Trisequens coated tablets

Package leaflet: Information for the user

Introduction

PACKAGE LEAFLET: INFORMATION FOR THE USER

Trisequens coated tablets

estradiol / norethisterone acetate

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.

• If you have any questions, ask your doctor or pharmacist.

• This medicine has been prescribed for you. Do not pass it on to others, even if they have the same symptoms as you, as it may harm them.

• If you consider any of the side effects you experience to be serious, or if you notice any side effects not mentioned in this leaflet, inform your doctor or pharmacist. See section 4.

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Contents of the leaflet:

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 combined sequential hormone replacement therapy (HRT) taken every day without interruption. Trisequens is used in postmenopausal women whose last natural menstrual period occurred at least 6 months ago.

Trisequens contains two hormones: an oestrogen (estradiol) and a progestogen (norethisterone acetate). The estradiol in Trisequens is identical to the estradiol produced by a woman's ovaries and is classified as a natural oestrogen. Norethisterone acetate is a synthetic progestogen that acts similarly to progesterone, another important female sex hormone.

Trisequens is used for:

Relieving symptoms occurring after menopause

During menopause, the amount of oestrogens produced by a woman's body decreases. This may cause symptoms such as heat in the face, neck and chest ("hot flushes"). Trisequens relieves these postmenopausal symptoms. Trisequens will only be prescribed to you if these symptoms seriously interfere with your daily life.

Preventing osteoporosis

After menopause, some women may develop fragile bones (osteoporosis). You should discuss with your doctor which treatment options are available.

If you are at increased risk of fractures due to osteoporosis, and no other suitable medications are available to you, Trisequens may be used to prevent postmenopausal osteoporosis.

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

2. What you need to know before starting Trisequens

Medical history and periodic check-ups

The use of HRT carries risks that must be considered before deciding to start or continue taking it.

Experience in treating women with premature menopause (due to ovarian failure or surgical intervention) is limited. If you have premature menopause, the risks of HRT may differ. Consult your doctor.

Before starting (or resuming) HRT, your doctor will ask about your personal and family medical history. They may decide to perform a physical examination, which could include a breast examination or a pelvic exam, if necessary.

Once you have started taking Trisequens, you should attend periodic check-ups (at least once a year). During these visits, you can discuss with your doctor the benefits and risks of continuing treatment with Trisequens.

Have regular breast examinations as recommended by your doctor.

Do not take Trisequens

If any of the following conditions apply to you. If you have any doubts about the points below, ask your doctor before taking Trisequens.

Do not take Trisequens

• if you have, have had, or suspect you may have breast cancer
• if you have, have had, or suspect you may have cancer of the lining of the uterus (endometrial cancer) or another estrogen-dependent cancer
• if you have vaginal bleeding of unknown cause
• if you have excessive thickening of the uterine lining (endometrial hyperplasia) that is not being treated
• if you have or have ever had blood clots in a vein (venous thromboembolism), either in the legs (deep vein thrombosis) or in the lungs (pulmonary embolism)
• if you have a blood clotting disorder (such as protein C, protein S, or antithrombin deficiency)
• if you have or have previously had a heart attack, stroke, or angina (chest pain) causing discomfort, pressure, or pain in the chest
• if you have liver disease and liver function tests have not yet returned to normal
• if you are allergic (hypersensitive) to estradiol, norethisterone acetate, or any of the other components of Trisequens (listed in section 6, Contents of the pack and other information)
• if you have a rare inherited blood disorder called "porphyria"

If any of these conditions occur for the first time while you are taking Trisequens, stop treatment immediately and consult your doctor as soon as possible.

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. If so, you should see your doctor more frequently:

• benign tumors in the uterus (fibroids)
• thickening of the uterine lining (endometriosis) or history of excessive thickening of the uterine lining (endometrial hyperplasia)
• increased risk of blood clot formation (see “Blood clots in a vein (venous thromboembolism)”)
• increased risk of developing estrogen-sensitive cancer (such as having a mother, sister, or paternal or maternal grandmother who had breast cancer)
• high blood pressure
• a liver disorder, such as a benign liver tumor
• diabetes
• gallstones
• migraine or severe headaches
• an autoimmune disease affecting multiple organs (systemic lupus erythematosus or SLE)
• epilepsy
• asthma
• a condition affecting the eardrum and hearing (otosclerosis)
• very high levels of fat in the blood (triglycerides)
• fluid retention due to heart or liver problems
• a hereditary condition causing recurrent episodes of severe swelling (hereditary angioedema), or if you have had episodes of rapid swelling of the hands, face, feet, lips, eyes, tongue, throat (airway obstruction), or digestive tract (acquired angioedema)
• lactose intolerance

Stop treatment with Trisequens and inform your doctor immediately

If you experience any of the following symptoms while taking HRT:

• any of the disorders mentioned in the section Do not take Trisequens
• yellowing of the skin or whites of the eyes (jaundice). These may be symptoms of liver disease
• swelling of the face, tongue, and/or throat and/or difficulty swallowing or hives, along with difficulty breathing, which are symptoms indicative of angioedema
• a significant increase in blood pressure (with symptoms such as headache, fatigue, dizziness)
• migraine-type headache, which may occur for the first time
• if you become pregnant
• if you notice symptoms of a blood clot, such as:
  • swelling with pain and redness in the legs
  • sudden chest pain
  • difficulty breathing

For more information, see Blood clots in a vein (venous thromboembolism).

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 still need to use a contraceptive method to prevent pregnancy. Seek advice from your doctor.

HRT and cancer

Excessive thickening of the uterine lining (endometrial hyperplasia) and cancer of the uterine lining (endometrial cancer)

Estrogen-only HRT increases the risk of excessive thickening of the uterine lining (endometrial hyperplasia) and cancer of the uterine lining (endometrial cancer).

The progestogen in Trisequens protects against this additional risk.

Comparison

In women aged 50 to 65 years with an intact uterus who do not take HRT, an average of 5 cases of endometrial cancer will be diagnosed per 1,000 women.

In women with an intact uterus aged 50 to 65 years who take estrogen-only HRT, between 10 and 60 cases of endometrial cancer will be diagnosed per 1,000 users (i.e., between 5 and 55 additional cases), depending on the dose and duration of treatment.

Unexpected bleeding

You will have a monthly bleed (also called breakthrough bleeding) while taking Trisequens. However, if you experience unexpected bleeding or spotting different from the monthly bleeds that:

• persists beyond the first 6 months
• starts after having taken Trisequens for more than 6 months
• continues after stopping Trisequens

you should contact your doctor as soon as possible.

Breast cancer

Available data show that the use of combined estrogen-progestogen hormone replacement therapy (HRT) or estrogen-only HRT increases the risk of breast cancer. The additional risk depends on how long you use HRT. The additional risk becomes apparent after 3 years of use. After stopping HRT, the additional risk will decrease over time, but the risk may persist for 10 years or more if you have used HRT for more than 5 years.

Comparison

In women aged 50 to 54 years not using HRT, an average of 13 to 17 out of 1,000 will be diagnosed with breast cancer over a 5-year period.

In women aged 50 who start estrogen-only HRT for 5 years, there will be between 16 and 17 cases per 1,000 women users (i.e., between 0 and 3 additional cases).

In women aged 50 who start combined estrogen-progestogen HRT for 5 years, there will be 21 cases per 1,000 women users (i.e., 4 to 8 additional cases).

In women aged 50 to 59 years not taking HRT, an average of 27 cases of breast cancer will be diagnosed per 1,000 women over a 10-year period.

In women aged 50 who start estrogen-only HRT for more than 10 years, there will be 34 cases per 1,000 women users (i.e., 7 additional cases).

In women aged 50 who start combined estrogen-progestogen HRT for 10 years, there will be 48 cases per 1,000 users (i.e., 21 additional cases).

Examine your breasts regularly. See your doctor if you notice any changes, such as:

• skin dimpling
• changes in the nipples
• any lump you can see or feel.

Additionally, it is advisable to participate in breast screening programs when offered.

During breast examinations, it is important to inform your nurse/healthcare professional that you are taking HRT when undergoing an X-ray examination, as this medication may increase breast density, which can affect the results of a mammogram. When breast density is higher, a mammogram may not detect all lumps.

Ovarian cancer

Ovarian cancer is less common than breast cancer. The use of estrogen-only HRT or combined estrogen-progestogen HRT has been associated with a slightly increased risk of ovarian cancer.

The risk of ovarian cancer varies with age. For example, in women aged 50 to 54 years not using HRT, about 2 cases of ovarian cancer are observed per 2,000 women over a 5-year period. In women receiving HRT for 5 years, about 3 cases per 2,000 patients are observed (i.e., about 1 additional case).

Effect of HRT on the heart and circulation

Blood clots in a vein (venous thromboembolism)

The risk of blood clots in veins is approximately 1.3 to 3 times higher in HRT users than in non-users, especially during the first year.

Blood clots can be serious, and if one reaches the lungs, it can cause chest pain, difficulty breathing, fainting, or even death.

The likelihood of developing blood clots in veins increases with age and if any of the following factors apply. If any of these situations may apply to you, inform your doctor:

• if you are unable to walk for a prolonged period due to major surgery, injury, or illness (see also section 3, If you need surgery)
• if you are significantly overweight (BMI > 30 kg/m²)
• if you have a blood clotting disorder requiring long-term anticoagulant treatment
• if a close relative has ever had a blood clot in the legs, lungs, or other organs
• if you have systemic lupus erythematosus (SLE)
• if you have cancer

For symptoms of a blood clot, see the section Stop treatment with Trisequens and inform your doctor immediately.

Comparison

It is estimated that, over a 5-year period, an average of 4 to 7 out of 1,000 women in their fifties not taking HRT will suffer a blood clot in a vein.

In women in their fifties taking combined estrogen-progestogen HRT for 5 years, there will be between 9 and 12 cases per 1,000 users (i.e., 5 additional cases).

Heart disease (myocardial infarction)

HRT has not been shown to prevent myocardial infarction.

Women over 60 years of age using combined estrogen-progestogen HRT have a slightly higher risk of developing heart disease than those not taking HRT.

Stroke

The risk of stroke is approximately 1.5 times higher in HRT users than in non-users. The number of additional stroke cases due to HRT use will increase with age.

Comparison

It is estimated that, over a 5-year period, on average 8 out of 1,000 women in their fifties not taking HRT will suffer a stroke.

In women in their fifties taking HRT, the number of cases will be 11 per 1,000 users over a 5-year period (i.e., 3 additional cases).

Other conditions

HRT does not prevent memory loss. An increased risk of memory loss has been reported in women who started HRT after age 65. Seek advice from your doctor.

Use of other medicines

Some medicines may interfere with the effect of Trisequens. This may cause irregular bleeding. These medicines include:

• Medicines for epilepsy (such as phenobarbital, phenytoin, and carbamazepine)

• Medicines for tuberculosis (such as rifampicin and rifabutin)

• Medicines for HIV infection (such as nevirapine, efavirenz, ritonavir, and nelfinavir)

• Medicines for hepatitis C infection (such as telaprevir)

• Herbal preparations containing St. John's wort (Hypericum perforatum)

HRT may affect the function of certain medicines:

• Medicine for epilepsy (lamotrigine), as it may increase the frequency of seizures

• Medicines for hepatitis C virus (HCV) (such as the combination regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir, and the regimen with glecaprevir/pibrentasvir) may cause increases in liver function blood test results (increase in liver enzyme ALT) in women using combined hormonal contraceptives (CHCs) containing ethinylestradiol. Trisequens contains estradiol instead of ethinylestradiol. It is unknown whether an increase in liver enzyme ALT may occur when using Trisequens with this HCV combination regimen.

Other medicines may increase the effects of Trisequens:

• Medicines containing ketoconazole (an antifungal)

Trisequens may affect concomitant treatment with cyclosporine.

Inform your doctor or pharmacist if you are taking or have recently taken any other medicines. This also applies to over-the-counter medicines, medicines purchased in another country, herbal remedies, high-potency vitamins and minerals, and dietary supplements. Your doctor will advise you.

Laboratory tests

If you need a blood test, inform your doctor or laboratory staff that you are taking Trisequens, as this medicine may alter the results of certain laboratory parameters.

Taking Trisequens with food and drinks

The tablets can be taken with or without food or drinks.

Pregnancy and breastfeeding

Pregnancy: Do not take Trisequens if you are pregnant. Trisequens should only be used in postmenopausal women. If you become pregnant, stop taking Trisequens, discontinue treatment, and contact your doctor.

Breastfeeding:

Do not take Trisequens if you are breastfeeding.

Driving and use of machines

Trisequens has no known effects on the ability to drive or use machines.

Important information about some of the ingredients of Trisequens

This medicine contains lactose monohydrate. If you have an intolerance to certain sugars, consult your doctor before taking Trisequens.

Trisequens tablets contain sodium. Trisequens tablets contain less than 1 mmol of sodium (23 mg) per tablet; this is essentially “sodium-free”.

3. HOW TO TAKE TRISEQUENS

Follow exactly the instructions for using this medicine as given by your doctor. If in doubt, consult your doctor or pharmacist.

If you are not switching from another hormone replacement therapy (HRT) product, you may start treatment with Trisequens on any convenient day. If you are switching from another HRT product, ask your doctor when you should start treatment with Trisequens.

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

Each pack contains 28 tablets.

Days 1 to 12: Take one blue tablet each day for 12 days.

Days 13 to 22: Take one white tablet each day for 10 days.

Days 23 to 28: Take one red tablet each day for 6 days.

Take the tablet with a glass of water.

When you have finished a pack, start a new one immediately to continue treatment without interruption. You will usually have a withdrawal bleed similar to menstruation (period) when you begin a new pack.

For further information on how to use the calendar pack, see DIRECTIONS FOR USE at the end of this leaflet.

Your doctor will aim to prescribe the lowest effective dose for the shortest possible duration that provides symptom relief. Speak with your doctor if you think the dose is too high or too low.

Talk to your doctor if you do not experience symptom relief after 3 months of treatment. Treatment should only be continued as long as benefits outweigh the risks.

If you take more Trisequens than you should

If you have taken more Trisequens than prescribed, consult a doctor or pharmacist. An overdose of Trisequens may cause nausea or vomiting.

In case of overdose or accidental ingestion, contact your doctor or pharmacist immediately or call the Toxicology Information Service at telephone number 91562 04 20, indicating the medicine and the amount ingested.

If you forget to take Trisequens

If you have forgotten to take your tablet at the usual time, take it within the next 12 hours. If more than 12 hours have passed, take the next tablet at the usual time the following day. Do not take a double dose to make up for the missed dose.

Missing a dose may increase the likelihood of breakthrough bleeding or spotting.

If you stop taking Trisequens

If you wish to stop treatment with Trisequens, speak to your doctor first. Your doctor will explain the effects of stopping treatment and discuss other options with you.

If you have any further questions about using this medicine, ask your doctor or pharmacist.

If you are undergoing surgery

If you are scheduled for surgery, inform your surgeon that you are taking Trisequens. You may need to stop taking Trisequens 4 to 6 weeks before the operation to reduce the risk of blood clots (see section 2, Blood clots in a vein (venous thromboembolism)). Ask your doctor when you can resume taking Trisequens.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them.

The following disorders have been reported more frequently in women using HRT compared to women who do not use HRT:

• breast cancer
• abnormal growth or cancer of the lining of the womb (endometrial hyperplasia or endometrial cancer)
• ovarian cancer
• blood clots in the veins of the legs or lungs (venous thromboembolism)
• heart disease
• stroke
• possible memory loss if HRT is started after the age of 65.

For more information about these adverse effects, see section 2, What you need to know before taking Trisequens.

Hypersensitivity/allergy (uncommon adverse effect – affects 1 to 10 users in 1,000)

Although uncommon, hypersensitivity/allergic reactions may occur. Signs of hypersensitivity/allergy may include one or more of the following symptoms: hives, itching, swelling, difficulty breathing, decreased blood pressure (pallor and skin cooling, increased heart rate), dizziness and sweating, which may be signs of an anaphylactic reaction or anaphylactic shock. If any of these symptoms occur, stop taking Trisequens and seek immediate medical help.

Very common adverse effects

• Breast pain or tenderness
• Irregular periods or excessive bleeding during periods

Common adverse effects

• Headache
• Weight gain due to fluid retention
• Vaginal inflammation
• Fungal vaginal infection
• Migraine, new onset or worsening of existing migraine
• Depression, new onset or worsening of existing depression
• Nausea
• Abdominal pain, swelling or discomfort
• Breast enlargement or swelling (mammary edema)
• Back pain
• Leg cramps
• Worsening, onset or recurrence of uterine fibroids (benign tumour)
• Swelling of arms and legs (peripheral edema)
• Weight gain

Uncommon adverse effects

• Flatulence or bloating
• Acne
• Hair loss (alopecia)
• Abnormal (male-pattern) hair growth
• Itching or hives (urticaria)
• Inflammation of a vein (superficial thrombophlebitis)
• Lack of therapeutic effect
• Allergic reaction
• Endometrial hyperplasia (excessive thickening of the lining of the womb)
• Painful periods
• Nervousness

Rare adverse effects

• Pulmonary embolism (blood clot) (see Blood clots in a vein in section 2, What you need to know before taking Trisequens)
• Deep vein inflammation associated with thrombosis (blood clot)

Very rare adverse effects

• Cancer of the lining of the womb (endometrial cancer)
• Increased blood pressure or worsening of existing hypertension
• Gallbladder disease, gallstones which may be new onset, recurrence or worsening of existing condition
• Excessive sebum secretion, skin eruption
• Acute or recurrent swelling (angioneurotic edema)
• Insomnia, dizziness, anxiety
• Changes in sexual desire
• Vision disturbances
• Weight loss
• Vomiting
• Gastric acidity
• Vaginal and genital itching
• Myocardial infarction and stroke

The frequency categories of the possible adverse effects listed above are defined 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 1,000)
Rare (affects 1 to 10 users in 10,000)
Very rare (affects less than 1 in 10,000 users)
Frequency not known (cannot be estimated from available data)

Other adverse effects of combined HRT

The following adverse reactions have been reported with other HRT products:

• various skin disorders:
  • skin pigmentation, especially on the face and neck, known as “pregnancy mask” (chloasma)
  • red, painful skin nodules (erythema nodosum)
  • rash with ulcers or red, target-like lesions (polymorphic erythema)

Reporting of adverse effects

If you experience any adverse effect, talk to your doctor or pharmacist, even if it is a possible adverse effect not listed in this leaflet. You can also report them directly via the Spanish Pharmacovigilance System for Human Medicines: http://www.notificaRAM.es.

By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of TRISEQUENS®

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date stated on the packaging after “EXP”. The expiry date refers to the last day of the month indicated.

Store below 25°C. Do not refrigerate.

Keep the container in the outer carton to protect it from light.

Medicines must not be disposed of via wastewater or household waste. Dispose of unused medicines and their containers at the SIGRE collection point at your pharmacy. If you are unsure, please ask your pharmacist how to properly dispose of unused medicines and their containers. This will help protect the environment.

6. Contents of the pack and other information

What Trisequens contains

• The active substances are estradiol and norethisterone acetate.

The blue coated tablets contain: estradiol 2 mg (as estradiol hemihydrate)
The white tablets contain: estradiol 2 mg (as estradiol hemihydrate) and norethisterone acetate 1 mg
The red tablets contain: estradiol 1 mg (as estradiol hemihydrate)

• The other ingredients are: monohydrate lactose, corn starch, hydroxypropylcellulose, talc, and magnesium stearate
• The coating of the blue tablets contains: hypromellose, talc, titanium dioxide (E171), indigo carmine (E132), and macrogol 400.

The coating of the white tablets contains: hypromellose, triacetin, and talc.

The coating of the red tablets contains: hypromellose, talc, titanium dioxide (E171), red iron oxide (E172), and propylene glycol.

Appearance of the product and contents of the pack

The film-coated tablets are round with a diameter of 6 mm. The blue tablets are marked with NOVO 280. The white tablets are marked with NOVO 281. The red tablets are marked with NOVO 282.

Each 28-tablet pack contains 12 blue tablets, 10 white tablets, and 6 red tablets.

Presentations:

• 28 film-coated tablets.
• 3 x 28 film-coated tablets.

Only certain pack sizes may be marketed.

Marketing Authorization Holder

ISDIN, S.A.
Provençals, 33
08019 Barcelona
Spain

Manufacturer

Novo Nordisk A/S
Novo Allé
DK-2880 Bagsvaerd
Denmark

Date of the most recent revision of this leaflet: December 2023

Other sources of information

“Detailed and up-to-date information on this medicine is available on the website of the Spanish Agency of Medicines and Health Products (AEMPS) http://www.aemps.gob.es/"

DIRECTIONS FOR USE

How to use the calendar blister pack

1. Set the day indicator

Rotate the inner disc to align the day of the week with the opening sealed by a plastic tab.

2. How to remove the first tablet

Break the plastic tab and remove the first tablet.

3. Move the dial each day

Simply rotate the transparent disc one position clockwise, as indicated by the arrow. Then remove the next tablet. Remember to take only 1 tablet per day.

The transparent disc can only be advanced after the corresponding tablet has been removed.