Activelle 1 mg/0.5 mg film-coated tablets

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Activelle 1 mg/0.5 mg 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 only, and you should not give it 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 these are adverse effects not listed in this leaflet. See section 4.

Leaflet contents

1. What Activelle is and what it is used for
2. What you need to know before taking Activelle
3. How to take Activelle
4. Possible side effects
5. How to store Activelle
6. Contents of the pack and other information

1. What Activelle is and what it is used for

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

Activelle is used for:

Relieving symptoms occurring after menopause

During menopause, the amount of oestrogen produced by a woman's body decreases. This may cause symptoms such as hot flushes affecting the face, neck, and chest. Activelle relieves these postmenopausal symptoms. Your doctor will prescribe Activelle only 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 the available treatment options.

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

Activelle is prescribed for women who have not had a hysterectomy and whose periods have ceased for more than 1 year.

There is only limited experience with Activelle treatment in women over 65 years of age.

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

Medical history and periodic check-ups

Hormone replacement therapy (HRT) carries risks that should be considered before deciding to start or continue treatment.

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. Please 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 an internal pelvic exam, if necessary.

Once you have started taking Activelle, 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 Activelle.

Have regular breast examinations as recommended by your doctor.

Do not take Activelle

If any of the following clinical conditions apply to you. If you have any doubts about the points listed below, consult your doctor before taking Activelle.

Do not take Activelle:

• If you currently have, have previously had, or suspect you may have breast cancer.
• If you currently have, have previously had, or suspect you may have cancer of the lining of the uterus (endometrial cancer) or another estrogen-dependent cancer.
• If you experience vaginal bleeding of unknown cause.
• If you have excessive thickening of the uterine lining (endometrial hyperplasia) that is not being treated.
• If you currently have or have ever had blood clots in a vein (thrombosis), 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 currently have or have previously had an arterial disease caused by blood clots, such as myocardial infarction, stroke, or angina pectoris.
• If you have a liver disease and liver function tests have not yet returned to normal.
• If you have a rare inherited blood disorder called "porphyria."
• If you are allergic (hypersensitive) to estradiol, norethisterone acetate, or any of the other components of Activelle (listed in section 6, “Contents of the pack and other information”).

If any of these conditions develops for the first time while you are taking Activelle, 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 Activelle. If so, you should have more frequent check-ups:

• Uterine fibroids

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

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

• Increased risk of developing estrogen-sensitive cancer (such as having a mother, sister, or grandmother who had breast cancer)

• High blood pressure

• Liver disorder, such as benign liver tumor

• Diabetes

• Gallstones

• Migraine or severe headaches

• An autoimmune disease affecting multiple body 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 kidney problems

• Hereditary or acquired angioedema

• Lactose intolerance

Stop treatment with Activelle and inform your doctor immediately

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

• Any of the conditions listed in the section “Do not take Activelle”
• 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, together with breathing difficulties, which are symptoms 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, pain, and redness in the legs
  • Sudden chest pain
  • Difficulty breathing.

For more information, see “Blood clots in a vein (thrombosis).”

Note: Activelle 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 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 irregular bleeding:

• Persists beyond the first 6 months
• Begins after you have been taking Activelle for more than 6 months
• Continues after you have stopped taking Activelle

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 increased risk becomes apparent after 3 years of use. After stopping HRT, the additional risk decreases over time, but 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 16 to 17 cases per 1,000 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 1,000 women (i.e., 4 to 8 additional cases).

In women aged 50 to 59 not using HRT, an average of 27 cases of breast cancer per 1,000 women will be diagnosed 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 (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 women (i.e., 21 additional cases).

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

• Dimpling of the skin
• 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 the nurse/healthcare professional that you are taking HRT when undergoing X-ray imaging, as this medication may increase breast density, which can affect the mammogram results. Higher breast density may make it harder for a mammogram to 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 not using HRT, about 2 cases of ovarian cancer per 2,000 women are observed over a 5-year period. In women using HRT for 5 years, about 3 cases per 2,000 women are observed (i.e., about 1 additional case).

Effect of HRT on the heart and circulation

Blood clots in a vein (thrombosis)

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

Venous blood clots can be serious, and if a clot travels to the lungs, it can cause chest pain, difficulty breathing, fainting, or even death.

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

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

For symptoms of a blood clot, see the section “Stop treatment with Activelle 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 using HRT will experience a venous blood clot.

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

Heart disease (myocardial infarction)

HRT has not been shown to help prevent myocardial infarction. Women over 60 years of age who use 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 women using HRT than in non-users. The number of additional stroke cases due to HRT use increases with age.

Comparison

It is estimated that, over a 5-year period, an average of 8 out of 1,000 women in their fifties not using HRT will have 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 disorders

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

Use with other medicines

Some medicines may interfere with the effect of Activelle. 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:

• Epilepsy medicine (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 a 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. Activelle contains estradiol instead of ethinylestradiol. It is unknown whether elevated ALT liver enzyme levels may occur when using Activelle with this HCV combination regimen.

Other medicines may increase the effects of Activelle:

• Medicines containing ketoconazole (an antifungal).

Activelle may affect 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 remedies, or other natural products. Your doctor will advise you.

Blood tests

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

Taking Activelle with food and drinks

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

Pregnancy and breastfeeding

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

Breastfeeding: You should not take Activelle if you are breastfeeding.

Driving and using machines

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

Important information about some of the components of Activelle:

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

3. How to take Activelle

Follow exactly the instructions for use of this medicine given by your doctor. If in doubt, consult your doctor or pharmacist. 6

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

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

You may start treatment with Activelle on any day of the week. However, if you have switched from another HRT product with which you had menstrual bleeding, begin the new treatment immediately after the bleeding has ended.

Your doctor should 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.

If you take more Activelle than you should

An overdose of Activelle may cause dizziness or vomiting. If you take more Activelle than you should, contact your doctor, pharmacist, or call the Toxicology Information Service at telephone 91.562.04.20, indicating the medication and the amount taken. It is recommended to bring the medicine pack and leaflet to the healthcare professional.

If you forget to take Activelle

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, skip the missed dose and take the next tablet at your usual time. Do not take a double dose to make up for the forgotten dose. Missing a dose may increase the likelihood of breakthrough bleeding and spotting, unless you have had your uterus removed.

If you stop taking Activelle

If you wish to stop treatment with Activelle, speak with 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 the use of this medicine, ask your doctor or pharmacist.

If you are undergoing surgery

If you are scheduled for surgery, inform the surgeon that you are taking Activelle. You may need to stop taking Activelle 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.

4. Possible adverse effects

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

Hypersensitivity/allergy (uncommon adverse effect – affects 1 to 10 users in every 1000)

Although uncommon, hypersensitivity/allergy 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 shock. If any of these symptoms occur, stop taking Activelle and seek immediate medical help.

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

• Breast pain or tenderness
• Vaginal bleeding.

Common adverse 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 migraine
• Vaginal fungal infection
• Depression, new onset or worsening of existing depression
• Nausea
• Breast enlargement or breast swelling (mammary edema)
• Back pain
• Worsening, onset, or recurrence of uterine fibroids (benign tumor)
• Swelling of arms and legs (peripheral edema)
• Weight gain.

Uncommon adverse effects (affects 1 to 10 users in every 1000 users)

• Abdominal swelling, pain, discomfort or flatulence
• Acne
• Hair loss (alopecia)
• Abnormal (male-pattern) hair growth
• Itching or hives (urticaria)
• Inflammation of a vein (superficial thrombophlebitis)
• Leg cramps
• Lack of therapeutic effect
• Allergic reaction
• Nervousness.

Rare adverse effects (affects 1 to 10 users in every 10,000)

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

Very rare adverse effects (affects fewer than 1 user in every 10,000)

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

Other adverse effects of combined HRT

• Gallbladder disease
• Various skin disorders:
  • skin pigmentation, especially on the face and neck, known as “chloasma” or “melasma”
  • red, painful skin nodules (erythema nodosum)
  • rash with ulcers or target-like redness (erythema multiforme)
  • red or purple skin and/or mucosal membrane discoloration (vascular purpura)

Reporting of adverse effects

If you experience any type of adverse effect, talk to your doctor or pharmacist, even if they are possible adverse effects not listed in this leaflet. You can also report them directly via the Spanish Pharmacovigilance System for Human Medicines: https://www.notificaram.es. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Activelle

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 on the outer packaging, following "EXP". The expiry date refers to 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.

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

6. Contents of the pack and other information

Composition of Activelle

• The active substances are estradiol (as estradiol hemihydrate) 1 mg and norethisterone acetate 0.5 mg.
• The other components are: lactose monohydrate, corn starch, copovidone, talc, and magnesium stearate.
• The coating contains: hypromellose, triacetin, and talc.

Appearance of the product and contents of the pack

Film-coated tablets, white, round, with a diameter of 6 mm. One side is engraved with "NOVO 288" and the other side bears the Novo Nordisk logo (a bull Apis).

Pack sizes:

• 1 x 28 film-coated tablets in a calendar pack

• 3 x 28 film-coated tablets in calendar packs

Only certain pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder:

Isdin S.A.

Provençals 33

Barcelona 08019

Spain

Manufacturer:

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsvaerd

Denmark

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

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

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 for Medicines and Health Products (AEMPS) http://www.aemps.gob.es/

DIRECTIONS FOR USE

How to use the calendar pack

1. Set the day indicator

Rotate the inner disc and align the day of the week with the compartment sealed by a plastic tab.

2. How to remove the tablet for the first day

Break the plastic tab and remove the first tablet.

3. Move the disc each day

The next day, 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 once the tablet has been removed from the open compartment.