Trisequens

Package Leaflet: Information for the User

Warning! Keep the leaflet. Information on the immediate packaging in a foreign language.

Trisequens

2 mg (blue), 2 mg + 1 mg (white), 1 mg (red), film-coated tablets

estradiol + norethisterone acetate

Read the leaflet carefully before using the medicine, as it contains important information for the patient.

• Keep this leaflet, so you can read it again if you need to.
• If you have any doubts, consult your doctor or pharmacist.
• This medicine has been prescribed specifically for you. Do not pass it on to others. The medicine may harm another person, even if their symptoms are the same as yours.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Table of Contents of the Leaflet

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

1. What is Trisequens and what is it used for

Trisequens is a medicine used in sequential combined hormone replacement therapy (HRT), taken daily without interruption. Trisequens is used in postmenopausal women, at least 6 months after their last natural menstrual period. Trisequens contains 2 hormones: estrogen (estradiol) and progestogen (norethisterone acetate). The estradiol in Trisequens is identical to the estradiol produced by the ovaries in women and is classified as a natural estrogen. Norethisterone acetate is a synthetic progestogen that acts similarly to progesterone, another important female sex hormone. Trisequens is used to:

• relieve symptoms that occur after menopauseDuring menopause, the amount of estrogen produced in a woman's body decreases, which can cause symptoms such as hot flashes on the face, neck, and chest. Trisequens relieves these symptoms after menopause. Trisequens should only be prescribed to a patient if symptoms significantly interfere with daily life;
• prevent osteoporosisAfter menopause, some women develop brittle bones (osteoporosis). All available options should be discussed with your doctor. If you are at increased risk of fractures due to osteoporosis and other medicines are not suitable, Trisequens can be used to prevent osteoporosis after menopause.

Experience with treating women over 65 years old is limited.

2. Important information before using Trisequens

Medical history and regular medical examinations

The use of HRT carries risks that should be considered when a patient decides to use hormone replacement therapy or continue its use. Experience with treating women in premature menopause (due to ovarian failure or surgical intervention) is limited. If a patient is experiencing premature menopause, the risk associated with HRT may differ. You should talk to your doctor. Before starting (or resuming) HRT, your doctor should take your medical history, including your family history. Your doctor may decide to perform tests, including a breast examination and/or gynecological examination, if necessary. If you start using Trisequens, you should regularly visit your doctor for check-ups (at least once a year). During these check-ups, you should discuss the benefits and risks of continuing Trisequens with your doctor. You should also regularly undergo breast examinations, as recommended by your doctor.

When not to use Trisequens

If you have any of the following conditions or are unsure, tell your doctor before using Trisequens. Do not start using Trisequens if:

• you are allergic(hypersensitive) to estradiol, norethisterone acetate, or any of the other ingredients of Trisequens (listed in section 6. Contents of the pack and other information);
• you have been diagnosed with breast cancer, have had it in the past, or are suspected of having it;
• you have been diagnosed with endometrial cancer(cancer of the lining of the uterus) or other estrogen-dependent tumors;
• you have unexplained vaginal bleeding;
• you have endometrial hyperplasia(excessive growth of the lining of the uterus) and it is not being treated;
• you have been diagnosed with blood clots in the veins(venous thromboembolism), such as deep vein thrombosis or pulmonary embolism;
• you have been diagnosed with blood clotting disorders(such as protein C, protein S, or antithrombin deficiency);
• you have been diagnosed with or have had arterial diseasescaused by blood clots, such as heart attack, stroke, or angina;
• you have been diagnosed with liver disease, and liver function tests have not returned to normal;
• you have a rare, inherited blood disordercalled porphyria.

If any of the above conditions occur for the first time while using Trisequens, stop using it and consult your doctor.

Warnings and precautions

Before starting treatment, tell your doctor if you have had any of the following conditions in the past, as they may recur or worsen during Trisequens use. In such cases, your doctor may require more frequent monitoring:

• uterine fibroids (fibroids),
• endometriosis (growth of the lining of the uterus outside the uterus) or endometrial hyperplasia (excessive growth of the lining of the uterus) in the past,
• factors that increase the risk of blood clots (see Blood clots in the veins (venous thromboembolism)),
• factors that increase the risk of estrogen-dependent tumors (such as breast cancer in your mother, sister, or grandmother),
• high blood pressure,
• liver disease, such as a benign liver tumor,
• diabetes,
• gallstones,
• migraine or severe headaches,
• systemic lupus erythematosus (an immune system disease that affects many organs),
• epilepsy,
• asthma,
• otosclerosis (a condition that causes gradual hearing loss),
• high levels of triglycerides in the blood,
• fluid retention due to heart or kidney problems,
• hereditary angioedema (a condition that causes recurring episodes of severe swelling) or if you have had episodes of swelling related to angioedema,
• lactose intolerance.

If you experience any of the following conditions while using HRT, stop using Trisequens and consult your doctor immediately:

• if you experience any of the conditions listed in the When not to use Trisequenssection,
• if your skin or the whites of your eyes turn yellow (jaundice), which may be a sign of liver problems,
• if you experience swelling of the face, tongue, and/or throat, and/or difficulty swallowing or hives, which may indicate angioedema,
• if you experience a significant increase in blood pressure (symptoms may include headache, fatigue, and dizziness),
• if you experience a migraine headache for the first time,
• if you become pregnant,
• if you experience symptoms of a blood clot, such as:
• painful swelling and redness of the legs,
• sudden chest pain,
• difficulty breathing.

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 need to use an additional method of contraception. Consult your doctor.

HRT and cancer

Endometrial hyperplasia (excessive growth of the lining of the uterus) and endometrial cancer

The use of estrogen-only HRT increases the risk of endometrial hyperplasia and endometrial cancer. The progestogen in Trisequens helps reduce this additional risk. Comparison In women aged 50-65 with an intact uterus who do not use HRT, endometrial cancer is diagnosed in approximately 5 out of 1000 women. In women aged 50-65 with an intact uterus who use estrogen-only HRT, the number of cases of endometrial cancer diagnosed ranges from 10 to 60 out of 1000 women (i.e., 5-55 additional cases), depending on the duration of treatment and the dose of estrogen used.

Unexpected bleeding

During Trisequens use, monthly bleeding (called withdrawal bleeding) usually occurs. However, if you experience additional unexpected bleeding or spotting that:

• lasts longer than the first 6 months,
• occurs after using Trisequens for more than 6 months,
• continues after stopping Trisequens, consult your doctor as soon as possible.

Breast cancer

Data confirm that taking HRT in the form of combined estrogen and progestogen or estrogen alone increases the risk of breast cancer. The additional risk depends on how long you use HRT. This additional risk becomes apparent after 3 years of HRT use. After stopping HRT, the additional risk will decrease over time but may persist for 10 years or more if HRT lasted more than 5 years. Comparison In women aged 50-54 who do not use HRT, breast cancer is diagnosed in approximately 13-17 out of 1000 women over a 5-year period. In women aged 50 who start 5-year estrogen-only HRT, the number of cases of breast cancer diagnosed will be 16-17 out of 1000 patients (i.e., 0-3 additional cases). In women aged 50 who start 5-year combined estrogen-progestogen HRT, the number of cases of breast cancer diagnosed will be 21 out of 1000 patients (i.e., 4-8 additional cases). In women aged 50-59 who do not use HRT, breast cancer is diagnosed in approximately 27 out of 1000 women over a 10-year period. In women aged 50 who start 10-year estrogen-only HRT, the number of cases of breast cancer diagnosed will be 34 out of 1000 patients (i.e., 7 additional cases). In women aged 50 who start 10-year combined estrogen-progestogen HRT, the number of cases of breast cancer diagnosed will be 48 out of 1000 patients (i.e., 21 additional cases).

You should have regular breast examinations. Consult your doctor if you notice any of the following changes:

• indentation of the skin,
• changes in the nipple,
• presence of lumps that are visible or palpable.

In addition, it is recommended to have regular mammography screenings as advised by your doctor. Before the examination, inform the nurse or medical staff performing the X-ray that you are using HRT, as it may increase breast density, which can affect the mammography result. Not all lumps can be detected during a mammography in areas with increased breast density.

Ovarian cancer

Ovarian cancer is rare - much rarer than breast cancer. The use of HRT that includes only estrogen or a combination of estrogen and progestogen is associated with a slightly increased risk of ovarian cancer. The risk of ovarian cancer depends on age. For example, in women aged 50-54 who do not use HRT, ovarian cancer is diagnosed in approximately 2 out of 2000 women over a 5-year period. In women who used HRT for 5 years, the number of cases of ovarian cancer diagnosed will be approximately 3 out of 2000 users (i.e., 1 additional case).

Effect of HRT on the heart and circulation

Blood clots in the veins (venous thromboembolism)

The risk of blood clots in the veinsis 1.3- to 3-fold higher in women using HRT compared to non-users, especially in the first year of use. Blood clots can be life-threatening and, if they move to the lungs, can cause chest pain, shortness of breath, loss of consciousness, and even death. The risk of blood clots in the veins is higher if you are older and have any of the following factors. Inform your doctor if:

• you are unable to walk for a long time due to major surgery, injury, or illness (see section 3. If you are going to have surgery);
• you are obese (body mass index (BMI) > 30 kg/m²);
• you have a history of blood clots that require long-term use of medicines to prevent blood clots;
• anyone in your close family has had blood clots in the legs, lungs, or other organs;
• you have systemic lupus erythematosus;
• you have been diagnosed with cancer.

If you experience symptoms of a blood clot, see If you experience any of the following conditions while using HRT. Comparison In women aged 50-59 who do not use HRT, the estimated number of cases of blood clots in the veins over a 5-year period is 4-7 out of 1000 women. In women aged 50-59 who use combined estrogen-progestogen HRT, the number of cases of blood clots in the veins over a 5-year period will be 9-12 out of 1000 women (i.e., 5 additional cases).

Coronary artery disease (heart attack)

There is no evidence that HRT helps prevent heart attacks. In women over 60 years old who use combined estrogen-progestogen HRT, there is a slightly increased risk of developing coronary artery disease compared to non-users.

Stroke

The risk of stroke is approximately 1.5-fold higher in women using HRT compared to non-users. The number of additional cases of stroke caused by HRT use will increase with age. Comparison In women aged 50-59 who do not use HRT, the estimated number of cases of stroke over a 5-year period is 8 out of 1000 women. In women aged 50-59 who use HRT, the number of cases of stroke over a 5-year period will be 11 out of 1000 women (i.e., 3 additional cases).

Other conditions

HRT does not prevent memory loss. The risk of memory loss may be slightly higher in women who start HRT at an age over 65. In such cases, consult your doctor.

Trisequens and other medicines

Certain medicines may affect the effectiveness of Trisequens, which may lead to irregular bleeding. These include:

• antiepileptic drugs(such as phenobarbital, phenytoin, and carbamazepine);
• antituberculosis drugs(such as rifampicin and rifabutin);
• medicines used to treat HIV(such as nevirapine, efavirenz, ritonavir, and nelfinavir);
• medicines used to treat hepatitis C(such as telaprevir);
• herbal products containing St. John's Wort(Hypericum perforatum).

HRT may affect the action of other medicines:

• the antiepileptic drug lamotrigine, which may increase the frequency of seizures,
• medicines used to treat hepatitis C (HCV; e.g., the combination treatment ombitasvir/paritaprevir/ritonavir with dasabuvir or without dasabuvir, as well as the combination glecaprevir/pibrentasvir) may cause increased liver enzyme levels in women using combined hormonal contraceptives containing ethinyl estradiol. Trisequens contains estradiol, not ethinyl estradiol. It is not known whether the use of Trisequens with this combination treatment may increase liver enzyme levels. Other medicines that may increase the effect of Trisequens:
• medicines containing ketokonazole(an antifungal medicine).

Trisequens may affect the simultaneous treatment with cyclosporin. Tell your doctor or pharmacistabout all medicines you are currently taking or plan to take, including those available without a prescription, herbal medicines, or other natural products. Your doctor will advise you on this matter.

Lab tests

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

Using Trisequens with food and drink

Tablets can be taken with or without food and drink.

Pregnancy and breastfeeding

Pregnancy:Trisequens is intended for use in postmenopausal women only. If you become pregnant, stop using Trisequens and consult your doctor immediately. Breastfeeding:do not use Trisequens while breastfeeding.

Driving and using machines

The effect of Trisequens on the ability to drive and use machines is not known.

Important information about some of the ingredients of Trisequens

Trisequens contains lactose monohydrate. If you have been diagnosed with an intolerance to some sugars, consult your doctor before taking Trisequens.

Trisequens contains sodium

Trisequens contains less than 1 mmol of sodium (23 mg) per tablet, which means it is essentially "sodium-free".

3. How to use Trisequens

Always use Trisequens as directed by your doctor. If you are unsure, consult your doctor or pharmacist. In women who are not using other hormone replacement therapy, treatment with Trisequens can be started on any day. Women who are currently using other hormone replacement therapy should consult their doctor to determine when to start Trisequens.

Take one tablet daily, approximately at the same time every day.

Each pack contains 28 tablets. Days 1 – 12 Take one blue tablet daily for 12 days. Days 13 – 22 Take one white tablet daily for 10 days. Days 23 – 28 Take one red tablet daily for 6 days. Swallow the tablets with water. After finishing the pack, continue treatment without interruption, starting the next pack. During the red tablets, bleeding usually occurs, similar to a menstrual period (withdrawal bleeding). The instructions for using the calendar pack are at the end of this leaflet, in the section "INSTRUCTIONS FOR THE USER". Your doctor should prescribe the lowest effective dose for the shortest duration necessary to alleviate symptoms. If you think the dose of Trisequens is too high or too low, consult your doctor. Inform your doctor if, after 3 months of treatment, symptoms have not improved satisfactorily. Treatment should only be continued as long as the benefits outweigh the risks.

Taking more than the recommended dose of Trisequens

If you take more Trisequens than recommended, consult your doctor or pharmacist. Overdose of Trisequens may cause nausea or vomiting.

Missing a dose of Trisequens

If you forget to take a tablet at the usual time, take it within the next 12 hours. If more than 12 hours have passed, take the next dose at the usual time the next day. Do not take a double dose to make up for a missed dose. Missing a dose may increase the likelihood of additional bleeding or spotting.

Stopping Trisequens use

If you want to stop using Trisequens, consult your doctor. Your doctor will explain the consequences of stopping treatment and discuss other possible therapies. If you have any further doubts about using Trisequens, consult your doctor or pharmacist.

If you are going to have surgery

If you are going to have surgery, tell your surgeon that you are using Trisequens. It may be necessary to stop using Trisequens 4-6 weeks before surgery to reduce the risk of blood clots (see section 2. Blood clots in the veins (venous thromboembolism)). Before restarting Trisequens, consult your doctor.

4. Possible side effects

Like all medicines, Trisequens can cause side effects, although not everybody gets them. Women using HRT are at increased risk of developing the following conditions compared to non-users:

• breast cancer;
• endometrial hyperplasia or cancer (excessive growth or cancer of the lining of the uterus);
• ovarian cancer;
• blood clots in the veins of the legs or lungs (venous thromboembolism);
• coronary artery disease;
• stroke;
• possibly memory loss, if HRT is started at an age over 65. For more information, see section 2. Important information before using Trisequens.

Hypersensitivity (allergic reaction); uncommon side effect – affects 1 to 10 women in 1000. Although hypersensitivity is an uncommon side effect, it can occur. Symptoms of hypersensitivity may include one or more of the following: hives, itching, swelling, difficulty breathing, low blood pressure (pale and cold skin, rapid heartbeat), dizziness, sweating, which can be symptoms of an anaphylactic reaction and/or anaphylactic shock. If any of the above symptoms occur, stop taking Trisequens and seek medical help immediately.

Very common side effects:

• breast tenderness or pain,
• irregular periods or heavy bleeding during periods.

Common side effects:

• headache,
• weight gain due to fluid retention,
• vaginal inflammation,
• fungal vaginal infection, appearance or worsening of migraine, appearance or worsening of depression, nausea, abdominal pain, feeling of bloating or discomfort in the abdomen, breast enlargement or swelling, back pain, muscle cramps in the legs, uterine fibroids (benign tumors of the uterus), worsening, appearance, or recurrence, swelling of the hands and feet (peripheral edema), weight gain.

Uncommon side effects:

• bloating or gas,
• acne,
• hair loss (alopecia),
• excessive hair growth (hirsutism),
• itching or hives,
• phlebitis (inflammation of the veins),
• ineffectiveness of the medicine,
• allergic reaction,
• endometrial hyperplasia (excessive growth of the lining of the uterus),
• painful periods,
• nervousness.

Rare side effects:

• pulmonary embolism (blood clot in the lungs). See Blood clots in the veinsin section 2. Important information before using Trisequens,”
• deep vein thrombosis with phlebitis (blood clot in the veins).

Very rare side effects:

• endometrial cancer (cancer of the lining of the uterus),
• high blood pressure or worsening of hypertension,
• gallbladder disease, appearance or worsening of gallstones, worsening of symptoms,
• excessive oil production, appearance of skin rash,
• acute or recurrent swelling (angioedema),
• insomnia, dizziness, anxiety,
• changes in sex drive,
• vision disturbances,
• weight loss,
• vomiting,
• heartburn (indigestion),
• vaginal and vulvar itching,
• heart attack and stroke,
• generalized allergic reactions (anaphylactic reaction, anaphylactic shock).

The frequency of possible side effects listed above is as follows: very common (affects more than 1 in 10 women) common (affects 1 to 10 women in 100) uncommon (affects 1 to 10 women in 1000) rare (affects 1 to 10 women in 10,000) very rare (affects less than 1 in 10,000 women) unknown (frequency cannot be estimated from available data).

Other side effects of combined HRT

The following side effects have been reported with the use of other HRT medicines:

• various skin disorders:
• skin discoloration, especially on the face or neck, called "pregnancy patches" (chloasma),
• red, painful lumps (erythema nodosum),
• rash, including erythema multiforme (a rash that looks like a target).

Reporting side effects

If you experience any side effects, including those not listed in this leaflet, tell your doctor or pharmacist. Side effects can be reported directly to the Department of Drug Safety, Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products: Al. Jerozolimskie 181 C, 02-222 Warsaw, tel.: +48 22 49 21 301, fax: +48 22 49 21 309, website: https://smz.ezdrowie.gov.pl. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Trisequens

Keep the medicine out of the sight and reach of children. Do not use this medicine after the expiry date stated on the packaging. The expiry date refers to the last day of the month stated. Store at a temperature below 25°C. Do not store in the refrigerator. Store the calendar pack in the outer packaging to protect it from light. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines that are no longer needed. This will help protect the environment.

6. Contents of the pack and other information

What Trisequens contains

• The active substances of Trisequens are estradiol and norethisterone acetate.
• The blue film-coated tablet contains 2 mg of estradiol (as estradiol hemihydrate).
• The white film-coated tablet contains 2 mg of estradiol (as estradiol hemihydrate) and 1 mg of norethisterone acetate.
• The red film-coated tablet contains 1 mg of estradiol (as estradiol hemihydrate).
• Other ingredients are lactose monohydrate, cornstarch, hydroxypropyl cellulose, talc, and magnesium stearate.
• The coating of the blue tablet contains hypromellose, talc, titanium dioxide (E 171), indigo carmine (E 132), and macrogol 400.
• The coating of the white tablet contains hypromellose, triacetin, and talc.
• The coating of the red tablet contains hypromellose, talc, titanium dioxide (E 171), iron oxide red (E 172), and propylene glycol.

What Trisequens looks like and contents of the pack

Blue film-coated, biconvex tablet with "NOVO 280" embossed, 6 mm in diameter. White film-coated, biconvex tablet with "NOVO 281" embossed, 6 mm in diameter. Red film-coated, biconvex tablet with "NOVO 282" embossed, 6 mm in diameter. Each pack contains 28 film-coated tablets - 12 blue, 10 white, and 6 red.

Pack sizes:

28 film-coated tablets in a round calendar pack made of polypropylene/polyethylene, in a cardboard box. For more detailed information, please contact the marketing authorization holder or the parallel importer.

Marketing authorization holder in Belgium, the country of export:

Novo Nordisk Pharma, Boulevard International 55, 1070 Brussels, Belgium

Manufacturer:

Novo Nordisk A/S, Novo Allé, DK-2880 Bagsværd, Denmark

Parallel importer:

InPharm Sp. z o.o., ul. Strumykowa 28/11, 03-138 Warsaw

Repackaged by:

InPharm Sp. z o.o. Services sp. k., ul. Chełmżyńska 249, 04-458 Warsaw Belgian marketing authorization number:BE156134 Parallel import authorization number:29/20

Translation of day symbols on the packaging:

M L M

• Monday D M D
• Tuesday W M M
• Wednesday D J D
• Thursday V V F
• Friday Z S S
• Saturday Z D S
• Sunday.

Date of leaflet approval: 30.01.2025

[Information about the trademark]

INSTRUCTIONS FOR THE USER

How to use the calendar pack

1. Setting the day indicator

Turn the inner dial to set the day of the week you start treatment, opposite the small plastic flap.

2. Removing the first tablet

Break off the plastic flap and remove the first tablet.

3. Moving the dial each day

The next day, turn the transparent dial clockwise by one place, as indicated by the arrow. Remove the next tablet. Remember to take only 1 tablet per day.

The transparent part can only be turned after the tablet has been removed from the opening.