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), coated tablets
Estradiol + Norethisterone acetate
Please read the entire leaflet carefully before using this medicine, as it contains
important information for the patient.

• Keep this leaflet, as 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 individual. Do not pass it on to others. It may harm them even if their symptoms are the same.
• If you experience any adverse effects, including any not listed in this leaflet, inform your doctor, pharmacist, or nurse. See section 4.

Leaflet contents:

1. What Trisequens is and what it is used for
2. What you need to know before taking Trisequens
3. How to take Trisequens
4. Possible side effects
5. 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 a continuous 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 naturally 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 oestrogen produced by a woman's body decreases, which may cause symptoms such as sudden feelings of heat in the face, neck, and chest (‘hot flushes’). Trisequens relieves these postmenopausal symptoms. Trisequens may be recommended only if these symptoms significantly interfere with daily life;
For prevention of 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 treatments 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 risks that should be considered when a woman decides whether to start or continue HRT.
Experience with treating women who experience premature menopause (due to ovarian failure or surgical intervention) is limited. If a woman experiences premature menopause, the risks associated with HRT may differ. Please 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 tests, including a breast examination 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 treatment.
You should have regular breast examinations, as recommended by your doctor.

When not to use Trisequens
If any of the conditions listed below apply, 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 cancer;
• you have unexplained vaginal bleeding;
• you have excessive growth of the lining of the womb (endometrial hyperplasia) that is untreated;
• you have been diagnosed with, or have had in the past, blood clots in the veins (venous thromboembolic disease), e.g. in the legs (deep vein thrombosis) or lungs (pulmonary embolism);
• you have a blood clotting disorder (such as protein C, protein S or antithrombin deficiency);
• you have been diagnosed with, or have had in the past, arterial blood clotting disorders such as heart attack, stroke, or angina pectoris;
• you have liver disease and liver function test results have not returned to normal;
• you have a rare, inherited blood disorder – porphyria.

If any of the above conditions occur for the first time while taking Trisequens, you must stop taking the medicine 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:

• uterine fibroids (myomas),
• endometriosis (growth of the womb lining outside the uterus) or a history of endometrial hyperplasia,
• factors increasing the risk of blood clots (see Blood clots in the veins (venous thromboembolic disease)),
• factors increasing the risk of estrogen-dependent cancers (such as breast cancer in mother, sister, or grandmother),
• high blood pressure,
• liver disease, e.g. benign liver tumour,
• diabetes,
• gallstones,
• migraine or severe headaches,
• an autoimmune disease affecting multiple organs (systemic lupus erythematosus),
• epilepsy,
• asthma,
• a disease of the ear leading to progressive hearing loss (otosclerosis),
• high levels of fats (triglycerides) in the blood,
• fluid retention due to impaired heart or kidney function,
• hereditary tendency to recurrent episodes of severe swelling (hereditary angioedema) or if you have experienced episodes of sudden swelling of the hands, face, feet, lips, eyes, tongue, throat (airway obstruction), 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 breathing difficulties, indicating angioedema,
• if you develop significantly increased blood pressure (symptoms may include headache, fatigue, and dizziness),
• if you experience a new migraine-type headache,
• if pregnancy is diagnosed,
• if you experience symptoms of blood clots 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 excessive growth of the lining of the womb (endometrial hyperplasia) and endometrial cancer.
The progestagen in Trisequens helps reduce this additional risk.

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

Unexpected bleeding
While taking Trisequens, monthly bleeding (called withdrawal bleeding) occurs. However, if additional unexpected bleeding or spotting occurs 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 combined with progestagen or estrogen alone, increases the risk of developing breast cancer. The additional risk depends on how long HRT is taken. 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 taken for more than 5 years.

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

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

• skin indentation,
• 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 may 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 containing only estrogens or a combination of estrogens and progestagens 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 years not taking HRT, ovarian cancer will be diagnosed in about 2 in 2,000 women over 5 years. Among women who have taken HRT for 5 years, it will occur in about 3 in 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.
Venous 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 any of the following risk factors apply. 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 symptoms of blood clots occur, see If any of the following conditions occur while taking HRT, stop taking Trisequens and contact your doctor immediately.

Comparison
Among women aged 50 to 59 years not taking 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 years taking estrogen-progestagen HRT, the number of cases over 5 years will be 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-progestagen HRT have a slightly increased risk of developing coronary heart disease compared to women not taking HRT.

Ischemic stroke
The risk of 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 will increase with age.

Comparison
Among women aged 50 to 59 years not taking HRT, the average number of stroke cases over 5 years is estimated at 8 per 1,000 women.
Among women aged 50 to 59 years taking HRT, the number of cases over 5 years will be 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 may 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 the treatment of 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 (HCV; e.g. the combination regimen of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, or the regimen of glecaprevir/pibrentasvir) may increase blood test results for liver function (increased activity of the liver enzyme AlAT) in women taking combined hormonal contraceptives containing ethinylestradiol. Trisequens contains estradiol, not ethinylestradiol. It is unknown whether increased AlAT enzyme activity may occur when Trisequens is used together with these HCV combination regimens.

Other medicines that may increase the effect of Trisequens:

• medicines containing ketoconazole (an antifungal agent).

Trisequens may affect concomitant treatment with cyclosporine.
You must 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 using machines
The effect of Trisequens on driving or operating machinery is unknown.

Important information about certain ingredients of Trisequens
Trisequens contains monohydrate lactose. If you have been diagnosed with an intolerance to certain sugars, you should 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 take Trisequens

This medicine should always be taken as directed by your doctor. If in doubt, consult your doctor or pharmacist.
Women who have not previously used any other hormonal replacement therapy may start taking Trisequens on any day. Women currently using another hormonal replacement therapy should consult 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, starting the next pack immediately. Bleeding similar to menstruation (a period) usually occurs during the intake of the red tablets.
Instructions for using the calendar pack are provided at the end of this leaflet, in the section entitled “USER INSTRUCTIONS”.
Your doctor should prescribe the lowest effective dose for the shortest duration necessary to relieve symptoms. If you feel the dose is too high or too low, consult your doctor.
Inform your doctor if symptoms have not improved satisfactorily after 3 months of treatment. Treatment should continue only as long as the benefits outweigh the risks.
Taking more Trisequens than recommended
If you take more Trisequens than recommended, contact your doctor or pharmacist immediately. Overdose of Trisequens may cause nausea or vomiting.
Missed dose of Trisequens
If you forget to take a tablet at your usual time, take it within the next 12 hours. If more than 12 hours have passed, take the next tablet at your 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 you are scheduled for surgery, inform your surgeon that you are 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. Venous thromboembolism (blood clots in veins)). Consult your doctor before restarting Trisequens after surgery.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
In women using HRT, there is an increased risk of developing the following diseases 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;
• possibly 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 from 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 and seek medical help immediately.

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,
• occurrence or worsening of migraine,
• occurrence or worsening of depression,
• nausea,
• abdominal pain, bloating or discomfort in the abdominal cavity,
• breast enlargement or swelling,
• back pain,
• muscle cramps in the lower limbs,
• uterine fibroids (benign uterine tumours), worsening, occurrence 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 (venous thromboembolic disease) 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 hypertension,
• gallbladder disease, occurrence 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 (indigestion),
• 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 the use of other HRT medicines:

• various skin disorders:
  • skin pigmentation, especially on the face or neck, known as "chloasma" (melasma),
  • 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 adverse reactions not listed in this leaflet, inform your doctor, pharmacist or nurse. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products,
Al. Jerozolimskie 181C, 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 to provide more information on the safety of this medicine.

5. How to store Trisequens

Keep the medicine out of 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 must 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 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 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 coated, biconvex tablet with the engraved code NOVO 280, 6 mm in diameter.
White coated, biconvex tablet with the engraved code NOVO 281, 6 mm in diameter.
Red coated, biconvex tablet with the engraved code NOVO 282, 6 mm in diameter.
Each 28-tablet pack contains 12 blue tablets, 10 white tablets and 6 red tablets.
Available pack sizes:
28 coated tablets

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 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
Poland

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

Marketing Authorisation number in Belgium, country of export: BE156134
Parallel Import Authorisation number: 138/19

Translation of weekday abbreviations appearing 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

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. Removing 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 part can only be rotated after removing the tablet located in the opening.