АКТИВЕЛЛЕ Coated tablet

Содержание инструкции

1. Activelle 1 mg/0.5 mg film-coated tablets
   1. What is Activelle and what is it 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
   7. Select the desired day
   8. How to take the tablet on the first day
   9. Move the selector every day
2. Activelle 0.5 mg/0.1 mg film-coated tablets
   1. What is Activelle and what it is used for
   2. What you need to know before taking Activelle
   3. How to use Activelle
   4. Possible side effects
   5. How to store Activelle
   6. Package Contents and Other Information
   7. Select the desired day
   8. Take the tablet for the first day
   9. Move the selector every day

Activelle 1 mg/0.5 mg film-coated tablets

Estradiol/norethisterone acetate

Read this leaflet carefully before you start taking this medicine because it contains important
information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you personally. Do not pass it on to others. Even if their symptoms of the illness are the same as yours, it could be harmful.
• If you get any side effects, even those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet:

• 1. What Activelle is and what it is used for
• 2. What you need to know before you take 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 combined continuous Hormone Replacement Therapy (HRT). It contains two types
of female hormones, an estrogen and a progestin. Activelle is used in postmenopausal women who have been
without a natural menstrual period for at least one year.
Activelle is used for:

Relief of symptoms that occur after menopause
During menopause, the amount of estrogen produced by a woman's body decreases. This can
cause symptoms, such as hot flushes on the face, neck and chest (‘hot flashes’). Activelle relieves these
symptoms after menopause. Activelle will only be prescribed to you if your symptoms seriously interfere with your
daily life.

Prevention of osteoporosis
After menopause some women may develop fragile bones (osteoporosis). You should discuss all the
available options with your doctor..
If you have a high risk of fractures due to osteoporosis and other medicines are not suitable for you, you can use
Activelle to prevent osteoporosis after menopause.
Activelle is prescribed to women who have not had their uterus removed and whose menstrual cycles have stopped more than
one year ago.
There is limited experience with Activelle treatment in women over 65 years of age.

2. What you need to know before taking Activelle

Medical history and regular medical check-ups
The use of HRT involves risks that must be considered when deciding to start taking the
therapy, or if you decide to continue taking it.
Experience in treating women with premature menopause (due to ovarian insufficiency or
surgery) is limited. If you have premature menopause, the risks associated with the use of HRT may differ.
Talk to your doctor.
Before starting to take (or restarting) Activelle, your doctor will ask about your medical history and
that of your family. The doctor will perform a physical examination. This includes a breast exam and/or an
internal examination, if necessary.
After starting treatment with Activelle, you should see your doctor for regular check-ups (at least once a
year). During these check-ups, discuss with your doctor the benefits and risks of continuing
therapy with Activelle.
Undergo regular breast screening, as recommended by your doctor.

Do not take Activelle
If you are in any of the conditions listed below. If you are unsure about any of the following points, talk to your
doctorbefore taking Activelle.
Do not take Activelle:

• If you have or have had, or there is a suspicion that you have breast cancer.
• If you have or have had a cancer sensitive to estrogens, such as a cancer of the uterine lining (endometrium) or suspect you have it.
• If you have unexpected vaginal bleeding.
• If you have excessive thickening of the uterine lining(endometrial hyperplasia) that has not been treated.
• If you have or have had the presence of blood clots in a blood vessel(thrombosis), in the legs (deep vein thrombosis) or in the lungs (or pulmonary embolism).
• If you have a blood coagulation disorder(such as protein C, protein S or antithrombin deficiency).
• If you have or have previously had a problem caused by blood clots in the arteries such as a heart attack, stroke or angina.
• If you have or have had liver diseaseor your liver function tests have not returned to normal.
• If you have a rare blood diseaseof hereditary type called "porphyria".
• If you are allergic(hypersensitive) to estradiol, noretisterone acetateor any of the excipients of Activelle (listed in section 6 “Contents of the pack and other information”).

If any of the conditions listed above occur for the first time during the use of Activelle, stop the
treatment and consult your doctor immediately.

Warnings and precautions
Tell your doctor if you have ever had any of the following problems before starting treatment, as
these conditions may recur or worsen during treatment with Activelle. If so, you should
see your doctor more often for medical check-ups:

• fibroids inside the uterus
• thickening of the uterine lining (endometriosis) or excessive thickening of the uterine lining (endometrial hyperplasia)
• increased risk of developing blood clots (see ‘Blood clots in a blood vessel (thrombosis)’)
• increased risk of developing estrogen-dependent tumors (such as having a mother, sister or grandmother who have had breast cancer)
• high blood pressure.
• liver disorders, such as a benign liver tumor
• diabetes
• gallstones
• migraines or severe headaches
• an autoimmune disease that affects many organs of the body (systemic lupus erythematosus (SLE) -
• epilepsy
• asthma
• a disease that affects the eardrum and hearing (otosclerosis).
• a very high level of fats in the blood (hypertriglyceridemia)
• fluid retention due to heart and kidney disorders
• lactose intolerance .

Stop taking Activelle and contact your doctor immediately
If you notice any of the following conditions listed below, when taking HRT:

• any of the conditions listed in section 2 “Do not take Activelle”
• yellowing of the skin or whites of the eyes (jaundice). These may be signs of liver problems
• increased blood pressure (symptoms may be headache, fatigue and dizziness)
• migraine-type headache for the first time
• if you are pregnant
• if you experience signs of a blood clot such as:
• painful swelling and redness in the legs
• sudden chest pain
• difficulty breathing. For more information, see ‘Blood clots in a blood vessel (thrombosis)’.

Note: Activelle is not a contraceptive. If less than 12 months have passed since your last menstrual period or
you are under 50 years of age, you may still need contraception to prevent pregnancy. Talk to your
doctor for advice.

HRT and cancer
Excessive thickening of the uterine lining (endometrial hyperplasia) and cancer of the
uterine lining (endometrial cancer)
Treatment based solely on estrogens will increase the risk of excessive thickening of the uterine
lining (endometrial hyperplasia) and cancer of the uterine lining (endometrial cancer).
The progestin contained in Activelle protects you from the additional risk.

Irregular bleeding
You may experience irregular bleeding or spotting during the first 3-6 months of
taking Activelle.
However, if irregular bleeding:

• occurs after the first 6 months
• starts after taking Activelle for more than 6 months
• occurs after stopping taking Activelle

consult your doctor as soon as possible.

Breast cancer
Evidence suggests that taking a combination of estrogens and progestins and possibly even estrogen alone increases the risk of breast cancer. The additional risk depends on the duration of HRT use
and is visible within a few years. However, it returns to normal within a few years (at most within 5 years)
after stopping treatment.

Comparative data
In women aged 50-79 who do not take HRT, breast cancer is diagnosed on average from
9 to 17 cases per 1,000 over a period of over 5 years.
For women aged 50-79 who take combined estrogen/progestin HRT for over 5 years, there are 13 to 23 cases per 1,000 women (additional 4 to 6 cases).
Regular breast screening. Consult your doctor if you notice changes such as:

• skin dimples
• changes in the nipple
• any lumps that can be seen or felt.

In addition, when offered, it is recommended to participate in a mammography screening program.
During mammography screening, it is important to inform the nurse/healthcare professional performing the
mammogram that you are taking HRT, as treatment may increase breast density affecting the outcome
of the mammogram itself. In areas where breast density is increased, mammography may not detect
all nodules.

Ovarian cancer
Ovarian cancer is rare, much rarer than breast cancer. The use of estrogen-only or estrogen-progestin therapy has been associated with a slight increase in the risk of ovarian cancer. The
risk of ovarian cancer varies depending on age. For example, in women aged 50-54 who
do not take HRT, about 2 women out of 2,000 will be diagnosed with ovarian cancer over a period of over
5 years.
For women who have taken HRT for more than 5 years, there are 3 cases per 2,000 users (e.g. about one
additional case).

Effect of HRT on heart and circulation
Blood clots in a blood vessel (thrombosis)
The risk of developing blood clots in a blood vesselis approximately 1.3-3 times higher in women
who take HRT compared to women who do not, especially during the first year of treatment.
Blood clots can be serious and if one reaches the lungs, it can cause chest pain, shortness of breath,
collapse or even death.
You are more likely to have a blood clot in the blood vessels if you are older and if one or more of the
following situations apply to you. Tell your doctor in any of the following cases:

• if you cannot walk or must be immobilized for a long time due to surgery, trauma or illness (see also the paragraph “If you need surgery”)
• if you are excessively overweight (BMI >30 kg/m²)
• if you have had problems with blood clotting for which you have needed long-term treatment with a drug used to prevent thrombosis
• if you or a family member has had a thrombus in the legs, lungs or other organ in the past
• if you suffer from systemic lupus erythematosus (SLE)
• if you have cancer.

For signs of blood clots, see “Stop taking Activelle and contact your doctor immediately”

Comparative data
Among women aged 50 who do not take HRT, on average over a period of over 5 years, a blood clot in a blood vessel may be expected in 4 to 7 cases per 1,000 women.
For women aged 50 who take combined estrogen/progestin HRT for over 5 years, the number of cases is
from 9 to 12 cases per 1,000 women (5 additional cases).

Heart disorders (heart attack)
There is no evidence that HRT helps prevent heart attack. Women over 60 who
take estrogen/progestin HRT have a slight increase in the likelihood of developing heart disorders
compared to women who do not take HRT.

Stroke
The risk of having a stroke is approximately 1.5 times higher in women who take HRT compared to women who
do not. The number of additional cases of stroke due to the use of HRT will increase in relation
to increasing age.

Comparative data
Among women aged 50 who do not take HRT, in a period of over 5 years, a stroke may be expected on average in 8 cases per 1,000.
For women aged 50 who take HRT for over 5 years, the number of cases is 11 per 1,000 women over 5 years (3 additional cases).

Other conditions
HRT has no preventive effect on memory loss. There is some evidence of a higher risk of
memory loss in women who start any type of HRT after age 65. Talk to your doctor for
advice.

Taking Activelle with other medicines
Some medicines may interfere with the effect of Activelle. This may lead to irregular bleeding. This applies to:

• medicines used for epilepsy(such as phenobarbital, phenytoin and carbamazepine)
• medicines used for tuberculosis(such as rifampicin and rifabutin)
• medicines used for HIVinfection (such as nevirapine, efavirenz, ritonavir and nelfinavir)
• St. John's wort(Hypericum perforatum)
• medicines for hepatitis C (such as telaprevir)

Other medicines may increase the effects of Activelle:

• medicines containing ketoconazole(an antifungal).

Activelle may have an impact on the concomitant administration of cyclosporine.

Tell your doctor or pharmacist,if you are taking or have recently taken other medicines, including
medicines obtained without a prescription, herbal medicines or other natural products.

Laboratory tests
If you need a blood test, tell your doctor or laboratory staff that you are taking
Activelle, as this medicine 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 only for use in postmenopausal women. If you are pregnant, stop Activelle
immediately and contact your doctor.

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

Driving and using machines
Activelle has no known effect on the ability to drive or operate machinery.

Important information about some excipients in Activelle
Activelle contains lactose monohydrate. If your doctor has diagnosed you with intolerance to some sugars,
contact him before taking this medicine.

3. How to take Activelle

Always take this medicine exactly as your doctor has told you. Always consult your doctor or pharmacist if you have any doubts.

Take one tablet once a day, preferably at the same time each day.Once you have taken all 28 tablets in the pack, start a new pack continuing treatment without interruption.
For further information on how to use the calendar pack, see “Instructions for Use” at the end of the

You can start treatment with Activelleon any day of the week. However, if you are switching to Activelle therapy after hormone replacement therapy that causes monthly bleeding, treatment with Activelle should begin immediately after the end of the bleeding.
For the treatment of symptoms, the doctor should use the lowest dose for the shortest period of time necessary. Contact your doctor if you think the dose is too high or not sufficient.

If you take more Activelle than you should
If you have taken more Activelle tablets than you should, inform your doctor or pharmacist. An overdose of Activelle may induce discomfort or vomiting.

If you forget to take Activelle
If you have forgotten to take the tablet at the usual time, do so within the next 12 hours. If more than 12 hours have passed, skip the missed dose and resume normally the next day. Do not take a double dose if you have forgotten a tablet. Missing a dose may increase the likelihood of bleeding and spotting if you still have a uterus.

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

If you need surgery
If you are going to have surgery, tell the surgeon that you are taking Activelle. It may be necessary to stop taking Activelle for about 4 - 6 weeks before surgery to reduce the risk of a blood clot (see section 2, "Blood clots in a blood vessel (thrombosis)"). Ask your doctor when you can start taking Activelle again.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The following diseases are reported more often in women using TOS than in women who do not use
TOS:

• breast cancer
• excessive thickening or tumor of the uterine lining (endometrial hyperplasia or tumor)
• ovarian cancer
• blood clots in the blood vessels of the legs or lungs (venous thromboembolism)
• heart disorders
• stroke
• probable memory loss if TOS is started after the age of 65. For more information on these side effects see section 2. “What you need to know before you take Activelle”.

Hypersensitivity/allergy(uncommon side effect – occurs in 1 to 10 users out of 1,000)
Although it is an uncommon event, 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 (paleness and cold skin, rapid heartbeat), dizziness,
sweating, which may be signs of anaphylactic reactions/shock. If you experience any of the symptoms
mentioned, stop taking Activelle and seek immediate medical assistance.

Very common side effects(which occur in 1 in 10 users)

• breast pain or tenderness
• vaginal bleeding.

Common side effects(which occur in 1 to 10 users out of 100)

• headache
• weight gain due to fluid retention
• vaginal inflammation
• onset or worsening of migraine
• vaginal fungal infection
• depression or worsening of existing depression
• nausea
• breast enlargement or swelling (breast edema)
• back pain
• uterine fibroma (benign tumor): worsening, onset or recurrence
• swelling of the arms and legs (peripheral edema)
• weight gain.

Uncommon side effects(which occur in 1 to 10 users out of 1,000)

• bloating, abdominal pain, discomfort or flatulence
• acne
• hair loss (alopecia)
• abnormal hair growth (hirsutism)
• itching or hives
• inflammation of a vein (superficial thrombophlebitis)
• leg cramps
• drug ineffectiveness
• allergic reaction
• nervousness

Rare side effects(which occur in 1 to 10 users out of 10,000)

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

Very rare side effects(which occur in less than 1 in 10,000 users)

• tumor of the uterine lining (endometrial cancer)
• excessive thickening of the uterine lining (endometrial hyperplasia)
• increased blood pressure or worsening of already high blood pressure
• gallbladder disorders, onset/recurrence of gallstones or worsening
• excessive sebum secretion, skin rashes
• acute or recurrent manifestations of edema (angioedema)
• insomnia, dizziness, anxiety
• changes in sexual desire
• vision changes
• weight loss
• vomiting
• heartburn
• vaginal and genital itching
• heart attacks or strokes

Other side effects of combined TOS

• Gallbladder disorders
• Various skin and subcutaneous tissue pathologies:
• Skin discoloration, particularly on the face or neck, known as “melasma gravidarum” (melasma)
• Painful red-purple nodules (erythema nodosum)
• Skin rash with redness or target lesions (erythema multiforme)
• Purple or dark red spots on the skin and/or mucous membranes (vascular purpura).

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any side effects not listed in this leaflet.
You can also report side effects directly through the national reporting system
at www.aifa.gov.it/content/segnalazioni-reazioni-avverse .
By reporting side effects you can help provide more information on the safety of this
medicine.

5. How to store 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 the packaging after
“EXP”. The expiry date refers to the last day of the month indicated.
Do not store at a temperature above 25  C.
Do not refrigerate.
Keep the container in the outer packaging to protect it from light.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment .

6. Contents of the pack and other information

What Activelle contains

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

Description of the appearance of Activelle and contents of the pack
The film-coated tablets are white, round with a diameter of 6 mm. The tablets are imprinted
with the inscription NOVO 288 on one side and the Novo Nordisk symbol (Apis bull) on the other.
Pack size:

• 1 x 28 film-coated tablets in calendar packs
• 3 x 28 film-coated tablets in calendar packs

Not all pack sizes may be available.

Marketing Authorisation Holder:
Novo Nordisk SpA
Via Elio Vittorini 129
00144 Rome, Italy

Manufacturer
Novo Nordisk A/S
Novo Allé
DK-2880 Bagsværd
Denmark

This medicinal product is authorised in the Member States of the European Economic Area under the
followingnames: Member States of the European Economic Area: Activelle except for Great
Britain: Kliovance.

Other sources of information
More detailed information on this medicine is available on the website of the Italian Medicines Agency

Instructions for use
How to use the calendar pack

1. Select the desired day

Rotate the inner dial to set the day of the week corresponding to the plastic tab.

2. How to take the tablet on the first day

Detach the plastic tab and release the first tablet.

3. Move the selector every day

The following day, simply move the transparent dial clockwise by 1 space as indicated by the
arrow. Extract the next tablet. Remember to take only 1 tablet once a day.

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

Activelle 0.5 mg/0.1 mg film-coated tablets

Estradiol/norethisterone acetate

Read this leaflet carefully before you start taking this medicine as it contains important
information for you.

• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others, even if their symptoms are the same as yours, because this medicine could be harmful.
• If you get any side effects, even those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

In this leaflet

• 7. What Activelle is and what it is used for
• 8. What you need to know before you take Activelle
• 9. How to use Activelle
• 10. Possible side effects
• 11. How to store Activelle

• 12. Contents of the pack and other information

1. What is Activelle and what it is used for

Activelle is a medicine for Combined Continuous Hormone Replacement Therapy (HRT). It contains two types
of female hormones, an estrogen and a progestin. Activelle is used in postmenopausal women for whom at least one year has
passed since the last natural menstrual period.
Activelle is used for:

Relief of symptoms that occur after menopause
During menopause, the amount of estrogen produced by a woman's body decreases. This can
cause symptoms such as flushing of the face, neck and chest (hot flashes). Activelle relieves these symptoms
after menopause. Activelle will only be prescribed to you if these symptoms seriously interfere with your daily
life.
Activelle is prescribed to women whose uterus has not been removed and whose menstrual cycles have ended for
more than one year.
Experience in the treatment of women over 65 years of age is limited.

2. What you need to know before taking Activelle

Medical history and regular medical check-ups
The use of HRT can lead to risks that must be considered when deciding to start therapy or if you decide to continue taking it.
There is limited experience in the treatment of women with premature menopause (due to early menopause or surgery on the ovaries). If you have premature menopause, the risk when using HRT may be different. Talk to your doctor.
Before starting (or resuming) HRT, your doctor will ask you about your personal and family medical history and decide to perform a physical examination. This may include a breast exam and/or a gynecological examination, if necessary.
After starting treatment with Activelle, you should see your doctor for regular check-ups (at least once a year). During these check-ups, your doctor can discuss the benefits and risks of continuing therapy with Activelle.
Undergo regular breast screening, as recommended by your doctor.

Do not take Activelle
If you are in any of the conditions listed below. If you are unsure about any of the points listed below, talk to your doctorbefore taking Activelle.
Do not take Activelle:

• If you have or have had, or there is a suspicion that you have breast cancer.
• If you have, have had, or there is a suspicion of cancer of the uterine lining(endometrial cancer) or any other estrogen-dependent cancer.
• If you have unexplained vaginal bleeding.
• If you have or have had a thickening of the uterine lining (endometrial hyperplasia)that has not been treated.
• If you have or have ever had blood clots in a blood vessel(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 previously had diseases caused by a clot in the arteries such as a heart attack, stroke or angina.
• If you have or have ever had liver diseaseand your liver function tests have not returned to normal.
• If you have a rare blood disease of hereditary type called ‘porphyria’.
• If you are allergic (hypersensitive)to estradiol, norethisterone acetate or any of the excipients of Activelle (listed in section 6 ‘Contents of the pack and other information’).

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

Warnings and precautions
If you have or have ever had any of the following problems, talk to your doctor before starting treatment, as these conditions may recur or worsen during treatment with Activelle. If so, your doctor may need to see you more often for medical check-ups:

• uterine fibroids
• growth of the uterine lining (endometriosis) or a history of excessive growth of the uterine lining (endometrial hyperplasia).
• increased risk of developing blood clots (see ‘Blood clots in a blood vessel’) (thromboembolism)
• increased risk of developing an estrogen-dependent cancer (if you have a mother, sister or grandmother who have already had this cancer)
• high blood pressure
• liver disorders, such as a benign liver tumor.
• diabetes
• gallstones
• migraines or severe headaches
• autoimmune disease affecting some organs of the body (systemic lupus erythematosus, SLE)
• epilepsy
• asthma
• a disorder affecting the eardrum and hearing (otosclerosis)
• high levels of fats in the blood (hypertriglyceridemia)
• fluid retention due to heart or kidney problems
• conditions in which the thyroid gland fails to produce enough thyroid hormone (hypothyroidism) and is treated with thyroid hormone replacement therapy
• hereditary condition that causes severe episodes of swelling (hereditary angioedema) or if you have had sudden episodes of swelling of the hands, face, feet, lips, eyes, tongue, throat (blockage of the airways) or digestive tract
• lactose intolerance.

Stop treatment with Activelle and consult a doctor immediately
If you notice any of the following conditions while taking HRT:

• any of the conditions mentioned in the ‘Do not take Activelle’ section
• yellowing of the skin and eyes (jaundice). These may be signs of a liver disorder
• a significant increase in blood pressure (symptoms may include headache, fatigue and dizziness)
• migraine-type headache that you have never had before
• if you become pregnant
• if you experience signs of a blood clot such as:
• painful and red swelling of the legs
• sudden chest pain
• difficulty breathing. For more information see ‘Blood clots in a blood vessel (venous thromboembolism)’.

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 additional contraception to prevent pregnancy. Talk to your doctor for advice.

HRT and cancer
Excessive thickening of the uterine lining (endometrial hyperplasia) and cancer of the uterine lining (endometrial cancer)
Taking HRT based on estrogen alone will increase the risk of excessive thickening of the uterine lining (endometrial hyperplasia) and cancer of the uterine lining (endometrial cancer).
The progestin that Activelle contains protects you from the additional risk.
Comparative data
In women who still have a uterus and who are not following HRT, endometrial cancer is diagnosed on average in 5 cases per 1,000 women between 50-65 years of age.
In women aged 50-65 who still have a uterus and who are taking HRT based on estrogen alone, endometrial cancer is diagnosed on average between 10 and 60 cases per 1,000 women (between 5 and 55 additional cases) depending on the dose and duration of intake.

Irregular bleeding
You may experience irregular bleeding or spotting during the first 3-6 months of taking Activelle. In particular if the irregular bleeding:

• continues beyond the first 6 months
• occurs after starting treatment with Activelle for more than six months
• continues after stopping treatment with Activelle contact your doctor as soon as possible. Breast cancer Evidence suggests that taking a combination of estrogens and progestins and possibly even estrogen alone increases the risk of breast cancer. The additional risk depends on the duration of HRT use and becomes visible within a few years. However, it returns to normal within a few years (at most within 5 years) after stopping treatment.

Comparative data
In women aged 50-79 who do not take HRT, breast cancer is diagnosed on average from 9 to 17 cases per 1,000 women over a period of over 5 years.
For women aged 50-79 who take combined estrogen/progestin HRT for over 5 years, 13 to 23 cases are diagnosed per 1,000 users (4 to 6 additional cases).

Check your breasts regularly. Contact your doctor if you notice any changes such as:

• skin dimples
• changes in the nipple
• any lumps you see or feel.

In addition, when offered, it is recommended to participate in a mammography screening program. During mammography screening, it is important to inform the nurse/healthcare professional performing the mammography that you are taking HRT, as treatment may increase breast density affecting the outcome of the mammography itself. In areas where breast density is increased, mammography may not detect all lumps.

Ovarian cancer
Ovarian cancer is rare - much rarer than breast cancer. The use of estrogen-only or estro-progestin therapy has been associated with a slight increase in the risk of ovarian cancer. The risk of ovarian cancer varies depending on age. For example, in women aged 50-54 who do not take HRT, about 2 women out of 2,000 will be diagnosed with ovarian cancer over a period of over 5 years.
For women who have taken HRT for more than 5 years, there are 3 cases per 2,000 users (about one additional case).

Effect of HRT on heart and circulation
Blood clots in a blood vessel (venous thromboembolism)
The risk of developing blood clots in blood vesselsis approximately 1.3-3 times higher in women taking HRT compared to women who are not taking it, especially during the first year of treatment.
Blood clots can be serious and if one reaches the lungs, it can cause chest pain, shortness of breath, fainting or even death.
You are more likely to have a blood clot in the blood vessels if you are elderly and if one of the following situations applies to you. Inform your doctor in any of the following cases:

• if you cannot walk for a long period due to surgery, trauma or illness (see also section 3 “If you need surgery”)
• if you are excessively overweight (BMI > 30 kg/m)
• if you have blood clotting problems for which you need long-term treatment with a medicine used to prevent blood clots
• if a relative has or has had in the past a clot in the legs, lungs or other organ
• if you suffer from systemic lupus erythematosus (SLE)
• if you have cancer.

For signs of blood clots see ‘Stop treatment with Activelle and consult a doctor immediately’.

• Comparative data Among women aged 50 who do not take HRT, on average over a period of over 5 years, a blood clot in a vein can be expected in 4 to 7 cases per 1,000 women. For women aged 50 who take combined estrogen/progestin HRT for over 5 years, 9 to 12 cases are diagnosed per 1,000 users (5 additional cases).

Heart disorders (heart attack)
There is no evidence that HRT prevents heart attack. Women over 60 who take estrogen/progestin HRT have a slight increase in the likelihood of developing heart disorders compared to women who do not take HRT.

Stroke
The risk of having a stroke is approximately 1.5 times higher in women taking HRT compared to women who are not taking it. The number of additional cases of stroke due to HRT use will increase in relation to increasing age.
Comparative data
Among women aged 50 who do not take HRT, on average over a period of over 5 years, 8 cases of stroke can be expected per 1,000. For women aged 50 who have been taking HRT for over 5 years, 11 cases are diagnosed per 1,000 users (3 additional cases).

Other conditions
HRT does not prevent memory loss. The risk of memory loss is higher in women who start a type of HRT after age 65. Talk to your doctor for advice.

Taking Activelle with other medicines
Some medicines can interfere with the effect of Activelle. These can lead to irregular bleeding. This refers 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 medicines containing St. John's wort(Hypericum perforatum).

Other medicines may increase the effects of Activelle:

• medicines containing ketoconazole(an antifungal).

Activelle may have an impact on the concomitant treatment with cyclosporine.

Tell your doctor or pharmacistif you are taking or have recently taken other medicines including over-the-counter medicines, herbal medicines or other natural products.

Laboratory tests
If you need to have blood tests, tell your doctor or laboratory personnel that you are taking Activelle, as this medicine 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 only indicated for women in postmenopause. If you are pregnant, stop Activelle immediately and contact your doctor.

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

Driving and using machines
Activelle has no known effect on the ability to drive or operate machinery.

Important information about some excipients of Activelle:

• Activelle contains lactose monohydrate. If your doctor has diagnosed you with intolerance to some sugars, contact him before taking this medicine.

3. How to use Activelle

Always take this medicine exactly as your doctor has told you. Always consult your doctor or pharmacist if you have any doubts.

Take one tablet once a day, preferably at the same time each day.Take the tablet with a glass of water.

Take one tablet a day without interruption.When you have used all 28 tablets from the calendar pack, start a new one.
For further information on using the calendar pack, read USER INSTRUCTIONS
You can start treatment with Activelleon any day of the week. However, if you are switching from hormone replacement therapy that causes monthly bleeding, treatment should begin immediately after the end of the bleeding.
For the treatment of symptoms, the doctor should use the lowest dose to treat the symptoms for the shortest period of time necessary. Contact your doctor if you think this dosage is too strong or not strong enough.

If you take more Activelle than you should
If you have taken more Activelle tablets than you should, inform your doctor or pharmacist as soon as possible.
Taking more estrogens than prescribed by your doctor can cause breast tenderness, nausea, vomiting and/or irregular vaginal bleeding (metrorrhagia). Taking more progestogens than prescribed by your doctor can lead to a depressive state, acne or growth of body and facial hair (hirsutism).

If you forget to take Activelle
If you have forgotten to take the tablet as usual, try to do so within the next 12 hours. If more than 12 hours have passed, resume normally the next day. Do not take a double dose if you have forgotten a tablet.
Missing a dose may increase the likelihood of bleeding and spotting if you still have a uterus.

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

If you need surgery
If you are about to undergo surgery, tell the surgeon that you are taking Activelle. You may need to stop Activelle for 4-6 weeks before the operation to reduce the risk of a thrombus (see ‘Blood clots in a blood vessel (venous thromboembolism)’ in paragraph 2). Ask your doctor when you can start treatment with Activelle again.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The following conditions are reported much more often in women using TOS than in those who do not
use TOS:

• breast cancer
• excessive thickening or cancer of the uterine lining (endometrial hyperplasia or cancer)
• ovarian cancer
• blood clots in the blood vessels of the legs or lungs (venous thromboembolism)
• heart disorders
• stroke
• probable memory loss if TOS is started over the age of 65. For further information on these side effects, see section 2, ‘What you need to know before you take Activelle’.

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

• Vaginal bleeding

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

• Fungal infections of the genitals or vaginal inflammation
• Excessive growth of the uterine lining (endometrial hyperplasia)
• Feeling unwell
• Stomach pain
• Back or neck pain
• Pain in the arms or legs
• Headache.

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

• Allergic reaction (hypersensitivity)
• Depression or worsening of existing depression
• Nervousness
• Dizziness
• Migraine (see ‘Do not take Activelle’ in section 2)
• Breast pain or discomfort
• Abdominal bloating or discomfort
• Weight gain due to fluid retention
• Swelling of the arms and legs (peripheral edema)
• Leg cramps
• Heartburn (dyspepsia)
• Acne
• Hair loss (alopecia)
• Itching and hives.

Very rare side effects (may affect up to 1 in 10,000 people)

• Generalised hypersensitivity reactions (e.g. anaphylactic/shock) have been reported.

Other side effects of combined TOS
Gallbladder disease
Various skin diseases:
skin discolouration, particularly on the face and neck, known as “chloasma” (pregnancy mask)
painful, reddish skin nodules (erythema nodosum)
skin rash with redness and sores (erythema multiforme)
purple or dark red spots visible through the skin (vascular purpura)

• dry eyes, alteration of the tear film composition.

Reporting of side effects
If you get any side effects, even those not listed in this leaflet, tell your doctor or pharmacist.
You can also report side effects directly through the national reporting system
at www.aifa.gov.it/content/segnalazioni-reazioni-avverse .
By reporting side effects you can help provide more information on the safety of this
medicine.

5. How to store 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 the outer packaging
after “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 should not be disposed of via wastewater or household waste. Ask your pharmacist how
to dispose of medicines you no longer use. This will help protect the environment.

6. Package Contents and Other Information

What Activelle contains

• The active ingredients are estradiol and norethisterone acetate. Each tablet contains 0.5 mg estradiol (as hemihydrate) and 0.1 mg norethisterone acetate.
• The other ingredients are: lactose monohydrate, corn starch, hydroxypropylcellulose, magnesium stearate, hypromellose, triacetin and talc.

Description of the appearance of Activelle and package contents
The film-coated tablets are white, round with a diameter of 6 mm. The tablets are imprinted
with the inscription NOVO 291 on one side and the Novo Nordisk logo (APIS bull) on the other.
Package size:

• 28 film-coated tablets
• 3 x 28 film-coated tablets Not all pack sizes may be marketed.

Marketing Authorisation Holder
Novo Nordisk SpA
Via Elio Vittorini, 129

• 00144 - Rome

Manufacturer
Novo Nordisk A/S
Novo Allé
DK-2880 Bagsværd
Denmark

This product is authorised in the Member States of the European Economic Area under the following
names:
Activelle: Austria, Portugal
Activelle low: Denmark, Iceland, Italy,
Activelle minor: Belgium, Luxembourg
Eviana: Estonia, Hungary, Netherlands, Norway, Spain, Sweden
Noviana: Finland

Other sources of information
More detailed information on this medicine is available on the website of the Italian Medicines Agency

INSTRUCTIONS FOR USE
How to use the calendar pack

2. Select the desired day

• 1. Rotate the inner disc to set the day of the week corresponding to the plastic tab.

4. Take the tablet for the first day

Detach the plastic tab and release the first tablet.

5. Move the selector every day

Simply move the transparent disc clockwise by 1 space as indicated by the arrow. Extract the next tablet. Remember to take only 1 tablet once a day.

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