PATIENT INFORMATION LEAFLET

Trisequens coated tablets

estradiol/ noretisterone acetate

Read this leaflet carefully before you start taking this medicine because it containsimportant information for you

- Keep this leaflet, as you may need to read it again.

- If you have any questions, ask your doctor or pharmacist.

- This medicine has been prescribed for you. Do not pass it on to others even if their

symptoms are the same, as it may harm them.

- If you think you have suffered a side effect, you can report it directly via the Yellow Card

Scheme Website: www.mhra.gov.uk/yellowcard.

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1. What Trisequens is and what it is used for

2.What you need to know before you take Trisequens

3. How to take Trisequens

4. Possible side effects

5. Storage of Trisequens

6.Contents of the pack and any other information

Trisequens is a combined sequential hormone replacement therapy (HRT) that is taken every day without interruption.Trisequensis used in postmenopausal women whose last natural period occurred at least 6 months ago.

Trisequens contains 2 hormones, an estrogen (estradiol) and a progestogen (noretisterone acetate). The estradiol in Trisequens is identical to the estradiol produced by the ovaries of a woman, and is classified as a natural estrogen. Noretisterone acetate is a synthetic progestogen that acts similarly to progesterone, another important female sex hormone.

Trisequens is used for:

To alleviate symptoms that occur after menopause

During menopause, the amount of estrogens produced by a woman's body decreases. This can cause symptoms such as hot flashes in the face, neck, and chest (“hot flashes”). Trisequens alleviates these symptoms after menopause. Trisequens will only be prescribed if the symptoms seriously hinder your daily life.

To prevent osteoporosis

After menopause, some women may develop fragile bones (osteoporosis). You should discuss with your doctor which options are available.

If you are at risk of suffering fractures due to osteoporosis, and there are no other suitable medications for you, you may use Trisequens to prevent osteoporosis after menopause.

The experience in treating elderly women (over 65 years old) is limited..

Medical History and Regular Check-ups

The use of THS entails risks that must be taken into account before deciding to start taking it or continue taking it.

The experience in treating women with premature menopause (due to ovarian failure or surgical intervention) is limited. If you have premature menopause, the risks of THS may be different. Consult your doctor.

Before starting (or resuming) THS, your doctor will ask you about your medical history and that of your family. They may decide to perform a physical examination, which may include a breast examination or an internal examination, if necessary.

Once you have started taking Trisequens, you should attend regular check-ups (at least once a year). In these check-ups, you can discuss with your doctor the benefits and risks of continuing treatment with Trisequens.

Attend regular breast examinations, as recommended by your doctor.

Do Not Take Trisequens

If you are affected by any of the following situations. If you have doubts about any of the following points, ask your doctor before taking Trisequens.

Do not take Trisequens

•if you have, have had, or suspect you may havebreast cancer

•if you have, have had, or suspect you may haveendometrial cancer (cancer of the cells that line the uterus) or other cancer dependent on estrogen

•if you suffer from anyunexplained vaginal bleeding

•if you have anexcessive thickening of the layer that lines the uterus(endometrial hyperplasia) that is not being treated

•if you have or have had anyblood clots in a vein(venous thromboembolism), either in the legs (deep vein thrombosis) or in the lungs (pulmonary embolism)

•if you have anycoagulation disorder(such as protein C deficiency, protein S deficiency, or antithrombin deficiency)

•if you have had aheart attack, a strokeorangina(chest pain) that causes discomfort, pressure, or pain in the chest

•if you have or have had anyliver diseaseand liver function tests have not yet normalized

•if you areallergic(hypersensitive) toestradiol,acetate of noretisteroneor any of the other components of Trisequens (detailed in section 6Container contents and additional information)

•if you have arare blood disorder called “porphyria”, of hereditary transmission

If any of these disorders first manifest while taking Trisequens, discontinue treatment immediately and consult your doctor as soon as possible.

Warnings and Precautions

Before starting treatment, inform your doctor if you have ever had any of the following problems, as they may recur or worsen during treatment with Trisequens. If so, you should attend your doctor more frequently:

•benign tumors in the uterus (fibroids)

•thickening of the layer that lines the uterus (endometriosis) or history of excessive thickening of the layer that lines the uterus (endometrial hyperplasia)

•increased risk of blood clots (seeblood clots in a vein (venous thromboembolism))

•increased risk of developing cancer sensitive to estrogen (such as having a mother, sister, or paternal or maternal grandmother who have had breast cancer)

•high blood pressure

•liver disease, such as a benign liver tumor

•diabetes

•gallstones

•migraines or severe headaches

•systemic lupus erythematosus (SLE) or other autoimmune diseases that affect multiple organs of the body

•epilepsy

•asthma

•otosclerosis (a disease that affects the eardrum and hearing)

•very high levels of fat in the blood (triglycerides)

•fluid retention due to heart or liver problems

•hereditary condition that causes recurrent episodes of severe swelling (hereditary angioedema) or if you have had episodes of rapid swelling of the hands, face, feet, lips, eyes, tongue, throat (obstruction of the airways) or digestive tract (acquired angioedema).•lactose intolerance

Discontinue treatment with Trisequens and inform your doctor immediately

If you notice any of the following symptoms while taking THS:

•any of the conditions mentioned in the sectionDo not take Trisequens.

•yellowing of the skin or white of the eyes (jaundice). This may be a sign of liver disease.

•swelling of the face, tongue, and/or throat and/or difficulty swallowing or urticaria, along with difficulty breathing, which are indicative of angioedema.

•severe increase in blood pressure (with symptoms such as headache, fatigue, dizziness).

•migraine-type headache, which may first appear.

•if you become pregnant.

•if you notice symptoms of a blood clot, such as:

- inflammation with pain and redness of the legs

- sudden chest pain

- difficulty breathing.

For more information, seeblood clots in a vein (venous thromboembolism).

Important Note:Trisequens is not a contraceptive. If you have had your last menstrual period less than 12 months ago or are less than 50 years old, you may still need to use a contraceptive method to prevent pregnancy. Ask your doctor for advice.

THS and Cancer

Endometrial hyperplasia and endometrial cancer

THS with estrogen alone increases the risk of endometrial hyperplasia and endometrial cancer.

The progestogen in Trisequens protects against this additional risk.

Comparison

In women aged 50-65 with an intact uterus who are not taking THS, a mean of 5 cases of endometrial cancer will be diagnosed per 1,000 women.

In women with an intact uterus aged 50-65 who take THS with estrogen alone, between 10 and 60 cases of endometrial cancer will be diagnosed per 1,000 users (i.e., between 5 and 55 additional cases), depending on the dose and duration of treatment.

Unexpected Bleeding

You will have a monthly bleeding (also known as metrorrhagia) while taking Trisequens. However, if you experience unexpected bleeding or blood loss (spots) that:

•persists beyond the first 6 months

•begins after taking Trisequens for more than 6 months

•continues after stopping Trisequens

you should contact your doctor as soon as possible.

Breast Cancer

The available data show that the use of hormone replacement therapy (HRT) with estrogen-progestogen combinations or with estrogen alone increases the risk of breast cancer. The additional risk depends on the duration of HRT use. The additional risk becomes apparent after 3 years of use. After stopping HRT, the additional risk will decrease over time, but the risk may persist for 10 years or more if HRT has been used for more than 5 years.

Comparison

In women aged 50-54 who are not using HRT, a mean of 13-17 out of 1,000 will be diagnosed with breast cancer over a 5-year period.

In women aged 50 who start HRT with estrogen alone for 5 years, there will be between 16 and 17 cases per 1,000 users (i.e., between 0 and 3 additional cases).

In women aged 50 who start taking HRT with estrogen-progestogen for 5 years, there will be between 21 cases per 1,000 users (i.e., 4-8 additional cases).

In women aged 50-59 who are not taking HRT, a mean of 27 cases of breast cancer will be diagnosed per 1,000 women over a 10-year period.

In women aged 50 who start HRT with estrogen alone for more than 10 years, there will be 34 cases per 1,000 users (i.e., 7 additional cases).

In women aged 50 who start HRT with estrogen-progestogen for 10 years, there will be 48 cases per 1,000 users (i.e., 21 additional cases).

Examine your breasts regularly. Consult your doctor if you notice any changes, such as:

•moles on the skin

•changes in the nipples

•any lump that you can see or feel.

Additionally, it is recommended that you participate in breast examination programs when offered.

In breast examinations, it is essential to inform your nurse/healthcare professional that you are taking HRT when they perform the X-ray examination, as this medication can increase breast density, which may affect the results of the mammogram. When breast density is higher, it may be that the mammogram does not detect all lumps.

Ovarian Cancer

Ovarian cancer occurs less frequently than breast cancer. The use of HRT with estrogen alone or with estrogen-progestogen combinations 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 cases of ovarian cancer per 2,000 women have been observed over a 5-year period. In women taking HRT for 5 years, approximately 3 cases per 2,000 patients (i.e., approximately 1 additional case) have been observed.

Effect of HRT on the Heart and Circulation

Vein Thromboembolism

The risk ofvein thromboembolismis approximately 1.3 to 3 times higher in HRT users than in non-users, especially during the first year.

Vein thromboembolism can be severe, and if one of them reaches the lungs, it can cause chest pain, difficulty breathing, syncope, or even death.

The likelihood of developing vein thromboembolism will be higher with increasing age and if any of the following factors are present. If any of these situations may apply to you, inform your doctor:

•if you were unable to walk for a long time due to a major surgical operation, injury, or illness (see also section 3,Before Surgery).

•if you have significant obesity (BMI > 30 kg/m²).

•if you have a coagulation disorder that requires prolonged treatment with medication to prevent blood clots.

•if a close relative has ever had a blood clot in the legs, lungs, or other organs.

•if you have systemic lupus erythematosus (SLE).

•if you have cancer.

For more information, seeInterruption of treatment with Trisequens and immediate notification to your doctor.

Comparison

It is estimated that, over a 5-year period, a mean of 4 to 7 out of 1,000 women in their 50s who are not taking HRT will experience a vein thromboembolism.

In women in their 50s who take HRT with estrogen-progestogen for 5 years, there will be between 9 and 12 cases per 1,000 users (i.e., 5 additional cases).

Cardiovascular Diseases (Myocardial Infarction)

HRT has not been shown to prevent myocardial infarction.

Women over 60 who use HRT with estrogen-progestogen have a slightly higher risk of developing cardiovascular diseases than those who do not take HRT.

Stroke

The risk of stroke is approximately 1.5 times higher in HRT users than in non-users. The number of additional stroke cases due to HRT use will increase with age.

Comparison

It is estimated that, over a 5-year period, a mean of 8 out of 1,000 women in their 50s who are not taking HRT will experience a stroke.

In women in their 50s who are taking HRT, the number of cases will be 11 per 1,000 users over a 5-year period (i.e., 3 additional cases).

Other Conditions

HRT does not prevent memory loss.There has been an indication of a higher risk of memory loss in women who started using HRT after the age of 65. Ask your doctor for advice.

Use of Other Medications

Some medications mayinteract with the effect of Trisequens. This may cause irregular bleeding. Such medications are the following:

•Medications forepilepsy(such as phenobarbital, phenytoin, and carbamazepine)

•Medications fortuberculosis(such as rifampicin and rifabutin)

•Medications forinfection with HIV(such as nevirapine, efavirenz, ritonavir

and nelfinavir)

•Medications for hepatitis C infection (such as telaprevir)

•Preparations based on plants containing St. John's Wort (Hypericum perforatum).

HRT may affect the functioning of certain medications:

•Medication for epilepsy (lamotrigine), as it may increase the frequency of seizures

•Medications for hepatitis C virus (HCV) (such as the combination regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir, as well as a regimen with glecaprevir/pibrentasvir) may cause increases in liver function test results (elevated ALT levels) in women taking combined hormonal contraceptives (CHCs) containing ethinylestradiol. Trisequens contains estradiol instead of ethinylestradiol. It is unknown whether this may cause an increase in ALT levels when using Trisequens with this HCV regimen.

Other medications may increase the effects of Trisequens:

•Medications containing ketoconazole (a fungicide)

Trisequens may affect concurrent treatment with cyclosporine.

Inform your doctor or pharmacistif you are taking or have recently taken any other medication.This also applies to medications without a prescription, medications purchased in another country, medications made from medicinal plants, high-potency vitamins and minerals, and dietary supplements. Your doctor will advise you.

Laboratory Tests

If you need a blood test, inform your doctor or laboratory personnel that you are taking Trisequens, as this medication may alter the results of some laboratory parameters.

Trisequens with Food and Beverages

The tablets can be taken with or without food or beverages.

Pregnancy and Lactation

Pregnancy: Do not takeTrisequens if you are pregnant. Trisequens should only be used in postmenopausal women. If you become pregnant, stop taking Trisequens, discontinue treatment, and contact your doctor.

Lactation:

Do not take Trisequens if you are breastfeeding.

Driving and Operating Machinery

Trisequenshas no known effects on the ability to drive or operate machinery.

Important Information about Some Ingredients of Trisequens

This medication contains lactose monohydrate. If you have a intolerance to certain sugars, consult your doctor before taking Trisequens.

Trisequens tablets contain sodium. Trisequens tablets contain less than 1 mmol of sodium (23 mg) per tablet; this is, essentially “sodium-free”..

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

If you are not changing from another hormone replacement therapy product, you can start treatment with Trisequens on any day that suits you. If you are changing from another hormone replacement therapy product, ask your doctor when to start treatment with Trisequens.

Take one tablet once a day, approximately at the same time each day.

Each package contains 28 tablets

Days 1 to 12Take a blue-colored tabletevery day for 12days

Days 13 to 22Take a white-colored tabletevery day for 10days

Days 23 to 28Take a red-colored tabletevery day for 6days.

Take the tablet with a glass of water.

When you have finished the package, start a new package to continue treatment without interruption. You will normally have a bleeding similar to menstruation (period) when starting a new package.

For more information on the use of the calendar package, see INSTRUCTIONS FOR USE, at the end of this leaflet.

Your doctor will try to prescribe the most effective dose and for the shortest time possible that will provide relief from symptoms. Talk to your doctor if you think the dose is excessive or insufficient.

Talk to your doctor if you do not experience relief from symptoms after 3 months of treatment. Treatment should only be maintained while the benefits outweigh the risks.

If you take more Trisequens than you should

If you have taken more Trisequens than you should,consult a doctor or pharmacist. A Trisequens overdose may cause nausea or vomiting.

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicology Information Service, phone 91562 04 20, indicating the medication and the amount ingested.

If you forget to take Trisequens

If you have forgotten to take the tablet at the usual time, take it within the next 12 hours. If more than 12 hours have passed, take it the next day at the usual time. Do not take a double dose to compensate for the missed dose.

Forgetting a dose may increase the likelihood of experiencing intercurrent metrorrhagia and oligometrorrhagia.

If you interrupt treatment with Trisequens

If you wish to interrupt treatment with Trisequens, first talk to your doctor, who will explain the effects of interrupting treatment and discuss other possibilities with you.

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

If you are to undergo surgery

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

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

The following disorders have been reported more frequently in women using THS compared to those not using it:

•breast cancer

•abnormal growth or cancer of the lining of the uterus (endometrial hyperplasia or endometrial cancer)

•ovarian cancer

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

•cardiopathy

•stroke

•probable memory loss if THS is started at an age of 65 years or older.

To obtain more information about these side effects, see section 2, "What you need to know before starting to take Trisequens."

Hypersensitivity/allergy(infrequent side effect–affects 1 to 10 users in every 1,000)

Although it is an infrequent side effect, it can occur. The signs of hypersensitivity/allergy may include one or more of the following symptoms: urticaria, itching, swelling, difficulty breathing, decrease in blood pressure (pallor and cooling of the skin, increase in heart rate), sensation of dizziness and sweating that may be signs of an allergic reaction oranaphylactic shock. If one of the mentioned symptoms occurs,stop taking Trisequens and seek immediate medical help.

Very common side effects

•breast pain or tenderness

•irregular periods or excessive bleeding during periods.

Common side effects

•headache

•weight gain due to fluid retention

•vaginal inflammation

•yeast infection of the vagina

•migraine, new onset or worsening of existing

•depression, new onset or worsening of existing

•nausea

•abdominal pain, swelling or discomfort

•breast enlargement or swelling (mammoplasty)

•back pain

•leg cramps

•worsening, new onset or recurrence of uterine fibroma (benign tumor)

•swelling of arms and legs (peripheral edema)

•weight gain.

Infrequent side effects

•flatulence or gas

•acne

•hair loss (alopecia)

•anomalous hair growth (male pattern)

•itching or hives (urticaria)

•inflammation of a vein (superficial thrombophlebitis)

•pharmacological ineffectiveness

•allergic reaction

•endometrial hyperplasia(excessive thickening of the lining of the uterus)

•painful periods

•nervousness

Rare side effects

•pulmonary embolism (blood clot)(seeBlood clots in a veinin section 2What you need to know before starting to take Trisequens)

•deep vein inflammation associated with thrombosis (blood clot).

Very rare side effects

•endometrial cancer

•increase in blood pressure or worsening of existing hypertension

•gallbladder disease, new onset, recurrence or worsening of existing gallstones

•excessive sebum secretion, skin rash

•acute or recurrent edema (angioneurotic edema)

•insomnia, dizziness, anxiety

•changes in sexual desire

•vision disturbances

•weight loss

•vomiting

•gastroesophageal reflux

•vaginal and genital itching

•myocardial infarction and stroke.

The frequency of possible side effects listed above is defined as follows:

Very common (affects more than 1 in 10 users)

Common (affects 1 to 10 users in 100)

Infrequent (affects 1 to 10 users in 1,000)

Rare (affects 1 to 10 users in 10,000)

Very rare (affects less than 1 in 10,000 users)

Frequency not known (cannot be estimated from available data).

Other side effects of combined THS

The following adverse reactions have been reported with other THS:

•various skin disorders:

–skin pigmentation, especially on the face and neck, known as "pregnancy mask" (melasma)

–red and painful skin nodules (erythema nodosum)

–skin rash with ulcers or redness in the shape of a target (erythema multiforme).

Reporting of side effects

If you experience any type of side effect, consult your doctor or pharmacist, even if it is apossible side effect that does not appear in this leaflet. You can also report them directly through theSistema Español de Farmacovigilancia de Medicamentos de Uso Humano http://www.notificaRAM.es.

By reporting side effects, you can contribute toproviding more information about the safety of this medicine

Keepthis medicationout 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 below 25°C.Do not refrigerate.

Store the packaging in the outer packaging to protect it from light.

Medicines should not be disposed of through drains or in the trash.Deposit the packaging and medicines that you no longer need at the SIGRE collection pointat the pharmacy. If in doubt, ask your pharmacist how to dispose of the packaging and medicines that you no longer need. By doing so, you will help protect the environment.”

What Trisequens contains

• The active principles are estradiol and noretisterone acetate.

The blue-coated tablets contain: estradiol 2 mg (as estradiol hemihydrate)

The white-coated tablets contain: estradiol 2 mg (as estradiol hemihydrate) and noretisterone acetate 1 mg

The red-coated tablets contain: estradiol 1 mg (as estradiol hemihydrate)

• The other ingredients are: lactose monohydrate, cornstarch, hydroxypropylcellulose, talc, and magnesium stearate
• The coating of the blue tablets contains: hypromellose, talc, titanium dioxide (E171), indigo carmine (E132), and macrogol 400.

The coating of the white tablets contains: hypromellose, triacetin, and talc

The coating of the red tablets contains: hypromellose, talc, titanium dioxide (E171), iron oxide red (E172), and propylene glycol.

Appearance of the product and contents of the package

The film-coated tablets are round with a diameter of 6 mm. The blue tablets are engraved with NOVO 280. The white tablets are engraved with NOVO 281. The red tablets are engraved with NOVO 282.

Each package of 28 tablets contains 12 blue tablets, 10 white tablets, and 6 red tablets.

Presentations:

•28 film-coated tablets.

•3 x 28 film-coated tablets.

Only some package sizes may be marketed.

Marketing authorization holder

ISDIN, S.A.

Provençals, 33

08019 Barcelona

Spain

Responsible for manufacturing

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsvaerd

Denmark

Last review date of this leaflet: December 2023

Other sources of information

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

INSTRUCTIONS FOR USEHOW TO USE THE DISC-CALENDAR PACKAGE

1. Place the day indicator

Turn the inner disc and fix the day of the week in front of the closed opening with a plastic latch.

2. How to take the first tablet

Break the plastic latch and take the first tablet.

1. Moving thedialeach day

Simply turn 1 space the transparent disc in the direction of the clock hands, as indicated by the arrow. Take the next tablet. Remember to take only 1 tablet a day.

The transparent disc can only be turned once the corresponding tablet has been taken