TRISEQUENS FILM-COATED TABLETS - patient leaflet, side effects, dosage

1. what trisequens® is and what it is used for

Trisequens® is a sequential combined Hormone Replacement Therapy (HRT) which is taken every day without interruption.

Trisequens® is used in postmenopausal women with at least 6 months since their last natural period.

Trisequens® contains 2 hormones, an oestrogen (estradiol) and a progestagen (norethisterone acetate). The estradiol in Trisequens® is identical to the estradiol produced in the ovaries of women, and is classified as a natural oestrogen. Norethisterone acetate is a synthetic progestagen, which acts in a similar manner as progesterone, another important female sex hormone.

Trisequens® is used for:

Relief of symptoms occurring after menopause

During the menopause, the amount of the oestrogen produced by a woman’s body drops. This can cause symptoms such as hot face, neck and chest (‘hot flushes’). Trisequens® alleviates these symptoms after menopause. You will only be prescribed Trisequens® if your symptoms seriously hinder your daily life.

Prevention of osteoporosis

After the menopause some women may develop fragile bones (osteoporosis). You should discuss all available options with your doctor.

If you are at an increased risk of fractures due to osteoporosis and other medicines are not suitable for you, you can use Trisequens® to prevent osteoporosis after menopause.

The experience of treating women older than 65 years is limited.

2. what you need to know before you take trisequens® medical history and regular check-ups

The use of HRT carries risks which need to be considered when deciding whether to start taking it, or whether to carry on taking it. The experience in treating women with a premature menopause (due to ovarian failure or surgery) is limited. If you have a premature menopause, the risks of using HRT may be different. Please talk to your doctor.

Before you start (or restart) HRT, your doctor will ask about your own and your family’s medical history. Your doctor may decide to perform a physical examination. This may include an examination of your breasts and/or an internal examination, if necessary.

Once you have started on Trisequens®, you should see your doctor for regular check-ups (at least once a year). At these checkups, discuss with your doctor the benefits and risks of continuing with Trisequens®.

Go for regular breast screening, as recommended by your doctor.

Do not take Trisequens®

If any of the following applies to you. If you are not sure about any of the points below, talk to your doctor before taking Trisequens®. Do not take Trisequens®:

• if you have, have had or suspect having breast cancer
• if you have, have had or suspect having cancer of the womb lining (endometrial cancer) or any other oestrogen dependent cancer
• if you have any unexplained vaginal bleeding
• if you have excessive thickening of the womb lining (endometrial hyperplasia) that is not being treated
• if you have or have ever had

a blood clot in a vein (venous thromboembolism), such as in the legs (deep venous thrombosis) or the lungs (pulmonary embolism)

• if you have a blood clotting disorder (such as protein C, protein S or antithrombin deficiency)
• if you have or previously have had a disease caused by blood clots in the arteries, such as

a heart attack, stroke or angina

• if you have or have ever had a liver disease and your liver function tests have not returned to normal
• 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)
• if you have a rare blood problem called ‘porphyria’ which is passed down in families (inherited).

If any of the above conditions appear for the first time while taking Trisequens®, stop taking it at once and consult your doctor immediately.

Warnings and precautions

Tell your doctor if you have ever had any of the following problems, before you start the treatment, as these may return or become worse during treatment with Trisequens®. If so, you should see your doctor more often for check-ups:

• fibroids inside your womb
• growth of womb lining outside your womb (endometriosis) or a history of excessive growth of the womb lining (endometrial hyperplasia)
• increased risk of developing blood clots (see Blood clots in a vein (venous thromboembolism))
• increased risk of getting an oestrogen-sensitive cancer (such as having a mother, sister or grandmother who has had breast cancer)
• high blood pressure
• a liver disorder, such as a benign liver tumour
• diabetes
• gallstones
• migraine or severe headaches
• a disease of the immune system that affects many organs of the body (systemic lupus erythematosus, SLE)
• epilepsy
• asthma
• a disease affecting the eardrum and hearing (otosclerosis)
• a very high level of fat in your blood (triglycerides)
• fluid retention due to cardiac or kidney problems
• hereditary and acquired angioedema
• lactose intolerance.

Stop taking Trisequens® and see a doctor immediately

If you notice any of the following when taking HRT:

• any of the conditions mentioned in the Do not take Trisequens® section
• yellowing of your skin or the whites of your eyes (jaundice). These may be signs of a liver disease
• swollen face, tongue and/or throat and/or difficulty swallowing or hives, together with difficulty breathing which are suggestive of an angioedema

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• a large rise in your blood pressure (symptoms may be headache, tiredness and dizziness)
• migraine-like headaches which happen for the first time
• if you become pregnant
• if you notice signs of a blood clot, such as:

• – painful swelling and redness of the legs

• – sudden chest pain

• – difficulty in breathing.

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

Note: Trisequens® is not a contraceptive. If it is less than 12 months since your last menstrual period or you are under 50 years old, you may still need to use additional contraception to prevent pregnancy. Speak to your doctor for advice.

HRT and cancer

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

Taking oestrogen-only HRT will increase the risk of excessive thickening of the lining of the womb (endometrial hyperplasia) and cancer of the womb lining (endometrial cancer).

The progestagen in Trisequens® protects you from this extra risk.

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In women who still have a womb and who are not taking HRT, on average, 5 in 1,000 will be diagnosed with endometrial cancer between the ages of 50 and 65.

For women aged 50 to 65 who still have a womb and who take

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Unexpected bleeding

You will have a bleed once a month (so-called withdrawal bleed) while taking Trisequens®. But if you have unexpected bleeding or drops of blood (spotting) besides your monthly bleeding which:

• carries on for more than the first 6 months
• starts after you have been taking Trisequens® more than 6 months
• carries on after you have stopped taking Trisequens®

see your doctor as soon as possible.

Breast cancer

Evidence shows that taking combined oestrogen-progestagen or oestrogen-only hormone replacement therapy (HRT) increases the risk of breast cancer. The extra risk depends on how long you use HRT. The additional risk becomes clear within 3 years of use. After stopping HRT the extra risk will decrease with time, but the risk may persist for 10 years or more if you have used HRT for more than 5 years.

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Women aged 50 to 54 who are not taking HRT, on average, 13 to 17 in 1,000 will be diagnosed with breast cancer over a 5-year period.

For women aged 50 who start taking oestrogen-only HRT for 5 years, there will be 16–17 cases in 1,000 users (i.e. an extra 0 to 3 cases).

For women aged 50 who start taking oestrogen-progestagen HRT for 5 years, there will be 21 cases in 1,000 users (i.e. an extra 4 to 8 cases).

Women aged 50 to 59 who are not taking HRT, on average, 27 in 1,000 will be diagnosed with breast cancer over a 10-year period.

For women aged 50 who start taking oestrogen-only HRT for 10 years, there will be 34 cases in 1,000 users (i.e. an extra 7 cases). For women aged 50 who start taking oestrogen-progestagen HRT for 10 years, there will be 48 cases in 1,000 users (i.e. an extra 21 cases).

Regularly check your breasts. See your doctor if you notice any changes such as:

• dimpling of the skin
• changes in the nipple
• any lumps you can see or feel.

Additionally, you are advised to join mammography screening programs when offered to you. For mammogram screening, it is important that you inform the nurse/healthcare professional who is actually taking the x-ray that you use HRT, as this medication may increase the density of your breasts which may affect the outcome of the mammogram. Where the density of the breast is increased, mammography may not detect all lumps.

Ovarian cancer

Ovarian cancer is rare – much rarer than breast cancer. The use of oestrogen-only or combined oestrogen-progestagen 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 who are not taking HRT, about 2 women in 2,000 will be diagnosed with ovarian cancer over a 5-year period. For women who have been taking HRT for 5 years, there will be about

3 cases per 2,000 users (i.e. about 1 extra case).

Effect of HRT on heart and circulation

Blood clots in a vein (venous thromboembolism)

The risk of blood clots in the veins is about 1.3 to 3 times higher in HRT users than in nonusers, especially during the first year of taking it.

Blood clots can be serious, and if one travels to the lungs, it can cause chest pain, breathlessness, fainting or even death.

• You are more likely to get a blood clot in your veins as you get older and if any of the following applies to you. Inform your doctor if any of these situations applies to you: you are unable to walk for a long time because of major surgery, injury or illness (see section 3, If you need to have surgery)
• you are seriously overweight (BMI > 30 kg/m2)
• you have any blood clotting problem that needs long-term treatment with a medicine used to prevent blood clots
• if any of your close relatives has ever had a blood clot in the leg, lung or another organ
• you have systemic lupus erythematosus (SLE)
• you have cancer.

For signs of a blood clot, see Stop taking Trisequens® and see a doctor immediately.

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Looking at women in their 50s who are not taking HRT, on average, over a 5-year period, 4 to 7 in 1,000 would be expected to get a blood clot in a vein.

For women in their 50s who have been taking oestrogen-progestagen HRT for over 5 years, there will be 9 to 12 cases in 1,000 users (i.e. an extra 5 cases).

Heart disease (heart attack) There is no evidence that HRT will prevent a heart attack.

Women over the age of 60 years who use oestrogen-progestagen HRT are slightly more likely to develop heart disease than those not taking any HRT.

Stroke

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

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Looking at women in their 50s who are not taking HRT, on average, 8 in 1,000 would be expected to have a stroke over a 5-year period. For women in their 50s who are taking HRT, there will be 11 cases in 1,000 users over 5 years (i.e. an extra 3 cases).

Other conditions

HRT will not prevent memory loss. There is some evidence of a higher risk of memory loss in women who start using HRT after the age of 65. Speak to your doctor for advice.

Using other medicines

Some medicines may interfere with the effect of Trisequens®. This might lead to irregular bleeding. This applies to the following medicines:

• 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)
• Herbal remedies containing

St John’s Wort (Hypericum perforatum ).

Other medicines may increase the effects of Trisequens®:

• Medicines containing ketoconazole (a fungicide).

Trisequens® may have an impact on a concomitant treatment with cyclosporine.

Medicines for Hepatitis C virus (HCV) (such as combination regimen ombitasvir/pa­ritaprevir/ri­tonavir with or without dasabuvir as well as a regimen with glecaprevir/ pibrentasvir) may cause increases in liver function blood test results (increase in ALT liver enzyme) in women using Combined Hormonal Contraceptives (CHCs) containing ethinylestradiol. Trisequens contains estradiol instead of ethinylestradiol. It is not known whether an increase in ALT liver enzyme can occur when using Trisequens with this HCV combination regimen. Your doctor will advise you.

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines including medicines obtained without a prescription, herbal medicines or other natural products.

3. How to take Trisequens®

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are unsure.

If you are not switching from another hormone replacement therapy, you can start treatment with Trisequens® on any convenient day. If you are switching from another hormone replacement therapy, ask your doctor when you should start treatment with Trisequens®.

4. Possible side effects

Like all medicines, this medicine can have side effects, although not everybody gets them.

5. how to store trisequens® keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date, which is stated on the label and carton.

6. contents of the pack and other information

What Trisequens® contains

• – The active substances are estradiol and norethisterone acetate.

The blue film-coated tablet contains: estradiol 2 mg (as estradiol hemihydrate). The white film-coated tablet contains: estradiol 2 mg (as estradiol hemihydrate) and norethisterone acetate 1 mg. The red film-coated tablet contains: estradiol 1 mg (as estradiol hemihydrate).

What Trisequens® looks like and contents of the pack

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

NOVO 282. Each pack of 28 tablets contains 12 blue tablets, 10 white tablets and 6 red tablets.

How to use the calendar pack

1. Set the day reminder

Turn the inner disc to set the day of the week opposite the little plastic tab.

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