Activelle

Patient Information Leaflet

Activelle, 1 mg + 0.5 mg, film-coated tablets
Estradiol hemihydrate + Norethisterone acetate
Please read all of this leaflet carefully before taking this medicine, because it contains important information for you.

• Keep this leaflet so that you can read it again if necessary.
• If you have any further questions, please consult your doctor or pharmacist.
• This medicine has been prescribed for a specific individual. Do not pass it on to others. It may harm them even if their symptoms are the same as yours.
• If you experience any adverse effects, including any not listed in this leaflet, inform your doctor or pharmacist. See section 4.

Table of Contents

1. What Activelle is and what it is 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 Activelle is and what it is used for

Activelle is a medicine used in continuous combined hormone replacement therapy (HRT). Activelle contains two female sex hormones: an oestrogen and a progestagen. Activelle is used in postmenopausal women who have been at least one year since their last natural menstrual period.

Activelle is used:
to relieve menopausal symptoms
During menopause, the amount of oestrogen produced by a woman's body decreases. This may cause symptoms such as sudden feelings of heat in the face, neck and chest (‘hot flushes’). Activelle helps relieve these postmenopausal symptoms. Activelle may be prescribed only if these symptoms significantly interfere with your daily life.

for prevention of osteoporosis
After menopause, some women develop brittle bones (osteoporosis). All available treatment options should be discussed with your doctor.
If you are at increased risk of fractures due to osteoporosis and other treatments are not suitable, Activelle may be used to prevent postmenopausal osteoporosis.
Activelle is indicated for women with an intact uterus and who are at least one year postmenopausal.
There is limited experience with the use of Activelle in women over 65 years of age.

2. Information before using Activelle

Medical history and regular medical check-ups
Hormone replacement therapy (HRT) carries risks that should be considered when deciding whether to start or continue hormonal therapy.
Experience with treating women experiencing premature menopause (due to ovarian failure or surgical intervention) is limited. If a woman is undergoing premature menopause, the risks associated with HRT may differ. Please discuss this with your doctor.
Before starting (or resuming) HRT, your doctor should take a full medical and family history. Your doctor may decide to perform medical examinations, including breast and/or gynaecological examinations, if necessary.
If you start taking Activelle, you should have regular medical check-ups (at least once a year). During these visits, you should discuss with your doctor the benefits and risks of continuing treatment with Activelle.
You should undergo regular mammograms as recommended by your doctor.

When not to use Activelle
If any of the conditions listed below are present, or if you have any doubts about the conditions listed below, you must inform your doctor before taking Activelle.
Do not start taking Activelle if:

• you have or have had breast cancer or there is suspicion of it;
• you have or have had, or there is suspicion of an estrogen-dependent tumour , such as cancer of the lining of the womb (endometrial cancer);
• you have unexplained vaginal bleeding ;
• you have excessive growth of the lining of the uterus (endometrial hyperplasia) that is untreated;
• you have or have had blood clots in the veins (venous thromboembolic disease), for example in the legs (deep vein thrombosis) or lungs (pulmonary embolism);
• you have a blood clotting disorder (such as protein C, protein S or antithrombin deficiency);
• you have or have had arterial diseases caused by blood clots, such as heart attack, stroke or angina pectoris ;
• you have or have had liver disease and liver function tests have not returned to normal;
• you have the rare, inherited blood disorder known as porphyria ;
• you are allergic (hypersensitive) to estradiol , norethisterone acetate or any of the other ingredients of Activelle (listed in section 6, "Contents in the pack and other information").

If any of the above conditions occur for the first time while you are taking Activelle, you must stop taking the medicine immediately and contact your doctor.

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. In such cases, your doctor may decide that you require more frequent monitoring:

• fibroids (uterine myomas);
• endometriosis (growth of the lining of the womb outside the uterus) or a history of endometrial hyperplasia;
• factors increasing the risk of blood clots (see "Blood clots in the veins (venous thromboembolic disease)");
• factors increasing the risk of estrogen-dependent cancers (such as breast cancer in mother, sister or grandmother);
• high blood pressure;
• liver disease, e.g. benign liver tumour;
• diabetes;
• gallstones;
• migraine or severe headaches;
• a systemic autoimmune disease affecting multiple organs (systemic lupus erythematosus);
• epilepsy;
• bronchial asthma;
• a disease of the ear leading to progressive hearing loss (otosclerosis);
• high levels of fats (triglycerides) in the blood;
• fluid retention due to heart or kidney dysfunction;
• hereditary or acquired angioedema;
• lactose intolerance.

If any of the following conditions occur while you are taking HRT, you must stop taking Activelle and contact your doctor immediately :

• if any of the conditions listed under "When not to use Activelle" occur;
• if your skin or the whites of your eyes turn yellow (jaundice), which may indicate liver problems;
• if you develop swelling of the face, tongue and/or throat, or difficulty swallowing, or hives together with breathing difficulties, which may indicate angioedema;
• if you develop significantly high blood pressure (symptoms may include headache, fatigue and dizziness);
• if you experience a migraine-type headache for the first time;
• if pregnancy is diagnosed;
• if you experience symptoms of blood clots such as:
  • painful swelling and redness in the legs,
  • sudden chest pain,
  • difficulty breathing. For further information, see section "Blood clots in the veins (venous thromboembolic disease)".

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 need to use an additional method of contraception. Please consult your doctor.

HRT and cancer

Excessive growth of the lining of the uterus (endometrial hyperplasia) and cancer of the lining of the uterus (endometrial cancer)
Taking estrogen-only HRT increases the risk of excessive growth of the lining of the uterus (endometrial hyperplasia) and cancer of the lining of the uterus (endometrial cancer).
The progestagen in Activelle helps 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 beyond the first 6 months,
• occurs after more than 6 months of taking Activelle,
• continues after stopping Activelle,
  you should contact your doctor as soon as possible.

Breast cancer
Evidence shows that taking hormone replacement therapy (HRT) in the form of estrogen combined with progestagen, or estrogen alone, 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 HRT use. After stopping HRT, the additional risk gradually decreases, but the risk may persist for 10 years or longer if HRT was taken for more than 5 years.

Comparison
In women aged 50 to 54 years not taking HRT, breast cancer will be diagnosed in an average of 13 to 17 out of 1,000 women over a 5-year period.
In women aged 50 who start a 5-year course of estrogen-only HRT, the number of cases will be 16–17 per 1,000 women (i.e. 0 to 3 additional cases).
In women aged 50 who start a 5-year course of estrogen-progestagen HRT, the number of cases will be 21 per 1,000 women (i.e. 4 to 8 additional cases).
In women aged 50 to 59 years not taking HRT, breast cancer will be diagnosed in an average of 27 out of 1,000 women over a 10-year period.
In women aged 50 who start a 10-year course of estrogen-only HRT, the number of cases will be 34 per 1,000 women (i.e. 7 additional cases).
In women aged 50 who start a 10-year course of estrogen-progestagen HRT, the number of cases will be 48 per 1,000 women (i.e. 21 additional cases).

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

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

Additionally, participation in available screening mammography programmes is recommended.
It is important to inform the nurse or medical staff performing the X-ray examination that you are taking hormone replacement therapy, as this medicine may increase breast density, which in turn may affect the mammogram results. Not all lumps may be detected during mammography in areas of increased breast density.

Ovarian cancer
Ovarian cancer is rare – significantly rarer than breast cancer. Taking HRT containing only estrogens or a combination of estrogens and progestagens is associated with a slightly increased risk of ovarian cancer.
The risk of ovarian cancer depends on age. For example, in women aged 50 to 54 years not taking HRT, ovarian cancer will be diagnosed in about 2 out of 2,000 women over a 5-year period.
In women who have taken HRT for 5 years, it will occur in about 3 out of 2,000 women (i.e. about 1 additional case).

Effect of HRT on the heart and circulation

Blood clots in the veins (venous thromboembolic disease)
The risk of venous blood clots is 1.3 to 3 times higher in women taking HRT compared to those not taking it, especially during the first year of use.
Venous blood clots can be life-threatening; if they travel to the lungs, they may cause chest pain, shortness of breath, fainting, or even death.
The risk of venous blood clots is higher if you are older or if any of the following risk factors apply. Inform your doctor if:

• you are unable to walk for prolonged periods due to major surgery, injury or illness (see also section 3, "If surgery is planned");
• you are obese (body mass index - BMI > 30 kg/m²);
• you have thromboembolic disorders requiring long-term anticoagulant therapy;
• a close family member has previously had blood clots in the legs, lungs or other organs;
• you have systemic lupus erythematosus;
• you have been diagnosed with cancer.

If symptoms of blood clots occur, see "If any of the following conditions occur while taking HRT, stop taking Activelle and contact your doctor immediately".

Comparison
In women aged 50 to 59 years not taking HRT, the average number of venous blood clot cases over 5 years is estimated at 4 to 7 per 1,000 women.
In women aged 50 to 59 years taking estrogen-progestagen HRT, the number of cases over 5 years will be 9 to 12 per 1,000 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 of age taking estrogen-progestagen HRT, there is a slightly increased tendency to develop coronary heart disease compared to women not taking HRT.

Stroke
The risk of stroke is approximately 1.5 times higher in women taking HRT compared to those not taking it. The number of additional stroke cases caused by HRT use will increase with age.

Comparison
In women aged 50 to 59 years not taking HRT, the average number of stroke cases over 5 years is estimated at 8 per 1,000 women.
In women aged 50 to 59 years taking HRT, the number of cases over 5 years will be 11 per 1,000 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. Please consult your doctor.

Activelle and other medicines
Some medicines may affect the effectiveness of Activelle, which may lead to irregular bleeding. These include:

• antiepileptic drugs (such as: phenobarbital, phenytoin and carbamazepine);
• antituberculosis drugs (such as: rifampicin and rifabutin);
• drugs used in HIV infection (such as: nevirapine, efavirenz, ritonavir and nelfinavir);
• drugs used in hepatitis C (such as telaprevir);
• herbal medicines and other herbal preparations containing St. John's wort ( Hypericum perforatum ).

HRT may affect the action of other medicines:

• the antiepileptic drug lamotrigine, which may lead to increased frequency of seizures;
• drugs used in viral hepatitis C (HCV; e.g. the combination regimen of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, or the regimen of glecaprevir/pibrentasvir) may cause increased liver function blood test results (increased liver enzyme AlAT activity) in women taking combined hormonal contraceptives containing ethinylestradiol. Activelle contains estradiol, not ethinylestradiol. It is not known whether taking Activelle together with these HCV combination therapies may lead to increased AlAT liver enzyme activity.

Other medicines may increase the effect of Activelle:

• medicines containing ketoconazole (an antifungal drug).

Activelle may affect concomitant treatment with cyclosporine.
You should tell your doctor or pharmacist about all medicines you are currently taking or have recently taken, as well as any medicines you plan to take, including over-the-counter medicines, herbal medicines or other natural products. Your doctor will advise you accordingly.

Laboratory tests
If blood tests are required, inform your doctor or laboratory staff that you are taking Activelle, as it may affect the results of certain tests.

Taking Activelle with food and drink
Tablets may be taken with or without food and drink.

Pregnancy and breastfeeding
Pregnancy: Activelle is intended for use only in postmenopausal women. If pregnancy occurs, stop taking Activelle immediately and contact your doctor.
Breastfeeding: Do not take Activelle while breastfeeding.

Driving and using machines
The effect of Activelle on driving or operating machinery is unknown.

Important information about certain ingredients of Activelle
Activelle contains monohydrate lactose. If you have been diagnosed with intolerance to certain sugars, you should contact your doctor before taking Activelle.

3. How to use Activelle

This medicine should always be taken exactly as directed by your doctor. If you are unsure,
you should consult your doctor or pharmacist.
Take one tablet daily at approximately the same time each day.
After using all 28 tablets in the pack, treatment should continue without a break by starting a new pack.
Instructions for using the calendar pack are provided at the end of this leaflet, in the section
entitled “USER INSTRUCTIONS”.
Treatment with Activelle may be started on any day. If the patient has previously been using a
hormone replacement therapy (HRT) product that caused withdrawal bleeding, treatment should begin
immediately after the bleeding has stopped.
Your doctor should prescribe the lowest effective dose that controls symptoms, for the shortest duration
possible. If the patient feels that the dose is too high or too low, she should consult her doctor.
Taking more Activelle than prescribed
If more Activelle has been taken than recommended, consult your doctor or pharmacist immediately.
Overdose of Activelle may cause nausea or vomiting.
Missed dose of Activelle
If a patient forgets to take a tablet at the usual time, she should take it within the next 12 hours.
If more than 12 hours have passed, the missed dose should be skipped and the next tablet should be
taken at the usual time the following day. A double dose should not be taken to make up for a missed dose.
In women with an intact uterus, missing a dose may increase the likelihood of breakthrough bleeding
or spotting.
Stopping Activelle treatment
A decision to stop taking Activelle should first be discussed with a doctor, who will explain the
consequences of stopping treatment and discuss other possible treatment options.
If you have any further questions about the use of this medicine, consult your doctor or pharmacist.
If surgery is planned
If a patient is scheduled for surgery, she should inform the surgeon that she is taking Activelle.
It may be necessary to stop taking Activelle 4 to 6 weeks before surgery to reduce the risk of blood clots
(see section 2. “Blood clots in veins (venous thromboembolic disease)”). Before restarting Activelle,
consult your doctor.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
In women using hormone replacement therapy (HRT), there is an increased risk of developing the following conditions
compared to women not using HRT:

• breast cancer;
• overgrowth or cancer of the lining of the womb (endometrial hyperplasia or cancer);
• ovarian cancer;
• blood clots in the veins of the legs or lungs (venous thromboembolic disease);
• coronary heart disease;
• stroke;
• possible memory loss, if HRT is started after the age of 65.

For further information, see section 2. "Important information before taking
Activelle".
Hypersensitivity (allergy) (uncommon adverse reaction - occurs in 1 to 10 women
per 1000)
Although hypersensitivity (allergy) is an uncommon adverse reaction, it may occur. Symptoms of hypersensitivity (allergy) may include one or more of the following:
urticaria, itching, swelling, difficulty breathing, low blood pressure (pale and cold skin, rapid heartbeat),
dizziness, sweating, which may be signs of an anaphylactic reaction and/or anaphylactic shock. If any of the symptoms listed above occur, you must stop taking Activelle immediately and seek medical help at once.
Very common adverse reactions (affects more than 1 in 10 women)

• breast tenderness or pain,
• vaginal bleeding.

Common adverse reactions (affects 1 to 10 in 100 women)

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

Uncommon adverse reactions (affects 1 to 10 in 1000 women)

• bloating, abdominal pain, abdominal distension, discomfort, flatulence,
• acne,
• hair loss (alopecia),
• excessive hair growth (hirsutism),
• itching or urticaria,
• inflammation of the veins (superficial thrombophlebitis),
• muscle cramps in the lower limbs,
• treatment failure,
• allergic reactions,
• nervousness.

Rare adverse reactions (affects 1 to 10 in 10,000 women)

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

Very rare adverse reactions (affects less than 1 in 10,000 women)

• cancer of the lining of the womb (endometrial cancer),
• overgrowth of the lining of the womb (endometrial hyperplasia),
• high blood pressure or worsening of hypertension,
• gallbladder disease, occurrence or recurrence of gallstones, worsening of symptoms,
• excessive sebum secretion, skin rash,
• acute or recurrent angioedema (vascular swelling),
• insomnia, dizziness, restlessness,
• changes in libido,
• visual disturbances,
• weight loss,
• vomiting,
• heartburn (dyspepsia),
• itching of the vagina and vulva,
• myocardial infarction and stroke,
• generalized allergic reactions (anaphylactic reaction, anaphylactic shock).

Other adverse reactions associated with combined HRT

• gallbladder disorders,
• various skin disorders:
  • skin pigmentation, especially on the face or neck, known as "chloasma" (melasma),
  • red, tender nodules (erythema nodosum),
  • skin rash, including ring-shaped erythematous and oedematous lesions (erythema multiforme),
  • red or purple skin and/or mucosal lesions (vasculitis).

Reporting of adverse reactions
If any adverse reactions occur, including those not listed
in this leaflet, you should inform your doctor, pharmacist, or nurse. Adverse reactions can be reported directly to the Department of Monitoring Adverse Reactions of Medicinal Products at the 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.
Adverse reactions can also be reported to the responsible entity.
Reporting adverse reactions helps 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 stated on the label and outer packaging following "Expiry date". The expiry date refers to the last day of the stated month.
Store below 25 °C in a dry place.
Do not store in the refrigerator.
To protect from light, keep the medicine in the outer packaging.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures 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.
• Other ingredients are: monohydrate lactose, corn starch, copovidone, talc, and magnesium stearate.
• Ingredients of the tablet coating are: hypromellose, triacetin, and talc.

What Activelle looks like and contents of the pack
The coated tablets are white, round, with a diameter of 6 mm. The tablets are embossed with the code NOVO 288 on one side and the Novo Nordisk logo (the Apis bull) on the other side.
Pack sizes:

• 28 coated tablets in a calendar pack.

Marketing Authorisation Holder and Manufacturer
Novo Nordisk A/S
Novo Allé
2880 Bagsværd, Denmark
For further information, please contact the local representative of the Marketing Authorisation Holder:
Novo Nordisk Pharma Sp. z o.o.
Tel.: 22 444 49 00
Fax: 22 444 49 01
Other sources of information
Detailed information on this medicinal product is available on the website of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products http://www.urpl.gov.pl .
USER INSTRUCTIONS
How to use the calendar pack
1. Setting the day indicator
Rotate the inner dial to align the day of the week 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, rotate the transparent dial clockwise by one position, as indicated by the arrow. Remove the next tablet. Remember to take only one tablet per day.
The transparent part can only be rotated after removing the tablet located in the opening.