Trisequens

Package leaflet: Information for the user

Warning! Keep this leaflet! Information on the immediate packaging in a foreign language.
Trisequens
2 mg (blue), 2 mg + 1 mg (white), 1 mg (red), coated tablets
estradiol + norethisterone acetate
Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, please ask your doctor or pharmacist.
• This medicine has been prescribed for a specific person. Do not pass it on to others. It may harm them even if their symptoms are the same.
• If you experience any side effects, including any not listed in this leaflet, please inform your doctor or pharmacist. See section 4.

Leaflet contents

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

• to relieve symptoms occurring after menopause During menopause, the amount of oestrogens produced in a woman's body decreases, which may cause symptoms such as hot flushes affecting the face, neck, and chest. Trisequens relieves these postmenopausal symptoms. Trisequens may be prescribed only if symptoms significantly interfere with daily life;
• to prevent osteoporosis After menopause, some women develop brittle bones (osteoporosis). All available treatment 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 may be used to prevent postmenopausal osteoporosis.

Experience with treatment in women over 65 years of age is limited.

2. Important information before using Trisequens

Medical history and regular medical examinations
Hormone replacement therapy (HRT) carries certain risks that should be considered when a woman decides whether to start or continue HRT.
Experience in treating women during premature menopause (due to ovarian failure or surgical intervention) is limited. If a woman experiences premature menopause, the risks associated with HRT may differ. Discuss this with your doctor.
Before starting (or resuming) HRT, your doctor should take a full medical and family history. Your doctor may decide to perform examinations, including breast and/or gynecological examination, if necessary.
If you start taking Trisequens, you should have regular medical check-ups (at least once a year). During these visits, you should discuss with your doctor the benefits and risks of continuing Trisequens.
You should have regular breast examinations as recommended by your doctor.

When not to use Trisequens
If any of the conditions listed below apply to you or if you are unsure, you must inform 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, have had, or suspect breast cancer;
• you have been diagnosed with, have had, or suspect endometrial cancer (cancer of the lining of the womb) or any other estrogen-dependent tumor;
• you have unexplained vaginal bleeding;
• you have excessive growth of the lining of the womb (endometrial hyperplasia) that has not been treated;
• you have or have had blood clots in the veins (venous thromboembolism), such as deep vein thrombosis in the legs or pulmonary embolism in the lungs;
• you have blood clotting disorders (such as protein C deficiency, protein S deficiency, or antithrombin deficiency);
• you have or have had arterial blood clotting disorders such as heart attack, stroke, or angina pectoris;
• you have liver disease, and liver function tests have not returned to normal;
• you have the rare inherited blood disorder porphyria.

If any of the above conditions occurs for the first time while taking Trisequens, stop taking the medicine immediately and consult your doctor.

Warnings and precautions
Before starting treatment, inform your doctor if you have ever had any of the following conditions, as they may recur or worsen during treatment with Trisequens. In such cases, your doctor may decide that you require more frequent monitoring:

• fibroids (uterine myomas),
• endometriosis (growth of the endometrial tissue outside the uterus) or a history of endometrial hyperplasia,
• conditions that increase the risk of blood clots (see Blood clots in the veins (venous thromboembolic disease)),
• conditions that increase the risk of estrogen-dependent cancers (such as breast cancer in your mother, sister, or grandmother),
• high blood pressure,
• liver disease, e.g. benign liver tumor,
• diabetes,
• gallstones,
• migraine or severe headaches,
• systemic lupus erythematosus (an autoimmune disease affecting multiple organs),
• epilepsy,
• asthma,
• otosclerosis (a progressive hearing loss due to ear disease),
• high levels of fat (triglycerides) in the blood,
• fluid retention due to heart or kidney problems,
• hereditary tendency to recurrent episodes of severe swelling (hereditary angioedema) or if you have experienced episodes of sudden swelling of the face, lips, tongue, throat (airway obstruction), hands, feet, or gastrointestinal tract (acquired angioedema),
• lactose intolerance.

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

• if any of the conditions listed under When not to use Trisequens occur,
• if your skin or the whites of your eyes turn yellow (jaundice), which may indicate liver problems,
• if you develop swelling of the face, tongue, and/or throat, and/or difficulty swallowing or hives, together with difficulty breathing, which may indicate angioedema,
• if you develop significantly high blood pressure (symptoms may include headache, fatigue, and dizziness),
• if you experience a new onset of migraine-type headache,
• if pregnancy is diagnosed,
• if you develop symptoms of a blood clot such as:
• painful swelling and redness in the legs,
• sudden chest pain,
• difficulty breathing. For further information, see Blood clots in the veins (venous thromboembolic disease).

Note: Trisequens is not a contraceptive. If less than 12 months have passed since your last menstrual period, or if you are under 50 years of age, you may need to use an additional method of contraception. Please discuss this with your doctor.

HRT and cancer

Endometrial hyperplasia and endometrial cancer
Taking estrogen-only HRT increases the risk of endometrial hyperplasia (excessive growth of the lining of the womb) and endometrial cancer.
The progestogen in Trisequens helps reduce this additional risk.

Comparison
Among women aged 50 to 65 with an intact uterus who do not use HRT, an average of 5 out of 1,000 will be diagnosed with endometrial cancer.
Among women aged 50 to 65 with an intact uterus who take estrogen-only HRT, depending on the duration of treatment and estrogen dose, between 10 and 60 out of 1,000 women will be diagnosed with endometrial cancer (i.e. 5 to 55 additional cases).

Unexpected bleeding
While taking Trisequens, you will have a monthly bleed (withdrawal bleeding). However, if you experience additional unexpected bleeding or spotting that:

• persists beyond the first 6 months of treatment,
• occurs after more than 6 months of taking Trisequens,
• continues after stopping Trisequens,
  you should contact your doctor as soon as possible.

Breast cancer
Evidence confirms that taking hormone replacement therapy (HRT), either estrogen-progestogen combination or estrogen-only, increases the risk of developing breast cancer. The additional risk depends on how long you take HRT. This additional risk becomes apparent after 3 years of HRT use. After stopping HRT, the additional risk gradually decreases, but may persist for 10 years or longer if HRT was used for more than 5 years.

Comparison
Among women aged 50 to 54 who do not use HRT, breast cancer will be diagnosed in an average of 13 to 17 out of 1,000 women over 5 years.
Among women aged 50 who start a 5-year course of estrogen-only HRT, the number of cases will be 16–17 per 1,000 women (i.e. 0 to 3 additional cases).
Among women aged 50 who start a 5-year course of estrogen-progestogen HRT, the number of cases will be 21 per 1,000 women (i.e. 4 to 8 additional cases).
Among women aged 50 to 59 who do not use HRT, breast cancer will be diagnosed in an average of 27 out of 1,000 women over 10 years.
Among women aged 50 who start a 10-year course of estrogen-only HRT, the number of cases will be 34 per 1,000 women (i.e. 7 additional cases).
Among women aged 50 who start a 10-year course of estrogen-progestogen HRT, the number of cases will be 48 per 1,000 women (i.e. 21 additional cases).

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

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

Additionally, screening mammograms are recommended as advised by your doctor. Before the examination, inform the nurse or radiology technician performing the X-ray that you are taking hormone replacement therapy, as this medicine may increase breast density, which could affect the mammogram results. Not all lumps may be detected during mammography in areas of increased breast density.

Ovarian cancer
Ovarian cancer is rare—much rarer than breast cancer. Taking HRT, whether estrogen-only or combined estrogen-progestogen, is associated with a slightly increased risk of ovarian cancer.
The risk of ovarian cancer depends on age. For example, among women aged 50 to 54 who do not use HRT, ovarian cancer will be diagnosed in about 2 out of 2,000 women over 5 years. Among women who have used HRT for 5 years, it will occur in about 3 out of 2,000 women (i.e. about 1 additional case).

Effects of HRT on the heart and circulation

Blood clots in the veins (venous thromboembolic disease)
The risk of venous blood clots is 1.3 to 3 times higher in women taking HRT compared to non-users, especially during the first year of use.
Blood clots can be life-threatening; if they travel to the lungs, they may cause chest pain, shortness of breath, loss of consciousness, or even death.
The risk of venous blood clots is higher if you are older or if you have any of the following risk factors. Inform your doctor if:

• you are unable to walk for a prolonged period due to major surgery, injury, or illness (see section 3. If surgery is planned);
• you are obese (body mass index - BMI > 30 kg/m²);
• you have thromboembolic disorders requiring long-term anticoagulant therapy;
• a close family member 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 blood clots, see If any of the following conditions occur while taking HRT, you must stop taking Trisequens and contact your doctor immediately.

Comparison
Among women aged 50 to 59 who do not use HRT, the number of venous blood clot cases over 5 years is estimated at 4 to 7 per 1,000 women.
Among women aged 50 to 59 taking estrogen-progestogen HRT, the number of cases over 5 years is 9 to 12 per 1,000 women (i.e. 5 additional cases).

Coronary heart disease (heart attack)
There is no evidence that HRT helps prevent heart attacks.
Women over 60 years of age taking estrogen-progestogen HRT have a slightly higher risk of developing coronary heart disease compared to non-users.

Ischemic stroke
The risk of ischemic stroke is about 1.5 times higher in women taking HRT compared to non-users. The number of additional stroke cases due to HRT use increases with age.

Comparison
Among women aged 50 to 59 who do not use HRT, the average number of stroke cases over 5 years is estimated at 8 per 1,000 women.
Among women aged 50 to 59 taking HRT, the number of cases over 5 years is 11 per 1,000 women (i.e. 3 additional cases).

Other conditions
HRT does not prevent memory loss. The risk of memory loss may be somewhat higher in women who start HRT after age 65. In such cases, consult your doctor.

Trisequens and other medicines
Some medicines may affect the effectiveness of Trisequens, which could lead to irregular bleeding. These include:

• antiepileptic drugs (such as: phenobarbital, phenytoin, and carbamazepine);
• antituberculosis drugs (such as: rifampicin and rifabutin);
• drugs used in HIV infection (such as: nevirapine, efavirenz, ritonavir, and nelfinavir);
• drugs used in 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 seizure frequency;
• drugs used in hepatitis C virus (HCV) treatment (e.g. the combination regimen of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, or the glecaprevir/pibrentasvir regimen) may cause increased liver function blood test results (increased liver enzyme AlAT activity) in women taking combined hormonal contraceptives containing ethinylestradiol. Trisequens contains estradiol, not ethinylestradiol. It is unknown whether increased AlAT activity may occur when Trisequens is used together with these HCV combination therapies.

Other medicines that may increase the effect of Trisequens:

• medicines containing ketoconazole (an antifungal agent).

Trisequens may affect concomitant treatment with cyclosporine.

Tell your doctor or pharmacist about all medicines you are currently taking or have recently taken, as well as any medicines you plan to take, including over-the-counter medicines, herbal remedies, or other natural products. Your doctor will advise you accordingly.

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

Taking Trisequens with food and drink
Tablets may be taken with or without food and drink.

Pregnancy and breastfeeding
Pregnancy: Trisequens is intended for use only in postmenopausal women. If pregnancy occurs, stop taking Trisequens immediately and contact your doctor.
Breastfeeding: Do not take Trisequens while breastfeeding.

Driving and operating machinery
The effect of Trisequens on driving or operating machinery is unknown.

Important information about some ingredients of Trisequens
Trisequens contains monohydrate lactose. If you have been diagnosed with an intolerance to certain sugars, consult your doctor before taking Trisequens.

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

3. How to use Trisequens

This medicine should always be taken according to the doctor's instructions. If in doubt, consult
your doctor or pharmacist.
For women who have not previously used any other hormonal replacement therapy, treatment with
Trisequens may be started on any day. Women currently using another hormonal replacement
therapy should contact their doctor to determine the appropriate time to start treatment with
Trisequens.
Take one tablet daily, at approximately the same time each 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.
Tablets should be taken with water.
After finishing a pack, continue treatment without a break by starting the next pack immediately.
Bleeding similar to menstruation (a period) usually occurs during the days when red tablets are taken.
Instructions for using the calendar pack can be found at the end of this leaflet, in the section
entitled “INSTRUCTIONS FOR THE USER”.
The doctor should prescribe the lowest effective dose for the shortest duration necessary to relieve
symptoms. If the patient feels the dose is too high or too low, she should consult her doctor.
Inform the doctor if satisfactory symptom relief has not been achieved after 3 months of treatment.
Treatment should continue only as long as the benefits outweigh the risks.
Taking more Trisequens than recommended
If more Trisequens has been taken than recommended, consult your doctor or pharmacist.
Overdose of Trisequens may cause nausea or vomiting.
Missing a dose of Trisequens
If a tablet has been missed at the usual time, it should be taken within the next 12 hours. If more than
12 hours have passed, take the next dose at the usual time the following day. Do not take a double
dose to make up for a missed dose.
Missing a dose may increase the likelihood of breakthrough bleeding or spotting.
Stopping Trisequens
If you wish to stop taking Trisequens, inform your doctor. He or she will explain the consequences of
stopping treatment and discuss alternative therapies.
If you have any further questions about the use of this medicine, consult your doctor or pharmacist.
If surgery is planned
If surgery is planned, the patient should inform the surgeon that she is taking Trisequens. It may be
necessary to stop taking Trisequens 4 to 6 weeks before surgery to reduce the risk of blood clots (see
section 2. Blood clots in the veins (venous thromboembolic disease)). Before restarting Trisequens,
consult your doctor.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
Women using hormone replacement therapy (HRT) have an increased risk of developing the following conditions compared to women not using HRT:

• breast cancer;
• overgrowth or cancer of the lining of the womb (endometrial hyperplasia or cancer);
• ovarian cancer;
• blood clots in the veins of the legs or lungs (venous thromboembolic disease);
• coronary heart disease;
• stroke;
• possible memory loss if HRT is started after the age of 65. For further information, see section 2. "Important information before taking Trisequens".

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

Very common adverse reactions:

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

Common adverse reactions:

• headache,
• weight gain due to fluid retention,
• vaginal inflammation,
• fungal vaginal infection, onset or worsening of migraine, onset or worsening of depression, nausea, abdominal pain, bloating or discomfort in the abdominal cavity, enlargement or swelling of the breasts, back pain, muscle cramps in the lower limbs, uterine fibroids (benign uterine tumours), worsening, onset or recurrence, swelling of hands and feet (peripheral oedema), weight gain.

Uncommon adverse reactions:

• bloating or flatulence,
• acneiform changes,
• hair loss (alopecia),
• abnormal hair growth (male-pattern),
• itching or urticaria,
• inflammation of veins (superficial thrombophlebitis),
• reduced effectiveness of the medicine,
• allergic reaction,
• endometrial hyperplasia (overgrowth of the lining of the womb),
• painful periods,
• nervousness.

Rare adverse reactions:

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

Very rare adverse reactions:

• cancer of the lining of the womb (endometrial cancer),
• high blood pressure or worsening of existing hypertension,
• gallbladder disease, development or recurrence of gallstones, worsening of symptoms,
• excessive sebum secretion, skin rash,
• acute or recurrent swelling (angioedema),
• insomnia, dizziness, restlessness,
• changes in sexual desire,
• visual disturbances,
• weight loss,
• vomiting,
• heartburn (dyspepsia),
• itching of the vagina and vulva,
• myocardial infarction and stroke,
• generalized allergic reactions (anaphylactic reaction, anaphylactic shock).

The frequency of the possible adverse reactions listed above is defined 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)
not known (frequency cannot be estimated from available data).

Other adverse reactions associated with combined HRT
The following adverse reactions have been reported during use of other HRT medicines:

• various skin disorders:
• skin discolouration, especially on the face or neck, known as "pregnancy mask" (chloasma),
• red, tender nodules (erythema nodosum),
• skin rash, including erythematous-oedematous ring-shaped lesions (erythema multiforme).

Reporting of adverse reactions
If any adverse reactions occur, including any not listed in this leaflet, inform your doctor or pharmacist. Adverse reactions can be reported directly to the Department of Monitoring Adverse Reactions of Medicinal Products at the 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.
Reporting adverse reactions helps 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 stated month.
Store below 25°C. Do not store in the refrigerator. Keep 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 what to do with medicines no longer in use. This will help protect the environment.

6. Contents of the pack and other information

What Trisequens contains

• The active substances in this medicine are estradiol and norethisterone acetate.
• The blue coated tablet contains 2 mg of estradiol (as estradiol hemihydrate).
• The white coated tablet contains 2 mg of estradiol (as estradiol hemihydrate) and 1 mg of norethisterone acetate.
• The red coated tablet contains 1 mg of estradiol (as estradiol hemihydrate).
• Other ingredients are: monohydrate lactose, corn starch, hydroxypropylcellulose, talc, and magnesium stearate.
• The coating of the blue tablet contains: hypromellose, talc, titanium dioxide (E 171), indigo carmine (E 132), and polyethylene glycol 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 the engraved code NOVO 280, 6 mm in diameter.
White, film-coated, biconvex tablet with the engraved code NOVO 281, 6 mm in diameter.
Red, film-coated, biconvex tablet with the engraved code NOVO 282, 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 blister pack made of polypropylene/polystyrene,
in a cardboard box.
For more detailed information, please contact the marketing authorisation holder or the parallel importer.
Marketing authorisation holder in Belgium, country of export:
Novo Nordisk Pharma, Boulevard International(e)laan 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, Poland
Repackaged in:
InPharm Sp. z o.o. Services sp. k., ul. Chełmżyńska 249, 04-458 Warsaw, Poland
Marketing authorisation number in Belgium, country of export: BE156134
Parallel import authorisation number: 29/20
Translation of the weekday symbols adjacent to each tablet in the immediate 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

USER INSTRUCTION
How to use the calendar pack

1. Setting the day indicator
Rotate the inner dial to align the day of the week on which treatment begins with the small plastic flap.

2. Taking the first tablet
Break open the plastic flap and remove the first tablet.

3. Moving the dial each day
The next day, rotate the transparent dial clockwise by one position, as indicated by the arrow. Remove the next tablet. Remember to take only one tablet per day.
The transparent section can only be rotated after the tablet located in the opening has been removed.