TRISEQUENS Coated Tablets

Introduction

PATIENT INFORMATION LEAFLET

Trisequens coated tablets

estradiol / norethisterone acetate

Read the entire leaflet carefully before starting to take the medicine, as it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.

If you think any of the side effects that you are suffering from is serious, or if you notice any side effect not mentioned in this leaflet, please tell your doctor or pharmacist. See section 4.

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Contents of the pack:

1. What Trisequens is and what it is used for
2. What you need to know before taking Trisequens
3. How to take Trisequens
4. Possible side effects
5. Storage of Trisequens
6. Contents of the pack and further information

1. What Trisequens is and what it is used for

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

Trisequens contains 2 hormones, an estrogen (estradiol) and a progestogen (norethisterone acetate). The estradiol in Trisequens is identical to the estradiol produced by the woman's ovaries and is classified as a natural estrogen. Norethisterone acetate is a synthetic progestogen that acts in a similar way to progesterone, another important female sex hormone.

Trisequens is used to:

Relieve symptoms that occur after menopause

During menopause, the amount of estrogens produced by the woman's body decreases. This can cause symptoms such as hot flashes. Trisequens relieves these symptoms after menopause. You will only be prescribed Trisequens if your symptoms seriously disrupt your daily life.

Prevent osteoporosis

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

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

Experience in treating elderly women (over 65 years) is limited.

2. What you need to know before taking Trisequens

Medical history and periodic reviews

The use of HRT involves risks that need to be considered before deciding to start or continue treatment.

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

Before starting (or resuming) HRT, your doctor will ask about your medical history and that of your family. He or she 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 periodic reviews (at least once a year). During these reviews, you can discuss the benefits and risks of continuing treatment with Trisequens with your doctor.

Attend regular breast examinations as recommended by your doctor.

Do not take Trisequens

If any of the following conditions apply to you. If you are unsure about any of the following points, ask your doctorbefore taking Trisequens.

Do not take Trisequens

If any of these conditions occur for the first time while taking Trisequens, stop 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 see your doctor more often:

• benign tumors of the uterus (fibroids)
• thickening of the lining of the uterus (endometriosis) or a history of excessive thickening of the lining of the uterus (endometrial hyperplasia)
• increased risk of blood clots (see "Blood clots in a vein (venous thromboembolism)")
• increased risk of estrogen-sensitive cancer (such as having a mother, sister, or grandmother who has had breast cancer)
• high blood pressure
• a liver disorder, such as a benign liver tumor
• diabetes
• gallstones
• migraine or severe headaches
• a disease that affects the immune system and several organs of the body (systemic lupus erythematosus or SLE)
• epilepsy
• asthma
• a disease that affects the eardrum and hearing (otosclerosis)
• a very high level of fat in the blood (triglycerides)
• fluid retention due to heart or liver problems
• a 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).

Stop treatment with Trisequens and inform your doctor immediately

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

• any of the conditions mentioned in the "Do not take Trisequens" section
• yellowing of the skin or the whites of the eyes (jaundice), which can be symptoms of liver disease
• swelling of the face, tongue, and/or throat and/or difficulty swallowing or hives, along with difficulty breathing, which are symptoms of angioedema
• a significant increase in blood pressure (with symptoms such as headache, fatigue, dizziness)
• a migraine-type headache that may occur for the first time
• inflammation with pain and redness of the legs
• sudden chest pain
• difficulty breathing

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

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

HRT and cancer

Excessive thickening of the uterine lining (endometrial hyperplasia) and cancer of the uterine lining (endometrial cancer)

HRT with only estrogens increases the risk of excessive thickening of the uterine lining (endometrial hyperplasia) and cancer of the uterine lining (endometrial cancer).

The progestogen in Trisequens protects against this additional risk.

Comparison

In women aged 50-65 who do not take HRT, an average of 5 cases of endometrial cancer are diagnosed per 1,000 women.

In women with an intact uterus aged 50-65 who take HRT with only estrogens, between 10 and 60 cases of endometrial cancer are 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 bleed (also called metrorrhagia) while taking Trisequens. However, if you experience unexpected bleeding or blood loss (spotting) that is different from your monthly bleeds, which:

• persists beyond the first 6 months
• starts after you have been taking Trisequens for more than 6 months
• continues after you have stopped taking Trisequens

you should contact your doctor as soon as possible.

Breast cancer

Existing data show that the use of hormone replacement therapy (HRT) with combined estrogens-progestogens or only estrogens 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 decreases 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 taking HRT, an average of 13-17 cases of breast cancer are diagnosed per 1,000 women over a 5-year period.

In women aged 50 who start HRT with only estrogens 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 estrogens-progestogens 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, an average of 27 cases of breast cancer are diagnosed per 1,000 women over a 10-year period.

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

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

• dimpling of the skin
• changes in the nipples
• any lump that you can see or feel

In addition, it is recommended to participate in breast screening programs when they are offered.

During breast screenings, it is important to inform your nurse/healthcare professional that you are taking HRT when you have an X-ray, as this medicine may increase breast density, which can affect the result 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 only estrogens or combined estrogens-progestogens 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 do not take HRT, approximately 2 cases of ovarian cancer are observed per 2,000 women over a 5-year period. In women treated with HRT for 5 years, approximately 3 cases are observed per 2,000 patients (i.e., approximately 1 additional case).

Effect of HRT on the heart and circulation

Blood clots in a vein (venous thromboembolism)

The risk of blood clots in the veins is approximately 1.3 to 3 times higher in HRT users than in non-users, especially during the first year.

Blood clots can be serious and, if one reaches the lungs, can cause chest pain, difficulty breathing, fainting, or even death.

The likelihood of blood clots in the veins will be higher with increasing age and if any of the following factors apply to you. If any of these situations may apply to you, inform your doctor:

30 kg/m²)

To learn about the symptoms caused by a blood clot, see the section Stop treatment with Trisequens and inform your doctor immediately.

Comparison

It is estimated that, over a 5-year period, an average of 4 to 7 women out of 1,000 in their 50s who do not take HRT will suffer a blood clot in a vein.

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

Heart disease (myocardial infarction)

HRT has not been shown to help prevent myocardial infarction.

Women over 60 who use HRT with estrogens-progestogens have a slightly higher risk of developing heart disease 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, an average of 8 women out of 1,000 in their 50s who do not take HRT will suffer 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 is an indication of a higher risk of memory loss in women who start using HRT after the age of 65. Ask your doctor for advice.

Use of other medicines

Some medicines may interfere with the effect of Trisequens. This can cause irregular bleeding. Such medicines are:

• Medicines for epilepsy(such as phenobarbital, phenytoin, and carbamazepine)

• Medicines for tuberculosis(such as rifampicin and rifabutin)

• Medicines for HIV infection (such as nevirapine, efavirenz, ritonavir, and nelfinavir)

• Medicines for hepatitis C infection (such as telaprevir)

• Herbal preparations containing St. John's Wort (Hypericum perforatum)

HRT may affect the functioning of certain medicines:

• Medicine for epilepsy (lamotrigine), as it may increase the frequency of seizures
• Medicines 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 (elevation of liver enzyme ALT) in women using combined hormonal contraceptives (CHC) containing ethinylestradiol. Trisequens contains estradiol instead of ethinylestradiol. It is not known whether an increase in liver enzyme ALT can occur when using Trisequens with this combination regimen against HCV.

Other medicines may increase the effects of Trisequens:

• Medicines containing ketoconazole (an antifungal)

Trisequens may affect treatment with concomitant use of cyclosporine.

Tell your doctor or pharmacistif you are taking or have recently taken any other medicines. This also applies to medicines without a prescription, medicines purchased in another country, herbal medicines, high-dose vitamins and minerals, and dietary supplements. Your doctor will advise you.

Laboratory tests

If you need a blood test, inform your doctor or laboratory staff that you are taking Trisequens, as this medicine may affect the results of some laboratory tests.

Taking Trisequens with food and drinks

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

Pregnancy and breastfeeding

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

Breastfeeding:

Do not take Trisequens if you are breastfeeding.

Driving and using machines

Trisequens has no known effects on the ability to drive or use machines.

Important information about some of the ingredients of Trisequens

This medicine contains lactose monohydrate. If you have an 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".

3. How to TAKE TRISEQUENS

Follow the administration instructions for this medication exactly as indicated by your doctor. If in 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 you should start treatment with Trisequens.

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

Each pack contains 28 tablets

Days 1 to 12 Take one blue tableteach day for 12 days

Days 13 to 22 Take one white tableteach day for 10 days

Days 23 to 28 Take one red tableteach day for 6 days.

Take the tablet with a glass of water.

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

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

Your doctor will try to prescribe you the lowest effective dose for the shortest possible time that provides relief from your symptoms. Talk to your doctor if you think the dose is too high or too low.

Talk to your doctor if you do not experience relief from symptoms after 3 months of treatment. Treatment should only be continued as long as 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. An overdose of Trisequens may cause nausea or vomiting.

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

If you forget to take Trisequens

If you have forgotten to take the corresponding 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 make up for the missed dose.

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

If you stop treatment with Trisequens

If you wish to stop treatment with Trisequens, talk to your doctor first, who will explain the effects of stopping 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 going to have surgery

If you are going to have surgery, inform the surgeon that you are taking Trisequens. You may need to stop taking Trisequens 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.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The following disorders have been reported more frequently in women using HRT 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)
• heart disease
• stroke
• possible memory loss if HRT is started after the age of 65.

For more information on these side effects, see section 2, What you need to know before taking Trisequens.

Hypersensitivity/allergic reaction(uncommon side effect – affects 1 to 10 users in every 1,000)

Although it is an uncommon side effect, hypersensitivity/allergic reaction may occur. The signs of hypersensitivity/allergic reaction may include one or more of the following symptoms: hives, itching, swelling, difficulty breathing, decrease in blood pressure (pallor and cooling of the skin, increased heart rate), feeling of dizziness and sweating that may be signs of an anaphylactic reaction or shock. If one of the mentioned symptoms occurs, stop taking Trisequens and seek immediate medical attention.

Very common side effects

• Pain or tenderness in the breasts
• Irregular periods or excessive bleeding during periods.

Common side effects

• Headache
• Weight gain due to fluid retention
• Vaginal inflammation
• Vaginal fungal infection
• Migraine, new onset or worsening of existing
• Depression, new onset or worsening of existing
• Nausea
• Pain, swelling, or discomfort in the abdomen
• Increased size or swelling of the breasts (breast edema)
• Back pain
• Leg cramps
• Worsening, appearance, or reappearance of uterine fibroids (benign tumor)
• Swelling of arms and legs (peripheral edema)
• Weight gain.

Uncommon side effects

• Flatulence or bloating
• Acne
• Hair loss (alopecia)
• Abnormal growth (male pattern) of hair
• Itching or hives (urticaria)
• Inflammation of a vein (superficial thrombophlebitis)
• Lack of efficacy
• Allergic reaction
• Endometrial hyperplasia (excessive thickening of the lining of the uterus)
• Painful periods
• Nervousness

Rare side effects

• Pulmonary embolism (blood clot) (see Blood clots in a vein in section 2 What you need to know before taking Trisequens)
• Deep vein inflammation associated with thrombosis (blood clot).

Very rare side effects

• Endometrial cancer (cancer of the lining of the uterus)
• Increased blood pressure or worsening of existing hypertension
• Gallbladder disease, gallstones that may be new onset, reappearance, or worsening of existing ones
• Excessive sebum secretion, skin rash
• Acute or recurrent edema (angioneurotic edema)
• Insomnia, dizziness, anxiety
• Changes in sexual desire
• Visual disturbances
• Weight loss
• Vomiting
• Heartburn
• Genital and vaginal itching
• Myocardial infarction and stroke.

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

Very common (affects more than 1 user in every 10)

Common (affects 1 to 10 users in every 100)

Uncommon (affects 1 to 10 users in every 1,000)

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

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

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

Other side effects of combined HRT

The following adverse reactions have been reported with other HRTs:

• various skin disorders:
  • skin pigmentation, especially on the face and neck, known as "pregnancy patch" (chloasma)
  • red and painful skin nodules (erythema nodosum)
  • rash with ulcers or redness in a target shape (erythema multiforme).

Reporting of side effects

If you experience any side effect, consult your doctor or pharmacist, even if it is a possible side effect not listed in this leaflet. You can also report them directly through the Spanish Medicines Agency's website http://www.notificaRAM.es.

By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of TRISEQUENS

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

Do not use this medicine after the expiry date stated on the pack after "EXP". The expiry date is the last day of the month indicated.

Store below 25°C. Do not refrigerate.

Keep the pack in the outer packaging to protect it from light.

Medicines should not be disposed of via wastewater or household waste. Dispose of the pack and any unused medicine in the pharmacy's SIGRE collection point. If in doubt, ask your pharmacist how to dispose of the pack and any unused medicine. This will help protect the environment.

6. Package contents and additional information

What Trisequens contains

• The active ingredients are estradiol and norethisterone acetate.

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

The white tablets contain: estradiol 2 mg (as estradiol hemihydrate) and norethisterone acetate 1 mg

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

• The other ingredients are: lactose monohydrate, corn starch, 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), red iron oxide (E172), and propylene glycol.

Appearance of the product and pack contents

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

Presentation:

• 28 film-coated tablets.
• 3 x 28 film-coated tablets.

Not all pack sizes may be marketed.

Marketing authorization holder

ISDIN, S.A.

Provençals, 33

08019 Barcelona

Spain

Manufacturer

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsvaerd

Denmark

Date of last revision 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 Health Products (AEMPS) http://www.aemps.gob.es/

INSTRUCTIONSFOR USE

How to use the calendar pack

1. Place the day indicator

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

1. How to remove the first tablet

Break the plastic tab and remove the first tablet.

1. Move thedialeach day

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

The transparent disk can only be turned once the corresponding tablet has been removed