Activelle

Package Leaflet: Information for the User

Activelle, 1 mg + 0,5 mg, coated tablets

Estradiol hemihydrate+ Norethisterone acetate

Read the package leaflet carefully before taking the medicine, as it contains important information for you.

• Keep this package leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If you experience any side effects, including those not listed in this package leaflet, tell your doctor or pharmacist. See section 4.

Table of Contents of the Package Leaflet

• 1. What is Activelle and what is it used for
• 2. Important information 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 is Activelle and what is it used for

Activelle is a medicine for continuous combined hormone replacement therapy (HRT). The medicine contains two female sex hormones: estrogen and progestogen. Activelle is used for women who have reached menopause, at least one year after their last natural menstrual period. Activelle is used to:

Relieve symptoms occurring after menopause

During menopause, the amount of estrogen produced by the body decreases, which can cause symptoms such as hot flashes. Activelle relieves these symptoms. Activelle should only be prescribed if symptoms significantly interfere with daily life;

Prevent osteoporosis

After menopause, some women develop brittle bones (osteoporosis). All available options should be discussed with your doctor. If you are at increased risk of fractures due to osteoporosis and other medicines are not suitable, Activelle can be used to prevent osteoporosis after menopause. Activelle is indicated for women with an intact uterus and for women who have had their uterus removed.

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

2. Important information before taking Activelle

Medical History and Regular Check-ups

Taking HRT involves risks, which should be considered when deciding whether to start or continue HRT. Experience with HRT in women who have had premature menopause (due to ovarian failure or surgery) is limited. If you are experiencing premature menopause, the risks associated with HRT may be different. You should discuss this with your doctor. Before starting (or resuming) HRT, your doctor should take your medical history, including your family history. Your doctor may decide to perform a physical examination, including a breast examination and/or gynecological examination, if necessary. If you start taking Activelle, you should have regular check-ups (at least once a year). During these check-ups, you should discuss the benefits and risks of continuing to take Activelle with your doctor. You should have regular mammograms as recommended by your doctor.

When Not to Take Activelle

If you have any of the following conditions, or if you are unsure about any of the conditions listed below, tell your doctor before taking Activelle. Do not start taking Activelle if:

• you have been diagnosed with, have had, or are suspected of having breast cancer;
• you have been diagnosed with, have had, or are suspected of having estrogen-dependent tumors, such as endometrial cancer;
• you have unexplained vaginal bleeding;
• you have endometrial hyperplasia(thickening of the lining of the uterus) and it is not being treated;
• you have been diagnosed with or have had blood clots in the veins(venous thromboembolism), such as deep vein thrombosis or pulmonary embolism;
• you have a blood clotting disorder(such as protein C, protein S, or antithrombin deficiency);
• you have had or have arterial thromboembolic diseases, such as heart attack, stroke, or angina;
• you have or have had liver disease, and your liver function tests have not returned to normal;
• you have a rare, inherited blood disordercalled porphyria;
• you are allergic(hypersensitive) to estradiolor norethisterone acetateor any of the other ingredients of Activelle (listed in section 6).

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

Warnings and Precautions

Before starting treatment, tell your doctor if you have ever had any of the following conditions, as they may recur or worsen during treatment with Activelle. Your doctor may need to monitor you more closely:

• uterine fibroids (fibroids),
• endometriosis (a condition in which tissue similar to the lining of the uterus grows outside the uterus) or endometrial hyperplasia (thickening of the lining of the uterus),
• factors that increase the risk of blood clots (see "Blood clots in the veins"),
• factors that increase the risk of estrogen-dependent tumors (such as breast cancer in your mother, sister, or grandmother),
• high blood pressure,
• liver disease, such as a benign liver tumor,
• diabetes,
• gallstones,
• migraine or severe headaches,
• systemic lupus erythematosus (a disease that affects many parts of the body),
• epilepsy,
• asthma,
• otosclerosis (a condition that affects hearing),
• high levels of triglycerides (a type of fat) in the blood,
• fluid retention due to heart or kidney problems,
• inherited or acquired angioedema (a condition that causes swelling of the face, lips, tongue, or throat),
• lactose intolerance.

If you experience any of the following conditions while taking HRT, stop taking Activelle and consult your doctor immediately:

• if you experience any of the conditions listed in the "When Not to Take Activelle" section,
• if your skin or the whites of your eyes turn yellow (jaundice), which can be a sign of liver problems,
• if you experience swelling of the face, lips, tongue, or throat, or difficulty swallowing or breathing, which can be signs of angioedema,
• if you experience a significant increase in blood pressure (symptoms may include headache, fatigue, and dizziness),
• if you experience a migraine headache for the first time,
• if you become pregnant,
• if you experience symptoms of a blood clot, such as:
• painful swelling and redness of the legs,
• sudden chest pain,
• difficulty breathing.

Note:Activelle is not a contraceptive. If it has been less than 12 months since your last menstrual period or you are under 50 years old, you may need to use an additional method of contraception. You should consult your doctor.

HRT and Cancer

Endometrial Hyperplasia and Endometrial Cancer

Taking estrogen-only HRT increases the risk of endometrial hyperplasia and endometrial cancer. The progestogen in Activelle helps to reduce this additional risk.

Irregular Bleeding

During the first 3 to 6 months of taking Activelle, you may experience irregular bleeding or spotting. However, if irregular bleeding:

• continues for more than 6 months,
• starts after 6 months of taking Activelle,
• continues after stopping Activelle, you should consult your doctor as soon as possible.

Breast Cancer

Data confirms that taking combined estrogen-progestogen HRT or estrogen-only HRT increases the risk of breast cancer. The additional risk depends on how long you take HRT. This additional risk becomes apparent after 3 years of taking HRT. After stopping HRT, the additional risk will decrease over time, but the risk may remain for 10 years or more if HRT lasted more than 5 years. Comparison: In women aged 50-54 who do not take HRT, breast cancer is diagnosed in approximately 13-17 per 1000 women over 5 years. In women aged 50 who start 5-year estrogen-only HRT, the number of cases will be 16-17 per 1000 women (i.e., 0-3 additional cases). In women aged 50 who start 5-year combined estrogen-progestogen HRT, the number of cases will be 21 per 1000 women (i.e., 4-8 additional cases).

Check Your Breasts Regularly

You should check your breasts regularly. You should consult your doctor if you notice any of the following changes:

• indentation of the skin,
• changes in the nipple area,
• presence of lumps that are visible or palpable.

In addition, it is recommended to participate in breast cancer screening programs. It is essential to inform the nurse or medical staff performing the mammography that you are taking HRT, as it may increase breast density, which can affect the mammography result. Not all lumps can be detected during a mammography in areas with increased breast density.

Ovarian Cancer

Ovarian cancer is rare, much rarer than breast cancer. Taking estrogen-only or combined estrogen-progestogen HRT is associated with a slightly increased risk of ovarian cancer. The risk of ovarian cancer depends on age. For example, in women aged 50-54 who do not take HRT, ovarian cancer will be diagnosed in approximately 2 per 2000 women over 5 years. In women who have taken HRT for 5 years, it will occur in approximately 3 per 2000 women (i.e., 1 additional case).

Effect of HRT on the Heart and Blood Vessels

Blood Clots in the Veins (Venous Thromboembolism)

The risk of blood clots in the veinsis 1.3 to 3 times higher in women taking HRT compared to those not taking HRT, especially in the first year of taking HRT. Blood clots can be life-threatening and can cause chest pain, shortness of breath, fainting, or even death. The risk of blood clots in the veins is higher if you are older and if you have any of the following factors. You should tell your doctor if:

• you are unable to walk for a long time due to major surgery, injury, or illness (see also section 3 "If you are going to have surgery"),
• you are obese (body mass index (BMI) > 30 kg/m^2),
• you have a history of blood clots that require long-term treatment with blood-thinning medicines,
• anyone in your close family has had blood clots in the legs or lungs,
• you have systemic lupus erythematosus,
• you have been diagnosed with cancer.

If you experience symptoms of a blood clot, see "If you experience any of the following conditions while taking HRT". Comparison: In women aged 50-59 who do not take HRT, the estimated number of cases of blood clots in the veins over 5 years is 4-7 per 1000 women. In women aged 50-59 who take combined estrogen-progestogen HRT, the number of cases over 5 years will be 9-12 per 1000 women (i.e., 5 additional cases).

Coronary Artery Disease (Heart Attack)

There is no evidence that HRT prevents heart attacks. In women over 60 years old taking combined estrogen-progestogen HRT, there is a slightly increased risk of developing coronary artery disease compared to those not taking HRT.

Stroke

The risk of stroke is approximately 1.5 times higher in women taking HRT compared to those not taking HRT. The number of additional cases of stroke due to HRT will increase with age. Comparison: In women aged 50-59 who do not take HRT, the estimated number of cases of stroke over 5 years is 8 per 1000 women. In women aged 50-59 who take HRT, the number of cases over 5 years will be 11 per 1000 women (i.e., 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 HRT after the age of 65. You should consult your doctor.

Activelle and Other Medicines

Certain medicines may affect the efficacy of Activelle, which may lead to irregular bleeding. These include:

• •antiepileptic medicines(such as phenobarbital, phenytoin, and carbamazepine),
• •antituberculosis medicines(such as rifampicin and rifabutin),
• •medicines used to treat HIV infection(such as nevirapine, efavirenz, ritonavir, and nelfinavir),
• medicines used to treat hepatitis C (such as telaprevir),
• herbal medicines and other herbal products containing St. John's Wort(Hypericum perforatum).

HRT May Affect the Efficacy of Other Medicines:

• the antiepileptic medicine lamotrigine, which may increase the frequency of seizures;
• medicines used to treat hepatitis C (e.g., the combination of ombitasvir/paritaprevir/ritonavir with dasabuvir, with or without dasabuvir) may cause increased liver enzyme levels in women taking combined hormonal contraceptives containing ethinylestradiol. Activelle contains estradiol, not ethinylestradiol. It is not known whether the concomitant use of Activelle with this combination regimen may increase liver enzyme levels.

Other medicines may increase the effect of Activelle:

• medicines containing ketokonazole(an antifungal medicine).

Activelle may affect the efficacy of cyclosporin. Tell your doctor or pharmacistabout all medicines you are currently taking or have recently taken, including those obtained without a prescription, herbal medicines, or other natural products. Your doctor will advise you on this.

Lab Tests

If you need to have a blood test, tell your doctor or the laboratory staff that you are taking Activelle, as it may affect the results of some tests.

Taking Activelle with Food and Drink

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

Pregnancy and Breastfeeding

Pregnancy:Activelle is for use in postmenopausal women only. If you become pregnant, stop taking Activelle and consult your doctor immediately. Breastfeeding:do not take Activelle while breastfeeding.

Driving and Using Machines

The effect of Activelle on the ability to drive and use machines is not known.

Important Information About Some Ingredients of Activelle

Activelle contains lactose monohydrate. If you have been told that you have an intolerance to some sugars, you should consult your doctor before taking Activelle.

3. How to Take Activelle

Always take this medicine exactly as your doctor has told you. If you are not sure, ask your doctor or pharmacist.

Take one tablet a day, every day, at about the same time.

After finishing all 28 tablets in the pack, continue with the next pack without a break. Instructions for using the calendar pack are at the end of this package leaflet, in the section "Instructions for the User". You can start taking Activelle on any day. If you have been taking another HRT product that caused withdrawal bleeding, start taking Activelle immediately after the bleeding has finished. Your doctor will prescribe the lowest dose that will relieve your symptoms, for the shortest time necessary. If you think that the dose of Activelle is too high or too low, you should talk to your doctor.

If You Take More Activelle Than You Should

If you take more Activelle than you should, talk to a doctor or pharmacist. Overdose of Activelle may cause nausea or vomiting.

If You Forget to Take Activelle

If you forget to take a tablet, take it within the next 12 hours. If more than 12 hours have passed, skip the missed dose and continue taking the tablets at the usual time the next day. Do not take a double dose to make up for a forgotten dose. If you forget a dose, you may experience bleeding or spotting.

Stopping Activelle

If you want to stop taking Activelle, you should talk to your doctor first. Your doctor will explain the effects of stopping treatment and discuss other possible treatments with you. If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

If You Are Going to Have Surgery

If you are going to have surgery, tell the surgeon that you are taking Activelle. You may need to stop taking Activelle 4 to 6 weeks before surgery to reduce the risk of blood clots (see section 2 "Blood clots in the veins"). Do not start taking Activelle again until your doctor tells you to.

4. Possible Side Effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Women taking HRT have an increased risk of developing the following conditions compared to women not taking HRT:

• breast cancer;
• endometrial hyperplasia or endometrial cancer;
• ovarian cancer;
• blood clots in the veins;
• coronary artery disease;
• stroke;
• possibly memory loss, if HRT is started after the age of 65.

For more information, see section 2 "Important information before taking Activelle".

Hypersensitivity (Allergic) Reactions (Uncommon, Affects 1 to 10 Users in 1000)

Hypersensitivity (allergic) reactions are uncommon. Symptoms of hypersensitivity (allergic) reactions may include:

hives, itching, swelling, difficulty breathing, low blood pressure (pale and cold skin, fast heartbeat), dizziness, sweating, which can be symptoms of anaphylactic reaction and/or anaphylactic shock. If you experience any of these symptoms, stop taking Activelle and seek medical help immediately.

Very Common Side Effects (Affects More Than 1 in 10 Users)

• breast tenderness or pain,
• vaginal bleeding.

Common Side Effects (Affects 1 to 10 Users in 100)

• headache,
• weight gain due to fluid retention,
• vaginal infection,
• appearance or worsening of migraine,
• fungal vaginal infection,
• appearance or worsening of depression,
• nausea,
• breast enlargement or swelling,
• back pain,
• uterine fibroids (benign tumors), worsening, appearance, or recurrence,
• swelling of the hands and feet (peripheral edema),
• weight gain.

Uncommon Side Effects (Affects 1 to 10 Users in 1000)

• bloating, abdominal pain, abdominal distension, discomfort, bloating with gas,
• acne,
• hair loss (alopecia),
• excessive hair growth (hirsutism),
• itching or hives,
• phlebitis (inflammation of the veins),
• leg cramps,
• ineffectiveness of the medicine,
• allergic reactions,
• nervousness.

Rare Side Effects (Affects 1 to 10 Users in 10,000)

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

Very Rare Side Effects (Affects Less Than 1 in 10,000 Users)

• endometrial cancer (cancer of the lining of the uterus),
• endometrial hyperplasia (thickening of the lining of the uterus),
• high blood pressure or worsening of hypertension,
• gallbladder disease, appearance or worsening of gallstones,
• excessive oiliness of the skin, appearance of skin rash,
• acute or recurrent angioedema (swelling),
• insomnia, dizziness, anxiety,
• changes in libido,
• vision disturbances,
• weight loss,
• vomiting,
• heartburn (indigestion),
• itching of the vagina and vulva,
• heart attack and stroke,
• generalized allergic reactions (anaphylactic reaction, anaphylactic shock).

Other Side Effects of Combined HRT

• gallbladder disease,
• various skin disorders:
• skin discoloration, especially on the face or neck, known as "pregnancy patches" (chloasma),
• red, painful lumps (erythema nodosum),
• rash, including erythema multiforme (a rash with target-shaped lesions),
• red or purple skin discoloration affecting the skin and/or mucous membranes (purpura).

Reporting Side Effects

If you experience any side effects, including those not listed in this package leaflet, tell your doctor or pharmacist. You can also report side effects directly to the Department of Drug Safety Monitoring, Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products: Al. Jerozolimskie 181C, 02-222 Warsaw, tel.: 22 49-21-301, fax: 22 49-21-309, website: https://smz.ezdrowie.gov.pl. You can also report side effects to the marketing authorization holder.

By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to Store Activelle

Keep out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the label and carton after "EXP". The expiry date refers to the last day of that month. Store below 25°C in a dry place. Do not store in a refrigerator. To protect from light, store in the original packaging. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Contents of the Pack and Other Information

What Activelle Contains

• The active substances are estradiol 1 mg (as estradiol hemihydrate) and norethisterone acetate 0.5 mg.
• The other ingredients are lactose monohydrate, maize starch, copovidone, talc, and magnesium stearate.
• The ingredients of the tablet coating are hypromellose, triacetin, and talc.

What Activelle Looks Like and Contents of the Pack

The tablets are white, round, and 6 mm in diameter. The tablets have "NOVO 288" engraved on one side and the Novo Nordisk logo (Apis bull) on the other. Pack sizes:

• 28 coated tablets in a calendar pack.

Marketing Authorization Holder and Manufacturer

Novo Nordisk A/S, Novo Allé, 2880 Bagsværd, Denmark

For More Information, Contact Your Local Representative of the Marketing Authorization Holder:

Novo Nordisk Pharma Sp. z o.o., Tel.: 22 444 49 00, Fax: 22 444 49 01

Date of Last Revision of the Package Leaflet:

Other Sources of Information

Detailed information on this medicine is available on the website of the Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products: http://www.urpl.gov.pl.

Instructions for the User

How to Use the Calendar Pack

1. Setting the Day Indicator

Turn the inner dial until the day of the week is opposite the small plastic flap.

2. How to Remove the First Tablet

Break off the plastic flap and remove the first tablet.

3. Moving the Dial Each Day

The next day, turn the transparent dial in the direction of the arrow until it clicks, as indicated by the arrow. Remove the next tablet. Remember to take only one tablet a day.

The transparent part can only be turned after the tablet in the hole has been removed.