Package Insert: Information for the User

Activelle 1 mg/0.5 mg Film-Coated Tablets

estradiol/norethisterone acetate

Read this package insert carefully before starting to take this medication, as it contains important information for you.

– Keep this package insert, as you may need to refer to it again.

– If you have any questions, consult your doctor or pharmacist.

– This medication has been prescribed only 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 adverse effects, consult your doctor or pharmacist, even if they are not listed in this package insert. See section 4.

1. What is Activelle and how is it used

2. What you need to know before starting to take Activelle

3. How to take Activelle

4. Possible adverse effects

5. Storage of Activelle

6. Contents of the package and additional information

Activelle is a continuous combined hormone replacement therapy (HRT). It contains two types of female hormones: an estrogen and a progestogen. Activelle is used in postmenopausal women whose last natural period occurred at least 1 year ago.

Activelle is used for:

To alleviate symptoms that occur after menopause

During menopause, the amount of estrogens produced by the woman's body decreases. This can cause symptoms such as hot flashes in the face, neck, and chest (“hot flushes”). Activelle alleviates these symptoms after menopause. Activelle will only be prescribed if symptoms seriously hinder daily life.

To prevent osteoporosis

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

If you are at risk of fractures due to osteoporosis and there are no other suitable medications for you, you may use Activelle to prevent osteoporosis after menopause.

Activelle is prescribed to women who have not had a hysterectomy and whose periods ended more than 1 year ago.

There is limited experience with the treatment of Activelle in women over 65 years old.

Medical History and Regular Check-Ups

The use of THS entails risks that must be taken into account before deciding to start taking it or continue taking it.

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

Before starting (or resuming) THS, your doctor will ask about your medical history and that of your family. They may decide to perform a physical examination, which may include a breast examination or an internal examination, if necessary.

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

Attend regular breast examinations, as recommended by your doctor.

Do Not Take Activelle

If you are affected by any of the following clinical situations. If you have doubts about any of the following points, ask your doctor before taking Activelle.

Do not take Activelle:

• If you have, have had, or suspect you may havebreast cancer.

• If you have, have had, or suspect you may haveendometrial canceror other cancer dependent on estrogens.

• If you suffer from anyunexplained vaginal bleeding.

• If you have anexcessive thickening of the uterine liningthat is not being treated.

• If you have or have had anyblood clots in a vein(deep vein thrombosis or pulmonary embolism).

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

• If you have or have had anyarterial disease, such as myocardial infarction, stroke, or angina pectoris.

• If you have or have had anyliver diseaseand liver function tests have not yet normalized.

• If you have arare blood disorder called “porphyria”, which is hereditary.

• If you areallergic(hypersensitive) toestradiol, tonoretisterone acetate, or to any of the other components of Activelle (including those listed in section 6, “Contents of the package and additional information”).

If any of these conditions become apparent for the first time while taking Activelle, discontinue 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 problems, as they may recur or worsen during treatment with Activelle.If so, you should attend regular check-ups more frequently:

• uterine fibroids

• thickening of the uterine lining (endometriosis) or history of excessive thickening of the uterine lining (endometrial hyperplasia)

• High risk of blood clots (see “Blood clots in a vein (thrombosis)”)

• Elevated risk of developing a cancer sensitive to estrogens (such as having a mother, sister, or grandmother who has had breast cancer)

• High blood pressure

• Liver disease, such as a benign liver tumor

• Diabetes

• Gallstones

• Migraines or severe headaches

• A disease of the immune system that affects multiple organs of the body (systemic lupus erythematosus or SLE)

• Epilepsy

• Asthma

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

• Very high levels of fat in the blood (triglycerides)

• Fluid retention due to heart or kidney problems

• Hereditary and acquired angioedema

• Lactose intolerance

Discontinue treatment with Activelle and inform your doctor immediately

If you notice any of the following symptoms while taking THS:

• Any of the conditions mentioned in the section “Do not take Activelle”

• Yellowing of the skin or white of the eyes (jaundice). This may be a sign of liver disease

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

• A significant increase in blood pressure (with symptoms such as headache, fatigue, dizziness)

• Severe headache of the type that may be migrainous, which may occur for the first time

• If you become pregnant

• If you notice symptoms 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 (thrombosis)”.

Note:Activelle is not a contraceptive. If you have had your last menstrual period less than 12 months ago or are less than 50 years old, you may still need to use a contraceptive method to prevent pregnancy. Ask your doctor for advice.

THS and Cancer

Endometrial hyperplasia and endometrial cancer

THS with estrogens alone increases the risk of endometrial hyperplasia and endometrial cancer.

The progestogen in Activelle protects against this additional risk.

Irregular bleeding

You may experience irregular bleeding or spotting during the first 3 to 6 months of taking Activelle.

However, if the irregular bleeding:

• persists beyond the first 6 months

• begins after taking Activelle for more than 6 months

• continues after stopping Activelle

you should contact your doctor as soon as possible.

Breast Cancer

The available data show that the use of hormone replacement therapy (HRT) with estrogen-progestogen combinations or with estrogens alone increases the risk of breast cancer. The additional risk depends on the duration of HRT use. 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 HRT has been used for more than 5 years.

Comparison

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

In women aged 50 who start HRT with estrogens alone for 5 years, there will be between 16 and 17 cases per 1,000 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 1,000 users (i.e., between 4 and 8 additional cases).

In women aged 50-59 who are not using HRT, on average 27 cases of breast cancer will be diagnosed per 1,000 women over a 10-year period.

In women aged 50 who start HRT with estrogens alone for more than 10 years, there will be 34 cases per 1,000 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 1,000 users (i.e., 21 additional cases).

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

• dimpling of the skin

• changes in the nipples

• any lump that you can see or feel.

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

During 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 can increase breast density, which may affect the results of the mammogram. When 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 estrogen-progestogen combinations 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 using HRT, approximately 2 cases of ovarian cancer per 2,000 women are observed over a 5-year period. In women taking HRT for 5 years, approximately 3 cases per 2,000 patients are observed (i.e., approximately 1 additional case).

Effect of HRT on the Heart and Circulation

Blood clots in a vein (thrombosis)

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

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

The probability of developing blood clots in veins will be higher with increasing age and if any of the following factors are present. If any of these situations may apply to you, inform your doctor:

• You will be unable to walk for a long time due to a major surgical operation, injury, or illness (see also section 3, “If you are to undergo surgery”)

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

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

• A close relative has had a blood clot in the legs, lungs, or other organs

• You have systemic lupus erythematosus (SLE)

• You have cancer.

To know the symptoms caused by a blood clot, see “Interruption of treatment with Activelle and inform your doctor immediately”.

Comparison

It is estimated that, over a 5-year period, on average 4-7 out of every 1,000 women in their 50s who are not using HRT will develop a blood clot in a vein.

In women in their 50s who take HRT with estrogen-progestogen for 5 years, there will be between 9 and 12 cases per 1,000 users (i.e., 5 additional cases).

Cardiovascular Diseases (Myocardial Infarction)

HRT has not been shown to prevent myocardial infarction. Women over 60 who use HRT with estrogen-progestogen have a slightly higher risk of developing cardiovascular disease than those who do not use 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.

Comparison5

It is estimated that, over a 5-year period, on average 8 out of every 1,000 women in their 50s who are not using HRT will develop a stroke.

In women in their 50s who are 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. There has been an indication of a higher risk of memory loss in women who started using HRT after the age of 65. Ask your doctor for advice.

Use with Other Medications

Some medications may interfere with the effect of Activelle, causing irregular bleeding. Such medications are the following:

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

• Medications fortuberculosis(such as rifampicin and rifabutin)

• Medications forinfection with the HIV virus(such as nevirapine, efavirenz, ritonavir, and nelfinavir)

•Medications forinfection with hepatitis C(such as telaprevir)

• Preparations based on plants containingSt. John's Wort(Hypericum perforatum)

HRT may affect the functioning of certain medications:

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

•Medications for the 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 (elevated ALT levels) in women using combined hormonal contraceptives (CHCs) that contain ethinylestradiol. Activelle contains estradiol instead of ethinylestradiol. It is unknown whether this may cause an increase in ALT levels when using Activelle with this HCV combination regimen.

Other medications may increase the effects of Activelle:

• Medications containingketoconazole(an antifungal medication).

Activelle may affect concurrent treatment with ciclosporin.

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

Laboratory Tests

If you need a blood test, inform your doctor or laboratory personnel that you are taking Activelle, as this medication may alter the results of some laboratory parameters.

Taking Activelle with Medications and Beverages

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

Pregnancy and Breastfeeding

Pregnancy:Activelle should only be used in postmenopausal women. If you become pregnant, stop taking Activelle and consult your doctor.

Breastfeeding:Do not take Activelle if you are breastfeeding.

Driving and Operating Machinery

Activelle has no known effects on the ability to drive or operate machinery.

Important Information about Some Components of Activelle:

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

Follow exactly the administration instructions of this medication indicated by your doctor. In case of doubt, consult your doctor or pharmacist..6

Take one tablet once a day, approximately at the same hour every day.When you have finished the 28 tablets in the package, start a new package to continue treatment without interruption.

For more information on the use of the package calendar, consult the section “Instructions for the user”, at the end of this prospectus.

You can start treatment with Activelle any day of the week.However, if you have changed from another THS product with which you had menstrual bleeding, start the new treatment just after having finished the bleeding.

Your doctor should prescribe the effective dose as low as possible and for the shortest time possible that will provide relief from symptoms. Talk to your doctor if you think the dose is excessive or insufficient.

If you take more Activelle than you should

Activelle overdose may cause dizziness or vomiting. If you take more Activelle than you should, consult your doctor, pharmacist, or call the toxicology information service, phone 91.562.04.20, indicating the medication and the amount taken. It is recommended to bring the package and the medication prospectus to the healthcare professional.

If you forgot to take Activelle

If you have forgotten to take the tablet corresponding to the usual hour, take it within the next 12 hours. If more than 12 hours have passed, skip the missed dose and take it the next day as usual. Do not take a double dose to compensate for the missed dose. Forgetting a dose may increase the likelihood of experiencing intercurrent bleeding and spotting, unless you have had a uterus removed.

If you interrupt treatment with Activelle

If you want to interrupt treatment with Activelle, talk to your doctor first, who will explain the effects of interrupting treatment and discuss other possibilities with you.

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

If you must undergo surgery

If you are to undergo a surgical procedure, inform the surgeon that you are taking Activelle. You may need to stop taking Activelle for 4 to 6 weeks before the operation to reduce the risk of blood clots (see section 2, "Blood clots in a vein (thrombosis). Ask your doctor when you can start taking Activelle again.

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

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

• breast cancer

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

• ovarian cancer

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

• heart disease

• stroke

• probable memory loss if THS is started at an age of 65 years or older.

To get more information about these side effects, see section 2, “What you need to know before starting to take Activelle”.

Hypersensitivity/allergy(infrequent side effect – affects 1 to 10 users in every 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, decrease in blood pressure (pale skin and coldness, increased heart rate), sensation of dizziness and sweating that may be signs of anaphylactic reaction or shock. If one of the mentioned symptoms occurs,stop taking Activelle and seek immediate medical help.

Very common side effects (affects more than 1 in 10 users)

• breast pain or tenderness

• vaginal bleeding.

Common side effects (affects 1 to 10 users in every 100)

• headache

• weight gain due to fluid retention

• vaginal inflammation

• migraine, new onset or worsening of existing

• vaginal yeast infection

• depression, new onset or worsening of existing

• nausea

• breast enlargement or swelling (mammoplasty)

• back pain

• worsening, new onset, or recurrence of uterine fibroma (benign tumor)

• swelling of arms and legs (peripheral edema)

• weight gain.

Infrequent side effects (affects 1 to 10 users in every 1000 users)

• abdominal bloating, pain, or discomfort, or flatulence

• acne

• hair loss (alopecia)

• abnormal hair growth (male pattern)

• itching or hives (urticaria)

• superficial vein inflammation (thrombophlebitis)

• leg cramps

• pharmacological ineffectiveness

• allergic reaction

• nervousness.

Rare side effects (affects 1 in every 1000 users)

• formation of blood clots in the veins of the legs or lungs (deep vein thrombosis, pulmonary embolism).

Very rare side effects (affects less than 1 user in every 10,000)

• cancer of the lining of the uterus (endometrial cancer)

• excessive thickening of the lining of the uterus (endometrial hyperplasia)

• increase in blood pressure or worsening of existing hypertension

• gallbladder disease, new onset, reappearance, or worsening of existing gallstones

• excessive sebum secretion, skin rash

• acute or recurrent edema (angioneurotic edema)

• insomnia, dizziness, anxiety

• changes in sexual desire

• vision disturbances

• weight loss

• vomiting

• acid reflux

• vaginal and genital itching

• myocardial infarction and stroke.

Other side effects of combined HRT

• gallbladder disease

• various skin disorders:

– skin pigmentation, especially on the face and neck, known as “pregnancy mask” (melasma)

– red, painful skin nodules (erythema nodosum)

– rash with ulcers or redness in the shape of a target (erythema multiforme).

– discoloration of red or purple color of the skin and/or mucous membranes (vascular purpura)

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 theSpanish System for Pharmacovigilance of Medicines for Human Use:https://www.notificaram.es. By reporting side effects, you can contribute to providing more information about 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 that appears on the label and on the outer packaging, after “CAD”. The expiration date is the last day of the month indicated.

Do not store above 25°C.

Do not refrigerate.

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

Medications should not be disposed of through drains or in the trash. Dispose of containers and medications you no longer need at the SIGRE collection point at the pharmacy. If in doubt, ask your pharmacist how to dispose of containers and medications you no longer need.This will help protect the environment.

Composition of Activelle

– The active principles are estradiol (as hemihydrate of estradiol) 1 mg and noretisterone acetate 0.5 mg.

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

– The coating contains: hypromellose, triacetin, and talc.

Appearance of the product and contents of the package

Coated tablets, white, round, with a diameter of 6 mm. On one face, “NOVO 288” is engraved, and on the other, the Novo Nordisk logo (a bee) is printed.

Presentations:

• 1 x 28 coated tablets in a calendar pack

• 3 x 28 coated tablets in calendar packs

Only some package sizes may be commercially available.

Holder of the marketing authorization and responsible for manufacturing

Holder:

Isdin S.A.

Provençals 33

08019 Barcelona

Spain

Responsible for manufacturing:

Novo Nordisk A/S

Novo Allé

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: Activelle – except in the United Kingdom (Northern Ireland): Kliovance.

Date of the last review 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/

INSTRUCTIONS FOR USE

How to use the calendar pack

1. Place the day indicator

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

2. How to extract the tablet for the first day

Break the plastic latch and extract the first tablet.

3. Move the disc each day

The next day, turn the transparent disc 1 space in a clockwise direction, as indicated by the arrow. Extract the next tablet. Remember to take only 1 tablet per day.

The transparent disc can only be turned once the tablet from the open compartment has been extracted.