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 the patient experiences any side effects, including any not listed in this leaflet, they should tell their doctor, pharmacist, or nurse. See section 4.

Table of Contents of the Leaflet:

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

1. What Trisequens is and what it is 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 alleviates 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 a 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 taking Trisequens

Medical history and regular medical examinations

Taking HRT involves risks that should be considered when a patient decides to take hormone replacement therapy or continue it.
Experience in 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, 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 taking Trisequens, they should regularly visit their doctor for check-ups (at least once a year). During these check-ups, they should discuss with their doctor the benefits and risks of continuing to take Trisequens.
The patient should regularly undergo breast examinations, as recommended by their doctor.

When not to take Trisequens

In case of any of the following conditions or in case of doubt, inform your doctor before taking Trisequens.
Do not start taking Trisequens if:

• the patient is 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);
• breast cancer has been diagnosed, has occurred in the past, or is suspected;
• endometrial cancer (cancer of the lining of the uterus) or other estrogen-dependent tumors have been diagnosed, have occurred in the past, or are suspected;
• there is unusual vaginal bleeding;
• there is endometrial hyperplasia(excessive thickening of the lining of the uterus) and it is not being treated;
• blood clots in the veins (venous thromboembolism), 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 tests have not returned to normal;
• a rare, inherited blood disorder, porphyria, is present.

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

Warnings and precautions

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

• uterine fibroids (fibroids),
• endometriosis (growth of endometrial tissue outside the uterus) or endometrial hyperplasia 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 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 (an immune system disorder that affects multiple organs),
• epilepsy,
• asthma,
• otosclerosis (a condition that causes progressive hearing loss),
• high levels of triglycerides in the blood,
• fluid retention due to heart or kidney problems,
• hereditary angioedema (a rare, inherited condition that causes recurring episodes of severe swelling) or if there have been episodes of swelling related to angioedema,
• lactose intolerance.

If any of the following conditions occur while taking HRT, stop taking Trisequens and consult your doctor immediately:

• if any of the conditions listed in the "When not to take Trisequens" section occur,
• if the skin or whites of the eyes turn yellow (jaundice), which may be a sign of liver problems,
• if there is swelling of the face, tongue, and/or throat, 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 confirmed,
• if there are 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 the last menstrual period or the patient is under 50 years old, additional contraceptive methods may be necessary. Consult a doctor.

HRT and cancer

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

Taking 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 who do not take HRT and have a uterus, endometrial cancer is diagnosed in approximately 5 out of 1000 women.
In women aged 50-65 who take only estrogens in HRT, the number of cases of endometrial cancer diagnosed ranges from 10 to 60 per 1000 women, depending on the duration of treatment and the dose of estrogens taken (i.e., 5-55 additional cases).

Unexpected bleeding

While taking Trisequens, 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 taking Trisequens for more than 6 months,
• continues after stopping Trisequens, consult a doctor as soon as possible.

Breast cancer

Data confirm that taking combined estrogen-progestogen HRT or estrogen-only HRT increases the risk of breast cancer. The additional risk depends on how long the patient takes HRT. This additional risk becomes apparent after 3 years of HRT. 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 take HRT, breast cancer is diagnosed in approximately 13-17 out of 1000 women over 5 years.
In women aged 50 who start 5-year estrogen-only HRT, the number of cases of breast cancer diagnosed will be 16-17 per 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 per 1000 patients (i.e., 4-8 additional cases).
In women aged 50-59 who do not take HRT, breast cancer is diagnosed in approximately 27 out of 1000 women over 10 years.
In women aged 50 who start 10-year estrogen-only HRT, the number of cases of breast cancer diagnosed 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 of breast cancer diagnosed will be 48 per 1000 patients (i.e., 21 additional cases).

Regular breast examinations are recommended. Consult a doctor if any of the following changes are noticed:

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

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

Ovarian cancer

Ovarian cancer is rare, much rarer than breast cancer. Taking HRT that includes only estrogens or a combination of estrogens and progestogens is associated with a slightly increased risk of ovarian cancer.
Risk of ovarian cancer depends on age. For example, in women aged 50-54 who do not take HRT, ovarian cancer is diagnosed in approximately 2 out of 2000 women over 5 years. In women who took HRT for 5 years, it occurs in approximately 3 out of 2000 women (i.e., about 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 times higher in women taking HRT compared to those not taking it, especially in the first year of treatment.
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 has any of the following factors. Inform your doctor if:

• the patient is unable to walk for a long time due to major surgery, injury, or illness (see section 3. If surgery is planned);
• obesity is present (body mass index (BMI) > 30 kg/m²);
• there are blood clotting disorders that require long-term treatment with anticoagulants;
• any close relative has had blood clots in the legs, lungs, or other organs;
• systemic lupus erythematosus is present;
• the patient has been diagnosed with cancer.

If symptoms of a blood clot occur, see If any of the following conditions occur while taking HRT, stop taking Trisequens and consult your doctor immediately.
Comparison
In women aged 50-59 who do not take HRT, the estimated number of cases of blood clots in the veins over 5 years is 4-7 per 1000 women.
In women aged 50-59 who take combined estrogen-progestogen HRT, the number of cases over 5 years is estimated to be 9-12 per 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 taking combined estrogen-progestogen HRT, there is a slightly increased risk of developing coronary artery disease compared to those not taking HRT.

Stroke

The risk of stroke is approximately 1.5 times higher in women taking HRT compared to those not taking it. The number of additional stroke cases due to HRT will increase with age.
Comparison
In women aged 50-59 who do not take HRT, the estimated number of stroke cases over 5 years is 8 per 1000 women.
In women aged 50-59 who take HRT, the number of cases over 5 years is estimated to 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 after the age of 65. In such cases, consult a doctor.

Trisequens and other medicines

Certain medicines may affect the efficacy of Trisequens, leading 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 glecaprevir/pibrentasvir) may cause increased liver enzyme levels in women taking combined hormonal contraceptives containing ethinyl estradiol. Trisequens contains estradiol, not ethinyl estradiol. It is not known whether Trisequens, when taken with this combination HCV treatment, may increase liver enzyme levels.

Other medicines that may increase the effect of Trisequens:

• medicines containing ketoconazole(an antifungal medicine).

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

Laboratory tests

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

Taking 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 in postmenopausal women only. If pregnancy is confirmed, stop taking Trisequens and consult a doctor.
Breastfeeding:do 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 of the ingredients of Trisequens

Trisequens contains lactose monohydrate. If you have been diagnosed with 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 the medicine is essentially "sodium-free".

3. How to take Trisequens

Always take this medicine exactly as your doctor has told you. If you are not sure, check with your doctor or pharmacist.
In women who are not taking any other hormone replacement therapy, treatment with Trisequens can be started on any day. Women who are currently taking another hormone replacement therapy should consult their doctor to determine when to start Trisequens.

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

Each pack contains 28 tablets.
Days 1 – 12
Take one bluetablet daily for 12 days.
Days 13 – 22
Take one whitetablet daily for 10 days.
Days 23 – 28
Take one redtablet daily for 6 days.
Swallow the tablets with water.
After finishing a pack, continue treatment without interruption by starting the next pack.
While taking the red tablets, bleeding usually occurs, similar to a menstrual period (withdrawal bleeding).
Instructions for using the calendar pack are at the end of this leaflet, in the section titled "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 is too high or too low, consult your doctor.
Tell your doctor if satisfactory relief of symptoms is not achieved 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 your doctor or pharmacist. Overdose of Trisequens may cause nausea or vomiting.

If you forget to take Trisequens

If you miss a tablet, 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 treatment

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

If surgery is planned

If you are going to have surgery, tell your surgeon that you are taking Trisequens. It may be necessary to stop taking 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.
In women taking HRT, there is an increased risk of developing the following conditions compared to women not taking HRT:

• breast cancer;
• endometrial hyperplasia or cancer (excessive thickening 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 after the age of 65. For more information, see section 2. Important information before taking Trisequens.

Hypersensitivity (allergic reaction); uncommon side effect – affects 1 to 10 users 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 may be symptoms of anaphylaxis 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 menstrual bleeding.

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,
• leg cramps,
• uterine fibroids (benign tumors of the uterus), worsening, occurrence, or recurrence,
• peripheral edema (swelling of hands and feet),
• 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 thickening of the lining of the uterus),
• painful periods,
• nervousness.

Rare side effects:

• pulmonary embolism (blood clot in the lungs). See Blood clots in the veins (venous thromboembolism)in section 2. Important information before taking Trisequens,
• deep vein thrombosis with pulmonary embolism (blood clot in the lungs).

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, or worsening of symptoms,
• •excessive oiliness of the skin, appearance of acne,
• •acute or recurrent angioedema (allergic reaction),
• •insomnia, dizziness, anxiety,
• changes in libido,
• vision disturbances,
• weight loss,
• •vomiting,
• heartburn (indigestion),
• •vaginal or vulvar itching,
• •heart attack and stroke,
• •generalized allergic reactions (anaphylaxis, anaphylactic shock).

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

Other side effects of combined HRT

The following side effects have been reported in users of other HRT medicines:

• various skin disorders:
• skin discolorations, especially on the face or neck, known as "pregnancy patches" (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, tell your doctor, pharmacist, or nurse. Side effects can be reported directly to the Department of Drug Safety, Urząd Rejestracji Produktów Leczniczych, Wyrobów Medycznych i Produktów Biobójczych,
Al. Jerozolimskie 181C, 02-222 Warszawa, Tel.: + 48 22 49 21 301, Faks: + 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 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 below 25°C.
Do not store in a refrigerator.
Store the calendar pack in the outer packaging to protect from light.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. 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, maize starch, 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 of 28 tablets contains 12 blue tablets, 10 white tablets, and 6 red tablets.
Pack sizes available:
28 film-coated tablets
For more detailed information, consult 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 Bagsvaerd
Denmark

Parallel importer:

Delfarma Sp. z o.o.
ul. Św. Teresy od Dzieciątka Jezus 111
91-222 Łódź

Repackaged by:

Delfarma Sp. z o.o.
ul. Św. Teresy od Dzieciątka Jezus 111
91-222 Łódź
Belgian Marketing Authorization Number: BE156134

Parallel import authorization number: 138/19

Translation of day abbreviations on the calendar pack:

M L M

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

Date of revision of the leaflet: 04.03.2024

[Information about the trademark]

INSTRUCTIONS FOR THE USER

How to use the calendar pack

1. Setting the day pointer

Turn the inner dial so that the day of the week when treatment starts is opposite the small plastic tab.

2. Removing the first tablet

Break off the plastic tab 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.