Package Leaflet: Information for the User

Duofemme Film-Coated Tablets

estradiol/noretisterone acetate

Read this leaflet carefully before you start taking this medicine because

it contains important information for you.

- Keep this leaflet, as you may need to read it again.

- If you are unsure about anything, ask your doctor or pharmacist.

- This medicine has been prescribed for you, and you should not give it to others even if they have

the same symptoms as you, as it may harm them.

- If you experience any side effects, consult your doctor or pharmacist, even if they are not

listed in this leaflet. See section 4

1. What Duofemme is and what it is used for

2. What you need to know before taking Duofemme

3. How to take Duofemme

4. Possible side effects

5. Storage of Duofemme

6. Contents of the pack and additional information

Duofemme is a combined sequential Hormone Replacement Therapy (HRT) that is taken every day without interruption. Duofemme is used in postmenopausal women who have had their last natural period at least 6 months ago.

Duofemme contains 2 hormones, an estrogen (estradiol) and a progestogen (noretisterone acetate). Estradiol in Duofemme is identical to the estradiol produced in the ovaries of women, and is classified as a natural estrogen. Noretisterone acetate is a synthetic progestogen that acts in a similar way to progesterone, another important female sex hormone.

Duofemme is indicated for:

Relief of symptoms that occur after menopause

During menopause, the amount of estrogens produced by women decreases. This can cause symptoms such as hot flashes in the face, neck, and chest.

Duofemme relieves these symptoms after menopause. Duofemme will only be prescribed if symptoms seriously hinder your daily life.

Prevention of osteoporosis

After menopause, some women may develop fragile bones (osteoporosis).

You should consult with your doctor about all possible options.

If you have a high risk of fractures due to osteoporosis and cannot use other medications for this purpose, you may use Duofemme to prevent osteoporosis after menopause.

Experience in treating women over 65 years old is limited.

Medical History and Regular Check-Ups:

The use of THS involves risks that must be evaluated before starting treatment or if it should be continued.

The experience in treating women with premature menopause (due to ovarian insufficiency or surgery) is limited. If you have premature menopause, the risks of using THS may be different. Consult your doctor.

Before starting (or restarting) THS, your doctor will ask about your medical history and that of your family. Your doctor may decide to perform a physical examination. This may include a breast examination and/or internal examination, if necessary.

Once you have started taking Duofemme, you must visit your doctor for regular medical check-ups (at least once a year). In these medical check-ups, your doctor will treat the benefits and risks of continuing treatment with Duofemme.

Regularly attend a breast medical review, recommended by your doctor.

Do not take Duofemme

If you are affected by any of the following situations. If you are unsure about any of the points indicated below, consult your doctor before taking Duofemme.

Do not take Duofemme:

• If you have or have hadbreast cancer, or if you suspect you may have it

• If you have or have hadendometrial cancer(cancer of the cells that line the uterus), or if you suspect you may have it

• If you experienceunexpected vaginal bleeding

• If you haveexcessive thickening of the cells that line the uterus(endometrial hyperplasia) that is not being treated

• If you have or have hadblood clots in a vein (venous thromboembolism), in the legs (deep vein thrombosis) or lungs (pulmonary embolism)

• If you have acoagulation disorder(such as deficiency of protein C, S or antithrombin)

• If you have or have had a disease previously caused by blood clots in the arteries, such as heart attack, stroke or angina.

• If you have or have hadany liver diseaseand your liver function tests have not returned to normal

• If you areallergic(hypersensitive) to estradiol, noretisterone acetate or to any other ingredient of Duofemme (see section 6 Package Leaflet and Additional Information)

• If you havea rare hereditary blood disorder called porphyria

If any of the conditions mentioned above appear for the first time while taking Duofemme, stop taking it and consult your doctor immediately.

Warnings and Precautions

Inform your doctor if you have ever had any of the following problems, before starting treatment, as they may recur or worsen during treatment with Duofemme. If so, you must visit your doctor more often for check-ups:

• Fibroids inside the uterus

• Growth of cells that line the uterus outside the uterus (endometriosis) or excessive growth of cells that line the uterus (endometrial hyperplasia)

• High risk of developing blood clots (see "blood clots in a vein (venous thromboembolism)")

• High risk of having a cancer related to estrogen (if you have a mother, sister or grandmother who has had breast cancer)

• High blood pressure

• A liver disorder, such as a benign liver tumor

• Diabetes

• Gallstones

• Migraine or severe headaches

• A disease of the immune system that affects many organs of the body (lupus erythematosus, LES)

• Epilepsy

• Asthma

• A disease that affects the eardrum and ear (otosclerosis)

• If you have high levels of fat in the blood (triglycerides)

• Fluid retention due to heart or kidney problems

• A condition where your thyroid gland does not produce enough thyroid hormone (hypothyroidism) and you are taking thyroid hormone replacement therapy

• A hereditary condition that causes recurrent episodes of severe inflammation (hereditary angioedema) or if you have had episodes of rapid inflammation of the hands, face, feet, lips, eyes, tongue, throat (obstruction of the airways) or digestive tract (acquired angioedema)

• Lactose intolerance

Stop taking Duofemme and contact your doctor immediately

if you experience any of the following situations when taking THS:

• Any of the conditions mentioned in the section "Do not take Duofemme"

• Yellowing of the skin or white eyes (jaundice). These may be signs of liver disease

• Swelling of the face, tongue and/or throat and/or difficulty swallowing or urticaria, along with difficulty breathing, which are indicative symptoms of angioedema

• A significant increase in your blood pressure (symptoms may include headache, fatigue and dizziness)

• Migraine-type headache for the first time

• If you become pregnant

• If you notice signs of a blood clot such as:

• Inflammation with pain and redness of the legs,

• Sudden chest pain

• Difficulty breathing

For more information, see "blood clots in a vein (venous thromboembolism)"

Note: Duofemme is not a contraceptive. If it has been less than 12 months since your last menstrual period or you are under 50 years old, it may be necessary to use a contraceptive to prevent pregnancy. Consult your doctor.

THS and Cancer

Endometrial hyperplasia and endometrial cancer

If you take THS exclusively with estrogen, you will increase the risk of excessive thickening of the uterine lining (endometrial hyperplasia) and endometrial cancer.

The progestogen in Duofemme protects you from this additional risk.

Comparison

In women aged 50-65 with an intact uterus who do not take THS, the average number of new cases of endometrial cancer could be 5 per 1000 users.

In women aged 50-65 with an intact uterus who take THS only with estrogens, between 10 and 60 of every 1000 users will be diagnosed with endometrial cancer depending on the dose and duration of treatment (between 5 and 55 additional cases).

Unexpected bleeding

You will have bleeding once a month (called withdrawal bleeding) while taking Duofemme. But if you have unexpected bleeding and blood loss (staining) in addition to the monthly bleeding, that:

• Continues for more than the first 6 months

• Starts after 6 months of taking Duofemme

• Or continues after stopping treatment with Duofemme

Inform your doctor as soon as possible.

Breast cancer

The existing data show that the use of hormone replacement therapy (HRT) with estrogen-progestogen combinations or with only estrogens increases the risk of breast cancer. The additional risk depends on the time 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 50-54 who are not using HRT, an average of 13-17 of every 1000 will be diagnosed with breast cancer in a 5-year period.

In women aged 50 who start HRT with only estrogens for 5 years, there will be between 16 and 17 cases per 1000 users (i.e. between 0 and 3 additional cases). In women aged 50 who start taking HRT with estrogen-progestogen for 5 years, there will be between 21 per 1000 users (i.e. between 4 and 8 additional cases).

In women aged 50-59 who are not taking HRT, an average of 27 cases of breast cancer will be diagnosed per 1000 women in a 10-year period.

In women aged 50 who start HRT with only estrogens for 10 years, there will be 34 cases per 1000 users (i.e. 7 additional cases).

In women aged 50 who start HRT with estrogen-progestogen for 10 years, there will be 48 cases per 1000 users (i.e. 21 additional cases).

Examine your breasts regularly. Visit your doctor if you detect any changes such as:

• Skin creases

• Changes in the nipple

• Any lump that you can see or feel

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

In breast screening, it is essential to inform your nurse/healthcare professional that you are taking HRT when they perform the X-ray examination, as this medication may increase the density of the breasts, which may affect the result of the mammogram. When the breast density is higher, it may be that the mammogram does not detect all lumps.

Ovarian cancer

Ovarian cancer occurs less frequently than breast cancer. The use of HRT with estrogens alone or with a combination of estrogens-progestogens has been associated with a slightly higher risk of ovarian cancer.

The risk of ovarian cancer varies with age. For example, in women aged 50-54 who are not taking HRT, there are approximately 2 cases of ovarian cancer per 2000 women in a 5-year period. In women taking HRT for 5 years, there are approximately 3 cases per 2000 patients (i.e. approximately 1 additional case).

Effect of HRT on the heart and circulation

Vein blood clots (venous thromboembolism)

The risk ofvein blood clotsis approximately 1.3 to 3 times higher in HRT users than in non-users, especially in the first year of taking it.

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

You are more likely to develop blood clots if you are older and if any of the following factors intervene. Inform your doctor if you experience any of the following situations:

• You cannot walk for a long time due to surgery, injury or illness (see also section 3, "If you need surgery")

• You have significant obesity (BMI >30 kg/m²)

• You have a coagulation disorder that requires prolonged treatment with a medication to prevent blood clots

• If you have a close relative who has ever had a blood clot in the legs, lungs or other organs

•You have lupus erythematosus (LES)

•You have cancer.

In case of signs of blood clots, see "Stop taking Duofemme" and visit your doctor immediately.

Comparison

In women aged 50 who are not taking HRT, 4-7 per 1000 will suffer from a vein blood clot during a 5-year period.

In women aged 50 who take HRT with estrogen-progestogen, there will be 9-12 cases per 1000 users during a 5-year period (up to 5 additional cases).

Heart disease (heart attack)

There is no evidence that HRT prevents heart attacks. In women over 60 who use HRT with estrogen/progestogen, there is a slightly higher risk of developing heart disease than in those who do not take HRT.

Stroke

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

Comparison

In women aged 50 who are not taking HRT, an average of 8 per 1000 will suffer from a stroke during a 5-year period.

In women aged 50 who take HRT, there will be 11 cases per 1000 users during a 5-year period (up to 3 additional cases).

Other conditions

HRT does not prevent memory loss. There is some evidence of a higher risk of memory loss in women who start taking HRT after the age of 65. Inform your doctor.

Use of other medications

Some medications may interfere with the effect of Duofemme.

This may lead to irregular bleeding. This applies to the following medications:

• Medications forepilepsy(such as phenobarbital, phenytoin and carbamazepine)

• Medications fortuberculosis(such as rifampicin and rifabutin)

• Medications forHIV infection(such as nevirapine, efavirenz, ritonavir and nelfinavir)

• Medications for hepatitis C infections (such as telaprevir)

• Herbal products containingSt. John's Wort(Hypericum perforatum)

HRT may affect the functioning of certain medications:

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

• Medications for hepatitis C virus (HCV) (such as the combination regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir, as well as a regimen with glecaprevir/pibrentasvir) may cause increases in liver function test results (elevation of the liver enzyme ALT) in women taking combined hormonal contraceptives (CHCs) that contain ethinylestradiol. Duofemme contains estradiol instead of ethinylestradiol. It is unknown whether this may cause an increase in liver enzyme ALT when taking Duofemme with this HCV combination regimen.

Other medications may increase the effects of Duofemme:

• Medications containingketoconazole(an antifungal)

Duofemme may interact with a concomitant treatment with ciclosporin.

Inform your doctor or pharmacistif you are taking or have recently taken any other medication, including those acquired without a prescription, herbal medicines or other natural products. Your doctor will advise you.

Clinical tests

If you require a blood test, inform your doctor that you are taking Duofemme, as this medication may affect the results of some tests.

Taking Duofemme with food and drinks

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

Pregnancy and breastfeeding

Pregnancy: Duofemme is only for postmenopausal women. If you are pregnant, stop taking Duofemme immediately and contact your doctor.

Breastfeeding: Do not take Duofemme if you are breastfeeding.

Driving and operating machinery

Duofemme has no known effect on the ability to drive or operate machinery.

Important information about some of the components of Duofemme

Duofemme contains lactose monohydrate. If your doctor has told you that you have a intolerance to certain sugars, consult him before taking this medication.

Take this medicine exactly as your doctor tells you to. Consult your doctor or pharmacist if you have any doubts.

If you are not taking any other hormone replacement therapy, you can start taking Duofemme on the day you consider convenient. If you are already taking another type of hormone replacement therapy, your doctor will tell you when to start taking Duofemme.

You will take one tablet once a day, approximately at the same time every day.

Each box contains 28 tablets

Days 1-16Take a red tablet every day for 16 daysevery day for 16 days

Days 17-28Take a white tablet every day for 12 daysevery day for 12 days

Take the tablets with a glass of water.

Once you have finished the box, start a new one and continue the treatment without interruption.

A normal menstrual period (period) usually occurs at the beginning of a new box.

For more information on the use of the calendar disc, see "INSTRUCTIONS FOR USE" at the end of the prospectus.

Your doctor will prescribe the lowest dose to treat your symptoms for the shortest period of time necessary.

Consult your doctor if you do not show an improvement after 3 months of treatment. You should only continue treatment when the benefits outweigh the risks.

If you take more Duofemme than you should

If you have taken more Duofemme than you should, consult your doctor or pharmacist. A hormone overdose can cause breast tenderness, nausea, vomiting, and/or irregular vaginal bleeding (metrorrhagia). A progestogen overdose can lead to depression, fatigue, acne, and facial or body hair growth (hirsutism).

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicological Information Service, phone 915 620 420, indicating the medicine and the amount ingested.

If you forget to take Duofemme

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

Forgetting to take a tablet may increase the likelihood of intermittent bleeding and spotting.

If you interrupt the treatment with Duofemme

If you want to stop taking Duofemme, first talk to your doctor. Your doctor will explain the effects of interrupting treatment and other options for you.

If you have any other questions about the use of this medicine, ask your doctor or pharmacist.

If you need to undergo surgery

If you are going to have surgery, inform the surgeon that you are taking Duofemme. You may need to stop taking Duofemme approximately 4 to 6 weeks before the operation to reduce the risk of a blood clot (see section 2, "blood clots in a vein (venous thromboembolism). Ask your doctor when you can start taking Duofemme again.

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

Some diseases occur more often in women using TSH compared to women who do not use TSH:

• breast cancer

• abnormal growth or cancer of the lining of the uterus (endometrial hyperplasia or cancer)

• ovarian cancer

• blood clots in the veins of the legs or lungs (venous thromboembolism)

• heart disease

• stroke

• probable loss of memory if TSH is started after the age of 65

To get more information about these side effects, see section 2, "What you need to know before using Duofemme".

Hypersensitivity/allergy (infrequent side effect that affects between 1 and 10 users per 1000)

Although it is an infrequent side effect, it can occur: The signs of hypersensitivity/allergy may include one or more of the following symptoms: urticaria, itching, swelling, difficulty breathing, low blood pressure (pale skin and cold skin, rapid heart rate), feeling of dizziness, sweating, which can be signs of anaphylactic shock. If one of the mentioned symptoms appears, interrupt the treatment with Duofemme and seek immediate medical help.

Very frequent side effects (can affect more than 1 in 10 people)

?? Headache

?? Breast pain

Frequent side effects (can affect up to 1 in 10 people)

?? Increased blood pressure and worsening of hypertension

?? Vaginal infection by fungi (e.g. candidiasis)

?? Dizziness, insomnia, depression

?? Dyspepsia (indigestion), abdominal pain, flatulence

?? Nausea (dizziness)

?? Pruritus, itching

?? Vaginal bleeding (see section 2 sub-section “Unexpected bleeding”)

?? Worsening of uterine fibroids (benign tumor of the uterus)

?? Edema (swelling of hands, wrists and feet)

?? Weight gain

Infrequent side effects (can affect up to 1 in 100 people)

?? Migraine

?? Changes in libido (change in sexual desire)

?? Peripheral embolism and thrombosis (blood clots)

?? Vomiting (dizziness)

?? Biliary tract disease or gallstones

?? Hair loss (alopecia)

?? Muscle cramps

Rare side effects (can affect up to 1 in 1000 people)

?? Allergic reactions

?? Nervousness

?? Vertigo (dizziness)

?? Diarrhea

?? Abdominal swelling

?? Acne

?? Uterine fibroids (benign tumor of the uterus)

Unknown (frequency cannot be estimated from available data)

?? Endometrial hyperplasia (excessive growth of uterine cells)

?? Increased facial and body hair

?? Anxiety

?? Visual disturbances

?? Seborrhea

?? Vaginal pruritus

Other side effects of combined TSH

The following side effects have been reported with other TSH medications:

• Several skin changes:

- Skin discoloration, especially on the face or neck, known as melasma

- Painful red nodules on the skin (erythema nodosum)

- Rash with redness in the shape of a target or blisters (erythema multiforme)

- Discolorations of red or purple skin and/or mucous membranes (purpura vascular)

• Dry eyes

• Changes in tear film composition

Reporting of side effects

If you experience any type of side effect, consult your doctor or pharmacist, even if it is a possible side effect that does not appear in this prospectus. You can also report them directly through the Spanish System of Pharmacovigilance of Medicines for Human Use http://www.notificaram.es.

By reporting side effects, you can contribute to providing more information on the safety of this medicine.

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

Do not use this medication after the expiration date indicated on the label and in

cartonage after “CAD”. The expiration date refers to the last day of the month.

Do not store above 25ºC. Do not refrigerate. Store the container in the outer packaging

to protect it from light.

Medicines should not be disposed of through drains or in the trash. Dispose of containers and

medicines that you no longer need at the SIGRE drop-off point at the pharmacy. If in doubt

ask your pharmacist how to dispose of containers and medicines that you no longer need. By doing so, you will help protect the environment.”

What Duofemme contains

The active principles are estradiol and noretisterone acetate.

The red-coated tablets contain: estradiol 1 mg (as estradiol hemihydrate).

The white-coated tablets contain: estradiol 1 mg (as estradiol hemihydrate) and noretisterone acetate 1 mg.

The other components are: lactose monohydrate, cornstarch, hydroxypropylcellulose, talc, and magnesium stearate.

Coating (red tablets): hypromellose, talc, titanium dioxide (E171), propylene glycol, and iron oxide red (E172).

Coating (white tablets): hypromellose, triacetin, and talc.

Appearance of Duofemme and contents of the package

The coated tablets are round with a diameter of 6 mm. The red tablets are engraved with NOVO 282.

The white tablets are engraved with NOVO 283.

Each package of 28 tablets contains 16 red tablets and 12 white tablets.

Package sizes:

1x28 coated tablets

3x28 coated tablets

Not all package sizes may be marketed.

Marketing authorization holder and manufacturer responsible

Marketing authorization holder:

Isdin S.A.

Provençals, 33

08019 Barcelona

Spain

Manufacturer responsible:

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsvaerd

Denmark

This medicine is authorized in the Member States of the European Economic Area and in the United Kingdom (Northern Ireland) with the following names:

Member States of the EEA:Novofem

Except:

France: Novofemme

Spain: Duofemme

Last review date of this leaflet: September 2024

Other sources of information

Detailed and updated information on this medicine is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS): http.//www.aemps.gob.es/

HOW TO USE

Using the calendar pack

1. Placing the day indicator

Turn the inner disc and fix the day of the week in front of the closed opening with a plastic clip.

2. How to take the first tablet

Break the plastic clip and take out the first tablet.

Moving the disc each day:Next day, simply turn one space on the transparent disc in the direction of the clock hands, as indicated by the arrow. Take out the next tablet. Remember to take only 1 tablet a day.

The transparent disc can only be turned once the corresponding tablet has been taken out.

.