Activelle

Package leaflet: Information for the user

Activelle 1 mg/0.5 mg film-coated tablets

Estradiol/norethisterone acetate
Please read this leaflet carefully before 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. Never give it to others. Even if their symptoms are the same as yours, it could be harmful.
• If you experience any side effects, including those not listed in this leaflet, contact 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 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) medicine. It contains two types
of female hormones, an oestrogen and a progestogen. 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 postmenopausal symptoms
During menopause, the amount of oestrogen produced by a woman's body decreases. This can cause
symptoms such as sudden feelings of heat in the face, neck and chest (‘hot flushes’). Activelle relieves these
symptoms after menopause. Your doctor will prescribe Activelle only if your symptoms are seriously affecting
your daily life.
Prevention of osteoporosis
After menopause, some women may develop brittle bones (osteoporosis). You should discuss all available
treatment options with your doctor.
If you have a high risk of fractures due to osteoporosis and other medicines are not suitable for you,
Activelle may be used to prevent osteoporosis after menopause.
Activelle is prescribed to women who still have their uterus and whose menstrual cycles have stopped for
more than one year.
There is limited experience with treatment using Activelle in women over 65 years of age.

2. What you should know before taking Activelle

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

Do not take Activelle
If you have, have had, or are suspected of having any of the following conditions. If you are unsure about any of the following points, talk to your doctor before taking Activelle.
Do not take Activelle:

• If you have, have had, or are suspected of having breast cancer.
• If you have, have had, or are suspected of having an estrogen-dependent tumour, such as a tumour of the lining of the womb (endometrium).
• If you have unexpected vaginal bleeding.
• If you have excessive thickening of the lining of the womb (endometrial hyperplasia) that has not been treated.
• If you have, or have had blood clots in a blood vessel (thrombosis), in the legs (deep vein thrombosis) or in the lungs (pulmonary embolism).
• If you have a blood clotting disorder (such as protein C deficiency, protein S deficiency, or antithrombin deficiency).
• If you have, or have previously had, a condition caused by blood clots in the arteries, such as heart attack, stroke, or angina.
• If you have, or have had liver disease, or if your liver function tests have not 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 excipients of Activelle (listed in section 6 “Contents of the pack and other information”).

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

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

• Fibroids in the uterus
• Thickening of the lining of the womb (endometriosis) or excessive thickening of the lining of the womb (endometrial hyperplasia)
• Increased risk of developing blood clots (see 'Blood clots in a blood vessel (thrombosis)')
• Increased risk of developing estrogen-dependent tumours (such as having a mother, sister, or grandmother who had breast cancer)
• High blood pressure
• Liver disorders, such as a benign liver tumour
• Diabetes
• Gallstones
• Migraine or severe headaches
• An autoimmune disease affecting multiple organs of the body (systemic lupus erythematosus (SLE))
• Epilepsy
• Asthma
• A disease affecting the eardrum and hearing (otosclerosis)
• Very high levels of fat in the blood (hypertriglyceridaemia)
• Fluid retention due to heart or kidney disorders
• Lactose intolerance

Stop treatment with Activelle and contact your doctor immediately
If you experience any of the following conditions while 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 could be signs of liver problems
• Increased blood pressure (symptoms may include headache, fatigue, and dizziness)
• First occurrence of migraine-type headache
• If you become pregnant
• If you notice signs of a blood clot such as:
  • Painful swelling and redness in the legs
  • Sudden chest pain
  • Difficulty breathing. For further 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 if 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 lining of the womb (endometrial hyperplasia) and cancer of the lining of the womb (endometrial cancer)
Treatment with oestrogen alone increases the risk of excessive thickening of the lining of the womb (endometrial hyperplasia) and cancer of the lining of the womb (endometrial cancer).
The progestogen contained in Activelle protects you from this 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 beyond the first 6 months
• Begins after taking Activelle for more than 6 months
• Occurs after stopping Activelle

consult your doctor as soon as possible.

Breast cancer
Evidence suggests that combined oestrogen-progestogen therapy, and possibly oestrogen-only therapy, increases the risk of breast cancer. The additional risk depends on the duration of HRT use and becomes apparent within a few years. However, it returns to normal within a few years (within a maximum of 5 years) after stopping treatment.

Comparative data
In women aged 50–79 years who do not take HRT, breast cancer is diagnosed on average in 9 to 17 cases per 1,000 women over a period of more than 5 years.
For women aged 50–79 years who take combined oestrogen-progestogen HRT for more than 5 years, there are 13 to 23 cases per 1,000 women (additional cases: 4 to 6).

Regular breast examination. Consult your doctor if you notice changes such as:

• Dimpling of the skin
• Changes in the nipple
• Any lumps that can be seen or felt.

In addition, when offered, it is recommended to participate in a mammographic screening programme.
During mammographic screening, it is important to inform the nurse/healthcare professional performing the mammogram that you are taking HRT, as treatment may increase breast density, which can affect the outcome of the mammogram. 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 oestrogen-only or combined oestrogen-progestogen therapy has been associated with a slight increase in the risk of ovarian cancer. The risk of ovarian cancer varies with age. For example, in women aged 50–54 years who do not take HRT, about 2 out of 2,000 women will be diagnosed with ovarian cancer over a period of more than 5 years.
For women who have taken HRT for more than 5 years, there are 3 cases per 2,000 users (approximately 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 vessel is approximately 1.3 to 3 times higher in women taking HRT than in women not taking HRT, particularly during the first year of treatment.
Blood clots can be serious, and if one travels to the lungs, it can cause chest pain, breathlessness, collapse, or even death.
You are more likely to develop a blood clot in blood vessels if you are older and if one or more of the following conditions apply to you. Inform your doctor in any of the following cases:

• If you are unable to walk or must remain immobile for long periods due to surgery, trauma, or illness (see also section “If you need surgery”)
• If you are significantly overweight (BMI >30 kg/m²)
• If you have a clotting disorder that required long-term treatment with a medicine used to prevent clots
• If you or a close relative have previously had a blood clot in the leg, lung, or another organ
• If you have systemic lupus erythematosus (SLE)
• If you have a tumour.

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

Comparative data
Among women aged 50 years who do not take HRT, on average 4 to 7 cases of blood clots in a blood vessel per 1,000 women might be expected over a period of more than 5 years.
For women aged 50 years taking combined oestrogen-progestogen HRT for more than 5 years, the number of cases is 9 to 12 per 1,000 women (5 additional cases).

Heart disorders (heart attack)
There is no evidence that HRT helps prevent heart attacks. Women over 60 years of age taking oestrogen-progestogen HRT have a slightly increased likelihood of developing heart disorders compared to women not taking HRT.

Stroke
The risk of stroke is approximately 1.5 times higher in women taking HRT than in women not taking HRT. The number of additional stroke cases due to HRT use increases with advancing age.

Comparative data
Among women aged 50 years who do not take HRT, about 8 cases of stroke per 1,000 women might be expected over a period of more than 5 years.
For women aged 50 years taking HRT, the number of cases is 11 per 1,000 women over 5 years (3 additional cases).

Other conditions
HRT does not prevent 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 could 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 HIV infection (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 affect the concomitant administration of cyclosporine.
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including over-the-counter medicines, 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 certain 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 become pregnant, stop taking Activelle immediately and contact your doctor.
Breastfeeding: You must not take Activelle if you are breastfeeding.

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

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

3. How to take Activelle

Always take this medicine exactly as instructed by your doctor. If you have any doubts, always consult your doctor or pharmacist.
Take one tablet once daily, preferably at the same time each day. Once all 28 tablets in the pack have been taken, start a new pack immediately without interruption.
For further information on how to use the calendar pack, see "Instructions for the user" at the end of the package leaflet.
You may start treatment with Activelle on any day of the week. However, if you are switching to Activelle from a hormone replacement therapy that causes monthly bleeding, treatment with Activelle should begin immediately after the bleeding has stopped.
For symptom treatment, your doctor should use the lowest effective dose for the shortest duration necessary. Contact your doctor if you think the dose is too high or too low.

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 cause nausea or vomiting.

If you forget to take Activelle
If you forget to take your tablet at the usual time, take it as soon as possible within the next 12 hours. If more than 12 hours have passed, skip the missed dose and take the next tablet at the usual time. Do not take a double dose to make up for a forgotten tablet. Missing a dose may increase the likelihood of bleeding or spotting if you still have your uterus.

If you stop taking Activelle
If you wish to stop treatment with Activelle, speak to your doctor first. Your doctor will explain the effects of stopping treatment and discuss alternative options with you.
If you have further questions about the use of this medicine, ask your doctor or pharmacist.

If you need surgery
If you are scheduled for surgery, inform your surgeon that you are taking Activelle. You may need to stop taking Activelle approximately 4–6 weeks before the procedure to reduce the risk of blood clots (see section 2, "Blood clots in blood vessels (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 everyone experiences them.
The following conditions are reported more frequently in women using HRT than in women not using HRT:

• breast cancer
• excessive thickening or tumour of the lining of the womb (endometrial hyperplasia or cancer)
• ovarian cancer
• blood clots in the blood vessels of the legs or lungs (venous thromboembolism)
• heart disorders
• stroke
• possible memory loss if HRT is started after age 65. For further information on these side effects, see section 2, “What you should know before taking Activelle”.

Hypersensitivity/allergy (uncommon side effect – occurs in 1 to 10 out of 1,000 users)
Although uncommon, hypersensitivity/allergic reactions may occur. Signs of hypersensitivity/allergy may include one or more of the following symptoms: hives, itching, swelling, difficulty breathing, low blood pressure (pallor and cold skin, rapid heartbeat), dizziness, sweating, which could be signs of anaphylactic reactions/shock. If any of the symptoms listed occur, stop taking Activelle and seek immediate medical help.

Very common side effects (occur in 1 out of 10 users)

• breast pain or tenderness
• vaginal bleeding

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

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

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

• bloating, abdominal pain, malaise or flatulence
• acne
• hair loss (alopecia)
• abnormal hair growth (hirsutism)
• itching or hives
• inflammation of a vein (superficial thrombophlebitis)
• leg cramps
• lack of effectiveness of the medicine
• allergic reaction
• nervousness

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

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

Very rare side effects (occur in fewer than 1 out of 10,000 users)

• cancer of the lining of the womb (endometrial cancer)
• excessive thickening of the womb lining (endometrial hyperplasia)
• increased blood pressure or worsening of pre-existing high blood pressure
• gallbladder disorders, occurrence/recurrence of gallstones or worsening
• excessive sebum secretion, skin eruptions
• acute or recurrent episodes of angioedema (angioneurotic oedema)
• insomnia, dizziness, anxiety
• changes in sexual desire
• changes in vision
• weight loss
• vomiting
• heartburn
• vaginal and genital itching
• heart attacks or stroke

Other side effects of combined HRT

• Gallbladder disorders
• Various skin and subcutaneous tissue disorders:
  • Skin discolouration, particularly on the face or neck, known as “pregnancy mask” (chloasma)
  • Painful red-purple nodules (erythema nodosum)
  • Skin rash with redness or target-like lesions (erythema multiforme)
  • Purple or dark red spots on the skin and/or mucous membranes (vasculitic purpura)

Reporting of side effects
If you experience any side effect, talk to your doctor or pharmacist. This includes any side effect not listed in this leaflet.
You can also report side effects directly via 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 on the packaging after
"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.
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. Package contents and other information

What Activelle contains

• The active substances are estradiol 1 mg (as estradiol hemihydrate) and norethisterone acetate 0.5 mg.
• The other components are: lactose monohydrate, maize starch, copovidone, talc and magnesium stearate.
• The film coating contains: 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 engraved
with the code "NOVO 288" on one side and the Novo Nordisk symbol (the Apis bull) on the other.
Pack sizes:

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

Not all pack sizes may be marketed.
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 European Economic Area countries under the
following names: European Economic Area countries: Activelle, except in the United Kingdom: Kliovance.
Further sources of information
More detailed information on this medicinal product is available on the website of the Italian Medicines Agency (Agenzia Italiana del Farmaco)
Instructions for the user
How to use the calendar pack

1. Select the desired day

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

2. How to take the first day's tablet

Peel off the plastic tab and push out the first tablet.

3. Move the selector each day

The following day, simply move the transparent disc one space clockwise, as indicated by the
arrow. Remove the next tablet. Remember to take only one tablet once a day.
The transparent disc can only be rotated after the tablet has been removed.

Package leaflet: Information for the user

Activelle 0.5 mg/0.1 mg film-coated tablets

Estradiol/norethisterone acetate
Please read this leaflet carefully before taking this medicine because it contains important information for you.

• Keep this patient information 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 only. Do not give it to others, even if their symptoms are the same as yours, because this medicine could be harmful.
• If you experience any side effect, including those not listed in this leaflet, contact 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 taking Activelle
9. How to take Activelle
10. Possible side effects
11. How to store Activelle
12. Contents of the pack and other information

1. What Activelle is and what it is used for

Activelle is a medicine for continuous combined Hormone Replacement Therapy (HRT). It contains two types of female hormones, an oestrogen and a progestogen. Activelle is used in postmenopausal women who have been at least one year since their last natural menstrual period.

Activelle is used for:
Relief of symptoms occurring after the menopause
During the menopause, the amount of oestrogens produced by a woman's body decreases. This can cause symptoms such as flushing of the face, neck and chest (hot flushes). Activelle relieves these postmenopausal symptoms. Your doctor will prescribe Activelle only if these symptoms seriously interfere with your daily life.

Activelle is prescribed to women who have not had a hysterectomy and whose menstrual cycles have ceased for more than one year.
Experience with treatment in women over 65 years of age is limited.

2. What you should know before taking Activelle

Medical history and regular medical check-ups
The use of HRT (hormone replacement therapy) may involve certain risks that should be considered when deciding whether to start treatment or continue taking it.
There is limited experience in treating women with premature menopause (due to early menopause or surgical removal of the ovaries). If you have premature menopause, the risks associated with HRT may differ. Please discuss this with your doctor.
Before starting (or restarting) HRT, your doctor will ask about your personal and family medical history and may decide to perform a physical examination. This may include a breast examination and/or a gynecological examination, if necessary.
After starting treatment with Activelle, you should visit your doctor for regular check-ups (at least once a year). During these visits, your doctor may discuss the benefits and risks of continuing therapy with Activelle.
Have regular breast monitoring, 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 doctor before taking Activelle.
Do not take Activelle:

• If you have or have had, or suspect you may have breast cancer.
• If you have, have had, or suspect you may have cancer of the lining of the womb (endometrial cancer) or any other estrogen-dependent tumor.
• If you have unexplained vaginal bleeding.
• If you have or have had untreated thickening of the lining of the womb (endometrial hyperplasia).
• 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 arterial diseases caused by blood clots, such as heart attack, stroke, or angina.
• If you have or have had liver disease and your liver function tests have not 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 excipients of Activelle (listed in section 6 'Contents of the pack and other information').

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

Warnings and precautions
If you have or have ever had any of the following conditions, 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 frequently for medical check-ups:

• uterine fibroids
• endometriosis (growth of uterine lining tissue outside the uterus) or history of excessive growth of the endometrial lining (endometrial hyperplasia)
• increased risk of developing blood clots (see 'Blood clots in a blood vessel') (thromboembolism)
• increased risk of developing an estrogen-dependent tumor (if you have a mother, sister, or grandmother who has had such a tumor)
• high blood pressure
• liver disorders, such as benign liver tumors
• diabetes
• gallstones
• migraine or severe headaches
• autoimmune disease affecting certain 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 where the thyroid gland does not produce enough thyroid hormone (hypothyroidism) and you are being treated with thyroid hormone replacement therapy
• hereditary condition causing severe episodes of swelling (hereditary angioedema) or if you have experienced sudden episodes of swelling in the hands, face, feet, lips, eyes, tongue, throat (airway obstruction), or digestive tract
• lactose intolerance

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

• any of the conditions mentioned in the section 'Do not take Activelle'
• yellowing of the skin or eyes (jaundice), which may be signs of liver problems
• significant increase in blood pressure (symptoms may include headache, fatigue, and dizziness)
• new type of migraine headache you have never had before
• if you become pregnant
• if you notice signs of a blood clot such as:
  • painful swelling and redness in the legs
  • sudden chest pain
  • difficulty breathing. For further 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 old, you may still need to use an additional contraceptive method to prevent pregnancy. Talk to your doctor for advice.

HRT and cancer

Excessive thickening of the lining of the womb (endometrial hyperplasia) and cancer of the lining of the womb (endometrial cancer)
Taking estrogen-only HRT increases the risk of excessive thickening of the lining of the womb (endometrial hyperplasia) and endometrial cancer. The progestogen contained in Activelle protects you from this additional risk.

Comparative data
In women who still have their uterus and who do not take HRT, endometrial cancer is diagnosed on average in 5 out of 1,000 women aged 50–65 years.
In women aged 50–65 years who still have their uterus and who take estrogen-only HRT, endometrial cancer is diagnosed on average in 10 to 60 out of 1,000 women (an additional 5 to 55 cases) depending on dose and duration of treatment.

Irregular bleeding
You may experience irregular bleeding or spotting during the first 3–6 months of taking Activelle. In particular, contact your doctor as soon as possible if irregular bleeding:

• continues beyond the first 6 months
• occurs after more than six months of starting treatment with Activelle
• continues after stopping treatment with Activelle

Breast cancer
Evidence suggests that combined use of estrogens and progestogens, and possibly estrogen alone, increases the risk of breast cancer. The additional risk depends on the duration of HRT use and becomes apparent after a few years. However, the risk returns to normal within a few years (at most within 5 years) after stopping treatment.

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

Regularly check your breasts. Contact your doctor if you notice any changes such as:

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

In addition, when offered, it is advisable to participate in a mammographic screening program. During mammographic 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 mammogram results. 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 combined estrogen-progestogen therapy has been associated with a slight increase in the risk of ovarian cancer. The risk of ovarian cancer varies with age. For example, in women aged 50–54 years who do not take HRT, about 2 out of 2,000 women will be diagnosed with ovarian cancer over a period of more than 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 vessels is about 1.3 to 3 times higher in women taking HRT than in women who do not, especially during the first year of treatment.
Blood clots can be serious, and if one travels to the lungs, it can cause chest pain, shortness of breath, fainting, or even death.
The likelihood of developing a blood clot in blood vessels increases if you are older and if any of the following apply to you. Inform your doctor in any of the following cases:

• if you cannot walk for a prolonged period due to surgery, trauma, or illness (see also section 3 “If you need surgery”)
• if you are significantly overweight (BMI > 30 kg/m²)
• if you have a clotting disorder requiring long-term treatment with anticoagulant medication
• if a close relative has or has had a blood clot in the legs, lungs, or another organ
• if you have systemic lupus erythematosus (SLE)
• if you have cancer.

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

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

Heart disorders (heart attack)
There is no evidence that HRT prevents heart attacks. Women over 60 years of age taking estrogen/progestogen HRT have a slightly increased likelihood of developing heart disease compared to women not taking HRT.

Stroke
The risk of stroke is about 1.5 times higher in women taking HRT than in women who do not. The number of additional stroke cases due to HRT use increases with advancing age.

Comparative data
Among women aged 50 who do not take HRT, on average 8 out of 1,000 women can be expected to have a stroke over a period of more than 5 years. For women aged 50 who take HRT for more than 5 years, 11 cases per 1,000 users are diagnosed (3 additional cases).

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

Taking with other medicines
Some medicines may interfere with the effect of Activelle. These may cause irregular bleeding. The following medicines are involved:

• 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 affect treatment with concomitant cyclosporine.
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including over-the-counter medicines, herbal medicines, or other natural products.

Laboratory tests
If you need to have blood tests, inform 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 drinks
The tablets can be taken with or without food and drinks.

Pregnancy and breastfeeding
Pregnancy: Activelle is indicated only for postmenopausal women. If you become pregnant, stop taking Activelle immediately and contact your doctor.
Breastfeeding: you must not take Activelle while breastfeeding.

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

Important information about some excipients of Activelle:

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

3. How to use Activelle

Always take this medicine exactly as directed by your doctor. If in doubt, consult your doctor or pharmacist.
Take one tablet once daily, preferably at the same time each day. Swallow the tablet with a glass of water.
Take one tablet every day without interruption. When you have used all 28 tablets in the calendar pack, start a new one immediately.
For further information on how to use the calendar pack, read the INSTRUCTIONS FOR THE USER at the end of this leaflet.

You may start treatment with Activelle on any day of the week. However, if you are switching from a hormone replacement therapy that causes monthly bleeding, treatment should begin immediately after the end of bleeding.

For symptom treatment, your doctor should use the lowest effective dose for the shortest duration necessary to relieve symptoms. Contact your doctor if you think this dose is too strong or not strong enough.

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

If you forget to take Activelle
If you forget to take your tablet at the usual time, take it as soon as possible within the next 12 hours. If more than 12 hours have passed, resume your normal dosing schedule the next day. Do not take a double dose to make up for a missed tablet.
Skipping a dose may increase the likelihood of breakthrough bleeding or spotting if you still have your uterus.

If you stop taking Activelle
If you wish to discontinue treatment with Activelle, speak with your doctor first. Your doctor will explain the consequences of stopping treatment and discuss alternative options 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 scheduled for surgery, inform your surgeon that you are taking Activelle. You may need to stop taking Activelle 4–6 weeks before the procedure to reduce the risk of a blood clot (see ‘Blood clots in a blood vessel (venous thromboembolism)’ in section 2). Ask your doctor when you can restart treatment with Activelle.

4. Possible side effects

Like all medicines, this medicinal product can cause side effects, although not everybody experiences them.
The following conditions are reported much more frequently in women using HRT than in women who do not use HRT:

• breast cancer
• excessive thickening or tumour of the lining of the uterus (endometrial hyperplasia or cancer)
• ovarian cancer
• blood clots in the blood vessels of the legs or lungs (venous thromboembolism)
• heart disorders
• stroke
• possible memory loss if HRT is started after age 65. For further information on these side effects, see section 2, 'What you should know before taking 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 genital area or vaginal inflammation
• Excessive growth of the uterine lining (endometrial hyperplasia)
• Malaise
• Stomach ache
• Back or neck pain
• Pain in 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 stomach discomfort
• Weight gain due to fluid retention
• Swelling of arms and legs (peripheral oedema)
• Leg cramps
• Heartburn (dyspepsia)
• Acne
• Hair loss (alopecia)
• Itching and hives

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

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

Other side effects of combined HRT
Gallbladder disease
Various skin disorders:
skin discolouration, particularly on the face and neck, known as "pregnancy mask" (chloasma)
painful red skin nodules (erythema nodosum)
skin rash with redness and sores (erythema multiforme)
purple or dark red spots visible under the skin (vasculitic purpura)

• Dry eyes, alteration in the composition of the tear film.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, please inform your doctor or pharmacist.
You can also report side effects directly via 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 stated on the label and 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 no longer required. This will help protect the environment.

6. Package contents and other information

What Activelle contains

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

Description of the appearance of Activelle and pack contents
The film-coated tablets are white, round, with a diameter of 6 mm. The tablets are marked
with the code "NOVO 291" on one side and the Novo Nordisk logo (bull APIS) on the other.
Pack sizes:

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

Marketing Authorization Holder
Novo Nordisk SpA
Via Elio Vittorini, 129
00144 - Roma, Italy
Manufacturer
Novo Nordisk A/S
Novo Allé
DK-2880 Bagsværd
Denmark
This product is authorized in the European Economic Area Member States 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
Further sources of information
More detailed information on this medicinal product is available on the website of the Italian Medicines Agency (Agenzia Italiana del Farmaco)
USER INSTRUCTIONS
How to use the calendar pack

2. Select the desired day

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

4. Taking the first tablet

Pull off the plastic tab and remove the first tablet.

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5. Move the selector each day

Simply move the transparent disc clockwise by 1 position, as indicated by the arrow. Remove 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.