter the expiration date that appears on the packaging after “CAD.”. The expiration date is the last day of the month indicated.

Store in the original packaging.

Do not store at a temperature above 25°C.

Do not freeze.

Medications should not be disposed of through drains or in the trash. Dispose of the containers and medications you no longer need at the SIGRE collection pointat the pharmacy. If in doubt, ask your pharmacist how to dispose of the containers and medications you no longer need. By doing so, you will help protect the environment.

Composition of Ovestinon

• The active principle is estriol. Each gram of cream contains 1 mg (milligram) of estriol.
• The other components are octyldodecanol, cetyl ester wax, glycerol (E‑422), cetilic alcohol, estearic alcohol, polisorbate 60, sorbitan stearate, lactic acid, chlorhexidine dihydrochloride, sodium hydroxide, and purified water

Appearance of the product and contents of the packaging

Homogeneous, smooth, white to almost white paste-like consistency. Ovestinon cream is presented in a box with a 15 g cream tube and an applicator.

Holder of the marketing authorization and responsible for manufacturing

Holder of the marketing authorization

ASPEN PHARMA TRADING LTD

3016 Lake Drive

Citywest Business Campus

Dublín 24

Irlanda

Tel: 0034 952010137

Responsible for manufacturing

Aspen Bad Oldesloe GmbH

Industriestrasse 32-36

D-23843 Bad Oldesloe

Alemania

Local representative

Aspen Pharmacare España S.L.

Avenida Diagonal, 512

Planta Interior 1, Office 4

08006 Barcelona España

Last review date of this leaflet: March 2024.

The detailed and updated information on this medication is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS) http://www.aemps.gob.es/