Trisequens

Leaflet attached to the packaging: information for the user

Trisequens

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

estradiol + norethisterone acetate

You should carefully read the contents of this leaflet before using the medicine, as it contains important information for the patient.

• You should keep this leaflet, so that you can read it again if you need to.
• If you have any further questions, you should ask your doctor or pharmacist.
• This medicine has been prescribed for a specific person. Do not give it to others. The medicine may harm another person, even if their symptoms are the same.
• If the patient experiences any side effects, including those not listed in this leaflet, they should tell their 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 packaging and other information

1. What is Trisequens and what is it used for

Trisequens is a medicine used for 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 menopause

During menopause, the amount of estrogen produced in a woman's body decreases, which can cause symptoms such as a feeling of heat on the face, neck, and chest ("hot flashes"). Trisequens relieves these symptoms after menopause. Trisequens may be prescribed to a patient only if the symptoms significantly interfere with daily life;

prevent osteoporosis

After menopause, some women develop brittle bones (osteoporosis). All available options should be discussed with a doctor. If the patient is at increased risk of fractures due to osteoporosis and other medicines are not suitable, Trisequens can be used to prevent osteoporosis after menopause. Experience in treating women over 65 years old is limited.

2. Important information before using Trisequens

Medical history and regular medical examinations

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

When not to use Trisequens

In case of any of the following conditions or if in doubt, you should tell your doctorbefore using Trisequens. You should not start using Trisequens if:

• the patient has an allergy(hypersensitivity) to estradiol, norethisterone acetate, or any of the other ingredients of Trisequens (listed in section 6. Contents of the packaging and other information);
• breast cancer has been diagnosed, has occurred in the past, or is suspected;
• endometrial cancer (endometrium cancer) or other estrogen-dependent tumors have been diagnosed, have occurred in the past, or are suspected;
• there are bleedings from the genital tract of unknown origin;
• there is excessive growth of the endometrium(endometrial hyperplasia) and it is not being treated;
• blood clots in the veins (venous thromboembolic disease), such as deep vein thrombosis or pulmonary embolism, have been diagnosed or have occurred in the past;
• blood clotting disorders (such as protein C, protein S, or antithrombin deficiency) have been diagnosed;
• diseases caused by blood clots in the arteries, such as heart attack, stroke, or angina, have been diagnosed or have occurred in the past;
• liver disease has been diagnosed, and liver function test results have not returned to normal;
• a rare, inherited blood disorder porphyriaoccurs.

If any of the above conditions occur for the first time while using Trisequens, you should stop using the medicine and consult a doctor.

Warnings and precautions

Before starting treatment, you should inform 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 a case, your doctor may determine that you need more frequent monitoring:

• uterine fibroids (uterine myomas),
• endometriosis or endometrial hyperplasia in the past,
• factors that increase the risk of blood clots (see Blood clots in the veins (venous thromboembolic disease)),
• factors that increase the risk of estrogen-dependent tumors (such as breast cancer in the mother, sister, or grandmother),
• high blood pressure,
• liver disease, such as a benign liver tumor,
• diabetes,
• gallstones,
• migraine or severe headaches,
• systemic lupus erythematosus (a disease that affects many organs),
• epilepsy,
• asthma,
• otosclerosis (a disease that leads to gradual hearing loss),
• high levels of fats (triglycerides) in the blood,
• fluid retention due to heart or kidney problems,
• hereditary tendency to recurrent episodes of severe swelling (hereditary angioedema) or if swelling episodes have occurred, associated with sudden swelling of the hands, face, feet, mouth, eyes, tongue, throat (airway obstruction) or gastrointestinal tract (acquired angioedema),
• lactose intolerance.

If any of the following conditions occur while using HRT, you should stop using Trisequens and immediately consult a doctor:

• if any of the conditions listed in the When not to use Trisequenssection occur,
• if the skin or whites of the eyes turn yellow (jaundice), which may be a sign of liver function disorders,
• if swelling of the face, tongue, and/or throat occurs, and/or difficulty swallowing or hives, which may indicate angioedema,
• if there is a significant increase in blood pressure (symptoms may include: headache, fatigue, and dizziness),
• if a migraine-type headache occurs for the first time,
• if pregnancy is detected,
• if symptoms of a blood clot occur, 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 the last menstrual period or the patient is under 50 years old, an additional method of contraception may be necessary. You should talk to your doctor.

HRT and cancer

Endometrial hyperplasia (excessive growth of the endometrium) and endometrial cancer

Using only estrogens in 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 ranges from 10 to 60 per 1000 women (i.e., 5 to 55 additional cases), depending on the duration of treatment and the dose of estrogens used.

Unexpected bleeding

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

• lasts longer than the first 6 months,
• occurs after using Trisequens for more than 6 months,
• persists despite stopping Trisequens use, you should consult a doctor as soon as possible.

Breast cancer

Data confirm that taking hormone replacement therapy (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 the patient uses HRT. This additional risk becomes apparent after 3 years of HRT use. After stopping HRT, the additional risk will decrease over time, but the risk 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 will be 16-17 per 1000 patients (i.e., 0 to 3 additional cases). In women aged 50 who start 5-year combined estrogen-progestogen HRT, the number of cases will be 21 per 1000 patients (i.e., 4 to 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 will be 34 per 1000 patients (i.e., 7 additional cases). In women aged 50 who start 10-year combined estrogen-progestogen HRT, the number of cases will be 48 per 1000 patients (i.e., 21 additional cases).

You should regularly examine your breasts. You should consult a doctor if you notice any of the following changes:

• skin retraction,
• nipple changes,
• presence of lumps that are visible or palpable.

In addition, it is recommended to undergo screening mammography as advised by your doctor. Before the examination, you should inform the nurse or medical staff performing the X-ray that you are using hormone replacement therapy, as this medicine may increase breast density, which can affect the mammography result. Not all lumps can be detected during mammography in areas with increased breast density.

Ovarian cancer

Ovarian cancer is rare - much rarer than breast cancer. Using HRT that includes only estrogens or a combination of estrogens and progestogens 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 have used HRT for 5 years, it occurs in approximately 3 out of 2000 users (i.e., approximately 1 additional case).

Effect of HRT on the heart and circulation

Blood clots in the veins (venous thromboembolic disease)

The risk of blood clots in the veinsis 1.3 to 3 times higher in women using HRT compared to those not using it, 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 the patient is older and if any of the following factors occur. You should inform your doctor if:

• the patient is unable to walk for an extended period due to major surgery, injury, or illness (see section 3. If surgery is planned);
• obesity occurs (body mass index - BMI > 30 kg/m²);
• thromboembolic disorders occur that require long-term use of anticoagulant medications;
• anyone in the immediate family has had blood clots in the legs, lungs, or other organs in the past;
• systemic lupus erythematosus has been diagnosed;
• cancer has been diagnosed.

If symptoms of a blood clot occur, see In case of the following conditions during HRT use, you should stop using Trisequens and immediately consult a doctor. 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 to 7 per 1000 women. In women aged 50-59 who use combined estrogen-progestogen HRT, the number of cases over a 5-year period will be 9 to 12 per 1000 women (i.e., 5 additional cases).

Coronary heart 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 heart disease compared to women not using HRT.

Stroke

The risk of stroke is approximately 1.5 times higher in women using HRT compared to those not using it. The number of additional stroke cases caused by HRT use will increase with age. Comparison: In women aged 50-59 who do not use HRT, the estimated number of stroke cases over a 5-year period is 8 per 1000 women. In women aged 50-59 who use HRT, the number of cases over a 5-year period will be 11 per 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 a case, you should consult a doctor.

Trisequens and other medicines

Certain medicines may affect the effectiveness of Trisequens, which can 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 infection(such as nevirapine, efavirenz, ritonavir, and nelfinavir);
• medicines used to treat hepatitis C virus infection(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 virus infection (HCV; e.g., the combination therapy ombitasvir/paritaprevir/ritonavir with dasabuvir or without dasabuvir, as well as the glecaprevir/pibrentasvir combination) may cause increased liver function test results (increased ALT enzyme activity) 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 HCV combination therapy may increase ALT enzyme activity.

Other medicines that may increase the effect of Trisequens:

• medicines containing ketoconazole(an antifungal medicine).

Trisequens may affect concurrent cyclosporin treatment. You should tell your doctor or pharmacistabout all medicines you are currently taking or have recently taken, as well as any medicines you plan to take, including those available without a prescription, herbal medicines, or other natural products. Your doctor will advise you on this matter.

Laboratory tests

If a blood test is necessary, you should inform your doctor or laboratory personnel that you are using Trisequens, as it may affect the results of some tests.

Using Trisequens with food and drink

The tablets can be taken with or without food and drink.

Pregnancy and breastfeeding

Pregnancy:Trisequens is intended for use only in postmenopausal women. If pregnancy is detected, you should stop using Trisequens immediately and consult a doctor. Breastfeeding:you should not take Trisequens while breastfeeding.

Driving and using machines

The effect of Trisequens on driving and using machines is not known.

Important information about some ingredients of Trisequens

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

Trisequens contains sodium

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

3. How to use Trisequens

This medicine should always be used as directed by your doctor. If you are unsure, you should consult your doctor or pharmacist. In women who are not using other hormone replacement therapy, Trisequens treatment 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 treatment.

You should take one tablet daily, approximately at the same time every day.

Each pack contains 28 tablets. Days 1 – 12: you should take one blue tabletdaily for 12 days. Days 13 – 22: you should take one white tabletdaily for 10 days. Days 23 – 28: you should take one red tabletdaily for 6 days. The tablets should be taken with water. After finishing the pack, you should continue treatment without interruption, starting the next pack. During the use of red tablets, bleeding usually occurs, similar to menstruation (period). 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 possible dose for use for the shortest possible time to alleviate symptoms. If you think the dose of Trisequens is too high or too low, you should consult your doctor. You should inform your doctor if satisfactory alleviation of symptoms does not occur after 3 months of treatment. Treatment should only be continued for as long as the benefits outweigh the risks.

Taking a higher dose of Trisequens than recommended

If you have taken a higher dose of Trisequens than recommended, you should consult your doctor or pharmacist. Overdose of Trisequens may cause nausea or vomiting.

Missing a dose of Trisequens

If you have forgotten to take a tablet at the usual time, you should take it within the next 12 hours. If more than 12 hours have passed, you should take the next dose at the usual time the next day. You should 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, you should consult your doctor. They will be able to explain the consequences of stopping treatment and discuss other possible forms of therapy. If you have any further questions about using Trisequens, you should consult your doctor or pharmacist.

If surgery is planned

If you are scheduled to undergo surgery, you should inform your surgeon that you are taking Trisequens. It may be necessary to stop using Trisequens 4 to 6 weeks before surgery to reduce the risk of blood clots (see section 2. Blood clots in the veins). Before resuming Trisequens use, you should 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 diseases compared to women not using HRT:

• breast cancer;
• excessive growth or cancer of the endometrium (endometrial hyperplasia or cancer);
• ovarian cancer;
• blood clots in the veins of the legs or lungs (venous thromboembolic disease);
• coronary heart 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 (allergy); an uncommon side effect – affects 1 to 10 women in 1000. Although hypersensitivity (allergy) is an uncommon side effect, it can occur. Symptoms of hypersensitivity (allergy) 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 anaphylactic reaction and/or anaphylactic shock. If any of the above symptoms occur, you should stop taking Trisequens and seek medical help immediately.

Very common side effects:

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

Common side effects:

• headache,
• weight gain due to fluid retention,
• vaginitis,
• fungal vaginitis,
• 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,
• leg cramps,
• uterine fibroids (uterine myomas), worsening, occurrence, or recurrence,
• peripheral edema (peripheral edema),
• weight gain.

Uncommon side effects:

• bloating or gas,
• acne-like skin changes,
• hair loss (alopecia),
• excessive hair growth (hirsutism),
• itching or hives,
• phlebitis (superficial thrombophlebitis),
• ineffectiveness of the medicine,
• allergic reaction,
• endometrial hyperplasia (excessive growth of the endometrium),
• painful periods,
• nervousness.

Rare side effects:

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

Very rare side effects:

• •endometrial cancer (endometrium cancer),
• •high blood pressure or worsening of hypertension,
• •gallbladder disease, occurrence or worsening of gallstones, worsening of symptoms,
• •excessive sebum production, appearance of skin rash,
• •acute or recurrent swelling (angioedema),
• •insomnia, dizziness, anxiety,
• changes in libido,
• vision disturbances,
• weight loss,
• •vomiting,
• heartburn (dyspepsia),
• •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 during the use of other HRT medicines:

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

Reporting side effects

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

5. How to store Trisequens

Keep out of the sight and reach of children. Do not use this medicine after the expiry date stated on the label and carton after "EXP". Store below 25°C. Do not store in the refrigerator. To protect from light, store in the outer packaging. Medicines should not be disposed of via wastewater or household waste. You should ask your pharmacist how to dispose of medicines that are no longer needed. This will help protect the environment.

6. Contents of the packaging 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 (E171), indigo carmine (E132), 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 (E171), iron oxide red (E172), and propylene glycol.

What Trisequens looks like and contents of the pack

Blue film-coated, biconvex tablet with the inscription NOVO 280, 6 mm in diameter. White film-coated, biconvex tablet with the inscription NOVO 281, 6 mm in diameter. Red film-coated, biconvex tablet with the inscription NOVO 282, 6 mm in diameter. Each pack of 28 tablets contains 12 blue tablets, 10 white tablets, and 6 red tablets. Pack sizes:

• 28 film-coated tablets.

Marketing authorization holder and manufacturer

Novo Nordisk A/S Novo Allé 2880 Bagsværd, Denmark.

For more information, contact the local representative of the marketing authorization holder:

Novo Nordisk Pharma Sp. z o.o. Tel.: 22 444 49 00 Fax: 22 444 49 01

Date of last revision of the leaflet:

Other sources of information

Detailed information about this medicine can be found on the website of the Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products: www.urpl.gov.pl.

INSTRUCTIONS FOR THE USER

How to use the calendar pack

1. Setting the day indicator

Turn the inner dial so that the day of the week when treatment starts is 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, 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.