Duofemme film-coated tablets

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Duofemme film-coated tablets

estradiol/norethisterone acetate

Read the entire 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 have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you and should not be given to other people, even if they have

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

• If you experience any adverse effects, consult your doctor or pharmacist, even if they are

effects not listed in this leaflet. See section 4.

Leaflet contents:

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 adverse effects
5. How to store Duofemme
6. Contents of the pack and other information

1. What Duofemme is and what it is used for

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

Duofemme contains two hormones: an oestrogen (estradiol) and a progestogen (norethisterone acetate). The estradiol in Duofemme 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 in a similar way to progesterone, another important female sex hormone.

Duofemme is indicated for:

Relief of symptoms occurring after menopause

During menopause, the amount of oestrogen produced by a woman's body decreases. This may cause symptoms such as sudden warmth in the face, neck, and chest (hot flushes).

Duofemme relieves these postmenopausal symptoms. Duofemme will only be prescribed if these symptoms seriously interfere with your daily life.

Prevention of osteoporosis

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

You should discuss all possible treatment options with your doctor.

If you are at high risk of fractures due to osteoporosis and other medications for this purpose cannot be used, Duofemme may be used to prevent postmenopausal osteoporosis.

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

2. What you need to know before taking Duofemme

Medical history and regular check-ups:

Hormone replacement therapy (HRT) carries risks that must be considered before starting treatment or deciding whether to continue it.

Experience with treating women who have premature menopause (due to ovarian insufficiency or surgery) is limited. If you have premature menopause, the risks of using HRT may differ. Please consult your doctor.

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

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

Attend regular breast examinations as recommended by your doctor.

Do not take Duofemme

If any of the following conditions apply to you. If you are unsure about any of the points listed below, consult your doctor before taking Duofemme.

Do not take Duofemme:

• If you have or have had breast cancer, or if you suspect you may have it
• If you have or have had cancer of the cells lining the uterus (endometrial cancer), or if estrogen-dependent cancer is suspected
• If you experience unexpected vaginal bleeding
• If you have excessive thickening of the cells lining the uterus (endometrial hyperplasia) that is not being treated
• If you have or have had blood clots in a vein (venous thromboembolism), 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 had a disease previously caused by blood clots in the arteries, such as heart attack, stroke, or angina
• If you have or have had liver disease and your liver function tests have not returned to normal
• If you are allergic (hypersensitive) to estradiol, norethisterone acetate, or any other ingredient of Duofemme (see section 6, Package contents and additional information)
• If you have a rare inherited blood disorder called porphyria

If any of the above conditions develop for the first time while you are taking Duofemme, stop taking it immediately and consult your doctor without delay.

Warnings and precautions

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

• Uterine fibroids
• Growth of the cells lining the uterus outside the uterus (endometriosis) or excessive growth of the cells lining the uterus (endometrial hyperplasia)
• High risk of developing blood clots (see “blood clots in a vein (venous thromboembolism)”)
• High risk of developing estrogen-related cancer (if your mother, sister, or grandmother had breast cancer)
• High blood pressure
• Liver disorder, such as a benign liver tumor
• Diabetes
• Gallstones
• Migraine or severe headaches
• An immune system disorder affecting multiple organs (systemic lupus erythematosus, SLE)
• Epilepsy
• Asthma
• A condition affecting the eardrum and ear (otosclerosis)
• 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 receiving thyroid hormone replacement therapy
• A hereditary condition causing recurrent episodes of severe swelling (hereditary angioedema), or if you have experienced episodes of rapid swelling of the hands, face, feet, lips, eyes, tongue, throat (airway obstruction), or digestive tract (acquired angioedema)
• Lactose intolerance

Stop taking Duofemme and contact your doctor immediately

If you experience any of the following while taking HRT:

• Any of the conditions listed under “Do not take Duofemme”
• Yellowing of the skin or whites of the eyes (jaundice). These may be signs of liver disease
• Swelling of the face, tongue, and/or throat and/or difficulty swallowing or hives, along with difficulty breathing, which are symptoms of angioedema
• A significant increase in blood pressure (symptoms may include headache, fatigue, and dizziness)
• First occurrence of migraine-type headache
• If you become pregnant
• If you notice signs 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: Duofemme is not a contraceptive. If it has been less than 12 months since your last menstrual period or you are under 50 years of age, you may need to use a contraceptive to prevent pregnancy. Consult your doctor.

HRT and cancer

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

If you take estrogen-only HRT, your risk of excessive thickening of the uterine lining (endometrial hyperplasia) and cancer of the uterine lining (endometrial cancer) increases. The progestogen in Duofemme protects you from this additional risk.

Comparison:

In women aged 50 to 65 years with an intact uterus who do not take HRT, the average number of new cases of endometrial cancer might be 5 per 1000 women.

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

Unexpected bleeding

You will have a monthly bleed (called a withdrawal bleed) while taking Duofemme. However, if you experience unexpected bleeding or spotting in addition to the monthly bleed that:

• continues beyond 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

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 decreases 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 1000 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 1000 women (i.e., 0 to 3 additional cases). In women aged 50 who start combined estrogen-progestogen HRT for 5 years, there will be 21 cases per 1000 women (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 1000 women over a 10-year period.

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

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

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

• Skin dimpling
• Changes in the nipple
• Any lump you can see or feel

In addition, you are advised to participate in breast screening programs when offered.

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

Ovarian cancer

Ovarian cancer is less common than breast cancer. The use of HRT with estrogen alone or combined estrogen-progestogen 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 2000 women over a 5-year period. In women using HRT for 5 years, about 3 cases per 2000 women 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 the veins is approximately 1.3 to 3 times higher in women using HRT than in non-users, especially during the first year of use.

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

Your risk of developing blood clots is higher if you are older and if any of the following factors apply. Inform your doctor if you experience any of the following:

• You are unable to walk for long periods due to surgery, injury, or illness (see also section 3, "If you need surgery")
• You have significant overweight (BMI >30 kg/m²)
• You have a blood clotting disorder requiring long-term treatment with blood-thinning medication
• You have a close relative who has ever had a blood clot in the legs, lungs, or other organs
• You have systemic lupus erythematosus (SLE)
• You have cancer

If you suspect blood clots, see “Stop taking Duofemme” and contact your doctor immediately.

Comparison:

In women aged 50 years not taking HRT, 4 to 7 out of 1000 will experience a venous blood clot over an average period of 5 years.

In women aged 50 years taking combined estrogen-progestogen HRT, there will be 9 to 12 cases per 1000 women over an average period of 5 years (up to 5 additional cases).

Heart disease (heart attack)

There is no evidence that HRT prevents heart attacks. In women over 60 years of age using estrogen-progestogen HRT, there is a slightly higher risk of developing heart disease compared to those not taking HRT.

Stroke

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

Comparison:

In women aged 50 years not taking HRT, an average of 8 out of 1000 will likely suffer a stroke over an average period of 5 years.

In women aged 50 years taking HRT, there will be 11 cases per 1000 women over an average period of 5 years (up to 3 additional cases).

Other conditions

HRT does not prevent memory loss. There is some evidence of an increased risk of memory loss in women who start using HRT after age 65. Inform your doctor.

Use of other medicines

Some medicines may interfere with the effect of Duofemme.

This could 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)
• Medicines for hepatitis C infection (such as telaprevir)
• Herbal products 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, as well as the regimen with glecaprevir/pibrentasvir) may cause increases in liver function blood test results (elevated liver enzyme ALT) in women using combined hormonal contraceptives (CHCs) containing ethinylestradiol. Duofemme contains estradiol instead of ethinylestradiol. It is unknown whether elevated ALT liver enzyme levels may occur when using Duofemme with this HCV combination regimen.

Other medicines may increase the effects of Duofemme:

• Medicines containing ketoconazole (an antifungal)

Duofemme may interact with concomitant treatment with cyclosporine.

Inform your doctor or pharmacist if you are taking or have recently taken any other medicines, including those obtained 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 medicine may affect the results of certain tests.

Taking Duofemme with food and drinks

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

Pregnancy and breastfeeding

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

Breastfeeding: Do not take Duofemme if you are breastfeeding.

Driving and using machines

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

Important information about some of the ingredients of Duofemme

Duofemme contains lactose monohydrate. If your doctor has informed you that you have an intolerance to certain sugars, consult with him before taking this medicine.

3. How to take Duofemme

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 currently taking any other hormone replacement therapy, treatment with Duofemme can be started on any day you consider convenient. If you are already taking another type of hormone replacement therapy, your doctor will advise you when to start treatment with Duofemme.

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

Each pack contains 28 tablets.

Days 1-16: Take one red tablet daily for 16 days.
Days 17-28: Take one white tablet daily for 12 days.

Swallow the tablets with a glass of water.

Once you have finished the pack, start a new one immediately, continuing treatment without interruption.

A menstrual-like bleed (period) usually occurs at the beginning of a new pack.

For further information on the use of the calendar disc, see “DIRECTIONS FOR USE” at the end of the leaflet.

Your doctor will prescribe the lowest effective dose to treat your symptoms for the shortest duration necessary.

Consult your doctor if you do not experience improvement after 3 months of treatment. Treatment should only be continued if 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. An overdose of estrogens may cause breast tenderness, nausea, vomiting, and/or irregular vaginal bleeding (metrorrhagia). An overdose of progestogens may lead to depression, fatigue, acne, and growth of facial or body hair (hirsutism).

In case of overdose or accidental ingestion, contact your doctor or pharmacist immediately or call the Toxicology Information Service at telephone number 915 620 420, indicating the medicine and the amount taken.

If you forget to take Duofemme

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

Missing one or more tablets may increase the likelihood of breakthrough bleeding or spotting.

If you stop taking Duofemme

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

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

If you require surgery

If you are scheduled for surgery, inform your 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 blood clots (see section 2, "Blood clots in a vein (venous thromboembolism)"). Ask your doctor when you can start taking Duofemme again.

4. Possible adverse effects

Like all medicines, this medicine may cause adverse effects, although not everyone experiences them.

The following diseases occur more frequently in women using HRT compared to women not using HRT:

• 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
• possible memory loss if HRT is started after the age of 65

For further information about these side effects, please refer to section 2, "What you need to know before using Duofemme".

Hypersensitivity/allergy (uncommon adverse effect affecting between 1 and 10 users per 1000)

Although rare, hypersensitivity/allergy may occur. Signs of hypersensitivity/allergy may include one or more of the following symptoms: hives, itching, swelling, difficulty breathing, low blood pressure (pallor and skin cooling, rapid heartbeat), dizziness, sweating, which may be signs of an anaphylactic reaction/shock. If any of these symptoms occur, stop treatment with Duofemme immediately and seek urgent medical attention.

Very common effects (may affect more than 1 in 10 people)

?? Headache
?? Breast tenderness

Common effects (may affect up to 1 in 10 people)

?? Increased blood pressure and worsening of hypertension
?? Vaginal fungal infection (e.g. candidiasis)
?? Dizziness, insomnia, depression
?? Dyspepsia (indigestion), abdominal pain, flatulence
?? Nausea (feeling sick)
?? Skin rash, itching
?? Vaginal bleeding (see section 2, subsection "Unexpected bleeding")
?? Worsening of uterine fibroids (benign uterine tumor)
?? Edema (swelling of hands, wrists, and feet)
?? Weight gain

Uncommon effects (may affect up to 1 in 100 people)

?? Migraine
?? Changes in libido (change in sexual desire)
?? Peripheral embolism and thrombosis (blood clots)
?? Vomiting (feeling sick)
?? Gallbladder disease or gallstones
?? Hair loss (alopecia)
?? Muscle cramps

Rare effects (may affect up to 1 in 1000 people)

?? Allergic reactions
?? Nervousness
?? Dizziness (vertigo)
?? Diarrhea
?? Abdominal swelling
?? Acne
?? Uterine fibroid (benign uterine tumor)

Unknown frequency (cannot be estimated from available data)

?? Endometrial hyperplasia (excessive growth of cells in the uterus)
?? Increased facial and body hair
?? Anxiety
?? Visual disturbances
?? Seborrhea
?? Vaginal pruritus

Other adverse effects of combined HRT

The following adverse effects have been reported with other HRT medicines:

• Various skin disorders:

  • Skin discoloration, especially on the face or neck, known as chloasma
  • Painful red nodules on the skin (erythema nodosum)
  • Rash with target-shaped redness or blisters (erythema multiforme)
  • Red or purple skin discolorations and/or on mucous membranes (vasculitic purpura)

• Dry eyes

• Changes in the composition of the tear film

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 may 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 Duofemme

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

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

Do not store above 25°C. Do not refrigerate. Keep the container in the outer packaging to protect it from light.

Medicines must not be disposed of via wastewater or household waste. Dispose of unused containers and medicines at the SIGRE collection point at your pharmacy. If you are in doubt, ask your pharmacist how to dispose of containers and medicines you no longer need. This will help protect the environment.

6. Package contents and other information

What Duofemme contains

The active substances are estradiol and norethisterone acetate.

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

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

The other components are: monohydrate lactose, corn starch, 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.

What Duofemme looks like and contents of the pack

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

The white tablets are marked with NOVO 283.

Each 28-tablet pack contains 16 red tablets and 12 white tablets.

Pack sizes:

1x28 film-coated tablets

3x28 film-coated tablets

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

Isdin S.A.

Provençals, 33

08019 Barcelona

Spain

Manufacturer:

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsvaerd

Denmark

This medicinal product is authorised in the European Economic Area (EEA) Member States and in the United Kingdom (Northern Ireland) under the following names:

EEA Member States: Novofem

Except:

France: Novofemme

Spain: Duofemme

Date of the most recent revision of this leaflet: September 2024

Other sources of information

Detailed and up-to-date information on this medicinal product 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 pack

1. Set the day indicator

Turn the inner disc and align the day of the week with the window covered by a plastic tab.

2. How to remove the first tablet

Break the plastic tab and remove the first tablet.

Move the disc daily: The next day, simply rotate the transparent disc one position clockwise, as indicated by the arrow. Remove the next tablet. Remember to take only one tablet per day.

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