Novo Nordisk Limited

Read all of this leaflet carefully before you start taking this medicine

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

1.What Activelle® is and what it is used for
2 Before you take Activelle®
3.How to use Activelle®
4 Possible side effects
5.How to store Activelle®
6. Further information

Activelle® is indicated

• To relieve unpleasant symptoms like hot flushes, night sweats and vaginal dryness, which occur when the oestrogen levels decline and the periods stop (menopause).
• For prevention of osteoporosis (thinning of the bones) in postmenopausal women if they are at high risk of future fractures and if they are unable to take other medications for this purpose.

Activelle® is prescribed for women who have not had their womb removed, and whose periods stopped more than a year ago.

The experience of treating women older than 65 years is limited.

Medical check-ups

Before you start taking Activelle® , your doctor will inform you about the risks and benefits of the treatment (see also section 4 Other side effects of combined HRT). Before you start treatment and regularly during treatment, your doctor will evaluate whether Activelle® is the right treatment for you. Your doctor will perform a physical examination. This includes an examination of your breasts, and may include an examination of your abdomen or an internal examination. Your doctor will tell you how often you should go for periodic check-ups, taking into account your general state of health. If you have any close relatives (mother, sister, maternal or paternal grandmother), who has suffered from serious illness, e.g. blood clot or breast cancer, you might be at an increased risk of developing the illness. You should therefore always tell your doctor about any close relatives suffering from a serious illness, and you should also tell your doctor about any changes, you might find in your breasts.

Once you have started on Activelle® , you should see your doctor for regular check-ups (at least once a year). At these checkups, your doctor may discuss the benefits and risks of continuing with Activelle® .

As well as regular check-ups with your doctor, be sure to:

• Regularly check your breasts for any changes, such as dimpling or sinking of the skin, changes in the nipple, or any lumps you can see or feel.
• Go for regular breast screening (mammography) and cervical smear tests.

Do not take Activelle®

If any of the following applies to you, talk to your doctor. Do not start taking Activelle® :

• If you have or have had breast cancer, or if it is suspected.
• If you have or have had cancer of the womb lining (endometrium), or if an oestrogen dependent cancer is suspected.
• If you have abnormal vaginal bleeding, which has not been diagnosed by your doctor.
• If you have endometrial hyperplasia (excessive thickening of the womb lining) that is not being treated.
• If you have or have had blood clots in a vein (venous thromboembolism), in the legs (deep venous thrombosis) or the lungs (pulmonary embolism).
• If you have a blood clotting disorder (thrombophilic disorder, such as protein C, protein S, or antithrombin deficiency).
• If you have or have had a heart attack, stroke, or have angina.
• If you have or have had liver problems and your liver function tests have not returned to normal.
• If you have a rare blood problem called “porphyria” which is passed down in families (inherited).
• If you are allergic (hypersensitive) to estradiol, norethisterone acetate or any other ingredients in Activelle® (listed in section 6 Further information).

Take special care with Activelle®

If you have (or have had) any of the following conditions, tell your doctor. He or she may want to see you more often for check-ups.

These conditions may in rare cases come back or get worse during treatment with Activelle® :

• If you have any condition affecting the womb lining, including fibroids, endometriosis or have had endometrial hyperplasia (excessive thickening of the lining of the womb).
• If you have a history of blood clots (thrombosis) or have risk factors for developing blood clots (see Blood clots in a vein) (these risk factors and symptoms for a blood clot are listed in section 4 Other side effects of combined HRT).
• If any of your immediate family has had breast cancer, or other cancers related to oestrogen (endometrial cancer).
• If you have high blood pressure.
• If you have a liver disorder such as liver adenoma (a benign tumour).
• If you have cardiac or kidney problems.
• If you have diabetes or gallstones.
• If you have epilepsy or asthma.
• If you get migraines or severe headaches.
• If you have systemic lupus erythematosus (SLE) - an autoimmune disease.
• If you have high levels of fat in the blood (hypertriglyceridaemia).
• If you have otosclerosis (hearing loss)
• If you have lactose intolerance.

If you need a blood test, tell your doctor that you are taking Activelle® since oestrogen can affect the results of certain laboratory tests.

If you are going to have surgery, talk to your doctor. You may need to stop taking these tablets 4 to 6 weeks before the operation to reduce the risk of a blood clot. Your doctor will tell you when you can start again.

Stop taking Activelle®

If you are experiencing any of the following conditions below, stop taking Activelle® and contact your doctor immediately:

• If you get a migraine-type headache for the first time.
• If you develop yellow skin or eyes (jaundice) or other liver problems.
• If your blood pressure goes up significantly while you are taking Activelle® (symptoms of high blood pressure e.g. headache, tiredness and dizziness).
• If you get signs of a blood clot (painful swelling and redness of the legs, sudden chest pain, difficulty in breathing).
• If you become pregnant.
• If any of the conditions listed in section 2 Do not take Activelle® occur.

Activelle® and cancer

Excessive thickening of the lining of the womb (endometrial hyperplasia) and cancer of the lining of the womb (endometrial cancer)

In women with an intact womb taking oestrogen-only HRT over a long period of time, the risk of excessive thickening of the lining of the womb (endometrial hyperplasia) and cancer of the womb lining (endometrial cancer) is increased.

Taking a progestagen in addition to the oestrogen, as in Activelle® , protects you from this extra risk.

Compare

In women who still have a womb and who are not taking HRT, on average 5 in 1,000 will be diagnosed with endometrial cancer.

For women who still have a womb and take oestrogen-only HRT, the number of extra cases could vary between 5 and 55 in 1,000 users between the ages of 50 and 65 depending on the dose and for how long it is taken.

The addition of a progestagen to oestrogen-only HRT substantially reduces the risk of endometrial cancer.

Breast cancer

Evidence suggests that taking combined oestrogen-progestagen and possibly also oestrogen-only HRT increases the risk of breast cancer.

The extra risk depends on how long you take HRT. The additional risk is visible after about 3 years.

However, it returns to normal within a few years (at most 5) after stopping treatment.

Compare

Women aged 50 to 65 who are not taking HRT, on average 9 to 12 in 1,000 will be diagnosed with breast cancer over a 5-year period.

For women aged 50 to 65 who are taking oestrogen-progestagen HRT over 5 years, the number of extra cases will be 6 in 1,000 users. Looking at women aged 50 to 79 who are not taking HRT, on average 14 in 1,000 will be diagnosed with breast cancer over a 5-year period.

For women aged 50 to 79 who are taking oestrogen-progestagen HRT over 5 years, the number of extra cases will be 4 in 1,000 users.

Ovarian cancer

Ovarian cancer is much rarer than breast cancer. A slightly increased risk of ovarian cancer has been reported in women taking HRT for at least 5 to 10 years. Some studies suggest that the long-term use of combined HRT may carry a similar or slightly smaller risk.

For women who have been taking HRT for over 5 years, there will be 1 extra case per 2,500 users.

Effect of Activelle® on heart and circulation

Blood clots in a vein (venous thromboembolism)

The risk of blood clots in the veins is about 1.3 to 3-times higher in HRT users than in nonusers, especially during the first year of taking it.

Blood clots are not always serious, but if one travels to the lungs, it can cause chest pain, breathlessness, collapse or even death.

You are generally more likely to get a blood clot in your veins if one or more of the following applies to you. Inform your doctor if any of these situations applies to you:

• You are older
• You are pregnant or have recently had a baby
• You use oestrogen containing preparations
• You or any of your close relatives have ever had a blood clot in the leg, lung or another organ
• You are seriously overweight
• You have systemic lupus erythematosus (SLE)
• You have a blood clotting problem that needs long-term treatment with a medicine used to prevent blood clots (anticoagulant)
• You are unable to walk or stand for a long time because of major surgery, injury or illness (prolonged immobilisation)
• You have cancer

Compare

Women in their 50s who are not taking HRT, on average over a 5-year period, 4 in 1,000 would be expected to get a blood clot in a vein.

For women in their 50s who have been taking oestrogen-progestagen HRT for over 5 years, the number of extra cases will be 5 in 1,000 users.

Heart disease (heart attack)

There is no evidence that HRT will help to prevent a heart attack.

Women over the age of 60 years who use oestrogen-progestagen HRT are slightly more likely to develop heart disease than those not taking any HRT.

Stroke

The risk of getting stroke is about 1.5-times higher in HRT users than in non-users. The risk of stroke strongly depends on age.

Therefore, the number of extra cases of stroke due to use of HRT will rise with more advanced age.

Compare

For women in their 50s who are taking HRT, the number of extra cases will be 3 in 1,000 users over 5 years.

Other conditions

HRT will not prevent memory loss. The risk of probable memory loss may be somewhat higher in women who start using any kind of HRT after the age of 65.

Using other medicines

Some medicines may reduce the effects of Activelle® :

• Drugs used for epilepsy (such as phenobarbital, phenytoin and carbamazepine)
• Drugs used for tuberculosis (such as rifampicin, rifabutin)
• Drugs used for HIV infections (such as nevirapine, efavirenz, ritonavir and nelfinavir)
• Herbal products with St John’s Wort (Hypericum perforatum)

Other medicines may increase the effects of Activelle® :

• Drugs containing ketoconazole (a fungicide)

Concomitant administration of cyclosporine may cause increased blood levels of cyclosporine.

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

Taking Activelle® with food and drink

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

Pregnancy and breast-feeding

Pregnancy: You should not take Activelle® if you are pregnant. If you become pregnant stop taking Activelle® immediately and contact your doctor.

Breast-feeding: You should not use Activelle® if you are breast-feeding.

Driving and using machines

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

Important information about some of the ingredients of Activelle®

Activelle® contains lactose monohydrate. If you have an intolerance to some sugars, contact your doctor before taking Activelle® .

If you take more Activelle® than you should

If you have taken more Activelle® than you should, talk to a doctor or pharmacist. An overdose of Activelle® could make you feel sick or vomit.

If you forget to take Activelle®

If you forget to take your tablet at the usual time, take it within the next 12 hours. If more than 12 hours have gone by, start again as normal the next day. Do not take a double dose to make up for a forgotten tablet.

Forgetting a dose may increase the likelihood of breakthrough bleeding and spotting if you still have your womb.

If you stop taking Activelle®

If you would like to stop taking Activelle® , talk to your doctor first. He/she will explain the effects of stopping treatment and discuss other possibilities with you.

Hypersensitivity/allergy

(uncommon side effect – affects 1 to 10 users in 1,000)

Though 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 in breathing, low blood pressure (paleness and coldness of skin, rapid heart beat), feeling dizzy, sweating, which could be signs of anaphylactic reaction/shock. If one of the mentioned symptoms appears, stop taking Activelle® and seek immediate medical help.

Bleeding with Activelle®

Activelle® will not cause regular monthly bleeding. When first starting the tablets, some women experience slight vaginal bleeding or spotting.

If you get breakthrough bleeding or spotting, it is usually nothing to worry about, especially during the first few months of taking HRT. However, contact your doctor as soon as possible:

• If bleeding carries on for more than the first 3 months.
• If bleeding only starts after taking HRT for a while.
• If bleeding continues after stopping HRT.

Your doctor may ask you about any vaginal bleeding with Activelle® at your regular check-ups. You may find it helpful to make a note of any bleeding in your diary.

Other side effects of combined HRT

Women using HRT have a slightly increased risk of developing the following diseases:

• Breast cancer
• Excessive thickening 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 thromboembolism)
• Heart disease
• Stroke
• Skin and subcutaneous disorders:
  • Darkening of the skin (chloasma)
  • Severe condition of the skin that may affect the mouth and other parts of the body (erythema multiforme)
  • Red-purple swellings on the shins, thighs and, less commonly, the arms. Joint and muscle pains and fever may also occur (erythema nodosum)
  • Purple or red-brown spots visible through the skin (vascular purpura)
• Probable memory loss if HRT is started over the age of 65.

What Activelle® contains

The active substances are estradiol 1 mg (as estradiol hemihydrate) and norethisterone acetate 0.5 mg.

Other ingredients are: lactose monohydrate, maize starch, copovidone, talc and magnesium stearate.

The film-coating contains: hypromellose, triacetin and talc.

What Activelle® looks like and contents of the pack

The film-coated tablets are white, round with a diameter of 6 mm.

The tablets are imprinted NOVO 288 on one side and the Novo Nordisk logo (an APIS bull) on the other side.

Pack sizes available:

• 28 film-coated tablets
• 3 x 28 film-coated tablets

Not all pack sizes may be marketed

Marketing Authorisation Holder and Manufacturer

How to use the calendar pack

1. Set the day reminder

Turn the inner disc to set the day of the week opposite the little plastic tab.

2. Take the first day’s tablet

Break the plastic tab and tip out the first tablet.

3. Move the dial every day

On the next day, simply move the transparent dial clockwise 1 space as indicated by the arrow. Tip out the next tablet. Remember to take only 1 tablet once a day.

You can only turn the transparent dial after the tablet in the opening has been removed.