Pharmacy Guide

Patient leaflets and SmPCs, drug interaction checker, official dosages and NHS pharmacy opening hours — all in one place.

Pharmacy Guide

Patient leaflets and SmPCs, drug interaction checker, official dosages and NHS pharmacy opening hours — all in one place.

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Evorel Conti

⚠ This medicine appears to have been discontinued

The electronic medicines compendium (emc) no longer publishes a Summary of Product Characteristics for this product, which usually means it is no longer marketed in the UK. The patient leaflet below is kept for reference, but the product may not be available.

If you were prescribed this medicine, other products containing Estradiol hemihydrate, Norethisterone acetate may still be available. Do not stop your treatment — ask your pharmacist or GP what to use instead.

Active substance: Estradiol hemihydrate, Norethisterone acetate

Equivalent medicines (same active substance, strength and form)

→ Evorel Sequi brand

Source: electronic medicines compendium (emc)
Official leaflet: Read the PIL on emc

What it is and what it is used for

for

The name of your medicine is Evorel Conti. Evorel Conti is a Hormone Replacement Therapy (HRT). Evorel Conti contains two medicines: An oestrogen (estradiol) A progestogen (norethisterone) They are both female hormones. Evorel Conti comes in a 'memory pack'. This can be used to help you remember when to change your patches. Each pack contains eight or twenty-four patches. The hormones are spread evenly in each patch. They pass slowly into your body through the skin. Evorel Conti is used for

  • The symptoms of the menopause (see 'What is the menopause?'). It is suitable for women who have not had a period (menstrual bleed) for at least 18 months
  • Prevent osteoporosis (fragile bones) in women who have had the menopause and are most likely to have bone problems. Evorel Conti are only used if other medicines for osteoporosis have been tried first and they have not worked. What is the menopause? Women produce oestrogen hormones from their ovaries throughout their adult life. These hormones are important in sexual development and control of the menstrual cycle. The menopause happens when the level of hormones produced by the ovaries goes down. This is a gradual process. During this time the levels of oestrogen can go up and down. This can cause:
  • Hot flushes, night sweats or mood swings 2
  • Vaginal problems such as dryness or itching
  • Uncomfortable or painful sexual intercourse You may get the same symptoms if you have had your ovaries taken out in an operation. Relief of symptoms occurring after menopause During the menopause, the amount of the oestrogen produced by a woman's body drops. This can cause symptoms such as hot face, neck and chest ("hot flushes"). Evorel Conti alleviates these symptoms after menopause. You will only be prescribed Evorel Conti if your symptoms seriously hinder your daily life. Prevention of osteoporosis After the menopause some women may develop fragile bones (osteoporosis). You should discuss all available options with your doctor. If you are at an increased risk of fractures due to osteoporosis and other medicines are not suitable for you, you can use Evorel Conti to prevent osteoporosis after menopause. How Evorel Conti works Evorel Conti is known as 'continuous combined' HRT. This is because both hormones in the patch are released all the time. Evorel Conti patches replace the oestrogen that is normally released by the ovaries. However, in women who still have a womb, taking an oestrogen hormone regularly may cause the lining of your womb to build up and get thicker.
  • This means it is necessary to add a progestogen hormone to the oestrogen
  • This helps shed the lining of the womb and stop any problems happening Most women do not have a regular monthly period with Evorel Conti. However, bleeding or spotting does often occur in the first few months until treatment settles down. Evorel Conti is not a contraceptive. If it is less than 12 months since your last menstrual period or you are under 50 years old, you may still need to use additional contraception to prevent pregnancy. Speak to your doctor for advice.

2.

What you need to know before you take it

e Evorel Conti

Medical history and regular check-ups The use of HRT carries risks which need to be considered when deciding whether to start taking it, or whether to carry on taking it. The experience in treating women with a premature menopause (due to ovarian failure or surgery) is limited. If you have a premature menopause the risks of using HRT may be different. Please talk to your doctor. Before you start (or restart) HRT, your doctor will ask about your own and your family's medical history. Your doctor may decide to perform a physical examination. This may include an examination of your breasts and/or an internal examination, if necessary. Once you have started on Evorel Conti you should see your doctor for regular check-ups (at least once a year). At these check-ups, discuss with your doctor the benefits and risks of continuing with Evorel Conti. Go for regular breast screening, as recommended by your doctor.

3

Do not use Evorel Conti:

  • If you have or have ever had breast cancer, or if you are suspected of having it;
  • If you have cancer which is sensitive to oestrogens , such as cancer of the womb lining (endometrium), or if you are suspected of having it;
  • If you have any unexplained vaginal bleeding;
  • If you have excessive thickening of the lining of the womb (endometrial hyperplasia) that is not being treated;
  • If you have or have ever had blood clot in a vein (thrombosis), such as in the legs (deep venous thrombosis) or 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 ever had a liver disease and your liver function tests have not returned to normal;
  • If you have or recently have had a disease caused by blood clots in the arteries, such as a heart attack, stroke or angina;
  • If you have a rare blood problem called 'porphyria' which is passed down in families (inherited);
  • If you are allergic to estradiol or norethisterone or any of the other ingredients of this medicine (listed in section 6). Do not use this medicine if any of the above applies to you. If you are not sure, talk to your doctor or pharmacist before using Evorel Conti. If any of the above conditions appear for the first time while taking Evorel Conti, stop taking it at once and consult your doctor immediately. When to take special care with Evorel Conti Tell your doctor if you have ever had any of the following problems, before you start the treatment, as these may return or become worse during treatment with Evorel Conti. If so, you should see your doctor more often for check-ups:
  • fibroids inside your womb;
  • growth of womb lining outside your womb (endometriosis) or a history of excessive growth of the womb lining (endometrial hyperplasia);
  • increased risk of developing blood clots (see "Blood clots in a vein (thrombosis)");
  • increased risk of getting an oestrogen-sensitive cancer (such as having a mother, sister or grandmother who has had breast cancer);
  • high blood pressure;
  • a liver disorder, such as a benign liver tumour;
  • diabetes;
  • gallstones;
  • migraine or severe headaches;
  • a disease of the immune system that affects many organs of the body (systemic lupus erythematosus, SLE);
  • epilepsy;
  • asthma;
  • a disease affecting the eardrum and hearing (otosclerosis);
  • a very high level of fat in your blood (triglycerides);
  • fluid retention due to cardiac or kidney problems;
  • hereditary and acquired angioedema;
  • Thyroid problems;
  • History of sudden swelling of the face or throat, which may cause difficulty in swallowing or breathing, rapid swelling of the hands and feet and, stomach cramps. You may still be able to use Evorel Conti, but you should discuss this with your doctor first. Also tell your doctor if these illnesses return or get worse while you are using Evorel Conti. 4

If you have had a premature menopause the risk of using HRT may be different. Talk to your doctor about the risks. Make sure that you:

  • Go for regular breast screening and cervical smear tests
  • Regularly check your breasts for any changes such as dimpling of the skin, changes in the nipple, or any lumps you can see or feel. Stop using Evorel Conti and see a doctor immediately If you notice any of the following when using Evorel Conti
  • any of the conditions mentioned in the 'DO NOT use Evorel Conti' section;
  • yellowing of your skin or the whites of your eyes (jaundice). These may be signs of a liver disease;
  • swollen face, tongue and/or throat and/or difficulty swallowing or hives, together with difficulty breathing which are suggestive of an angioedema;
  • a large rise in your blood pressure (symptoms may be headache, tiredness, dizziness);
  • migraine-like headaches which happen for the first time;
  • if you become pregnant;
  • if you notice signs of a blood clot, such as:

–

painful swelling and redness of the legs

–

sudden chest pain

–

difficulty in breathing.

For more information, see 'Blood clots in a vein (thrombosis) Note: Evorel Conti is not a contraceptive. If it is less than 12 months since your last menstrual period or you are under 50 years old, you may still need to use additional contraception to prevent pregnancy. Speak to your doctor for advice. As well as benefits, HRT has some risks. Consider the following when deciding to take or continue HRT. HRT and cancer Excessive thickening of the lining of the womb (endometrial hyperplasia) and cancer of the lining of the womb (endometrial cancer) Taking oestrogen-only HRT will increase the risk of excessive thickening of the lining of the womb (endometrial hyperplasia) and cancer of the womb lining (endometrial cancer). The progestogen in Evorel Conti protects you from this extra risk. Irregular bleeding You may have irregular bleeding or drops of blood (spotting) during the first 3-6 months of taking Evorel Conti. However, if the irregular bleeding:

  • carries on for more than the first 6 months;
  • starts after you have been taking Evorel Conti for more than 6 months;
  • carries on after you have stopped taking Evorel Conti; see your doctor as soon as possible. If you still have your womb, your doctor will usually prescribe a progestogen as well as oestrogen. These may be prescribed separately, or as a combined HRT product. If you have had your womb removed (a hysterectomy), your doctor will discuss with you whether you can safely take oestrogen without a progestogen. 5

If you have had your womb removed because of endometriosis, any endometrium left in your body may be at risk of cancer. This means your doctor may prescribe HRT that includes a progestogen as well as an oestrogen. Your product, Evorel Conti, contains a progestogen. Compare Looking at women aged 50 to 65 who still have a womb, on average:

  • In women not taking HRT – 5 in 1000 will get endometrial cancer
  • In women taking oestrogen-only HRT- between 10 and 60 in 1000 will get endometrial cancer, (i.e. between 5 and 55 extra cases) depending on the dose and how long you take it for. The addition of a progestogen to oestrogen-only HRT substantially reduces the risk of endometrial cancer. Breast cancer Evidence shows that taking combined oestrogen-progestogen or oestrogen-only hormone replacement therapy (HRT) increases the risk of breast cancer. The extra risk depends on how long you use HRT. The additional risk becomes clear within a 3 years of use. After stopping HRT the extra risk will decrease with time, but the risk may persist for 10 years or more if you have used HRT for more than 5 years. Compare Women aged 50 to 54 who are not taking HRT, on average 13 to 17 in 1000 will be diagnosed with breast cancer over a 5-year period. For women aged 50 who start taking oestrogen-only HRT for 5 years, there will be 16-17 cases in 1000 users (i.e. an extra 0 to 3 cases). For women aged 50 who start taking oestrogen-progestogen HRT for 5 years, there will be 21 cases in 1000 users (i.e.an extra 4-8 cases). Women aged 50 to 59 who are not taking HRT, on average, 27 in 1000 will be diagnosed with breast cancer over a 10-year period. For women aged 50 who start taking oestrogen-only HRT for 10 years, there will be 34 cases in 1000 users (i.e. an extra 7 cases) For women aged 50 who start taking oestrogen-progestogen HRT for 10 years, there will be 48 cases in 1000 users (i.e. an extra 21 cases). Regularly check your breasts. See your doctor if you notice any changes such as:
  • Dimpling of the skin
  • Changes in the nipple
  • Any lumps you can see or feel Make an appointment to see your doctor as soon as possible. Additionally, you are advised to join mammography screening programs when offered to you. For mammogram screening, it is important that you inform the nurse/healthcare professional who is actually taking the x-ray that you use HRT, as this medication may increase the density of your breasts which may affect the outcome of the mammogram. Where the density of the breast is increased, mammography may not detect all lumps. Ovarian cancer Ovarian cancer (cancer of the ovaries) is rare, much rarer than breast cancer. The use of oestrogenonly or combined oestrogen-progestogen HRT has been associated with a slightly increased risk of ovarian cancer. The risk of ovarian cancer varies with age. For example, in women aged 50 to 54 who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5-year period. 6

For women who have been taking HRT for 5 years, there will be about 3 cases per 2000 users (i.e. about 1 extra case). Effect of HRT on heart and circulation Blood clots in a vein (thrombosis) The risk of blood clots in the veins is about 1.3 to 3- times higher in HRT users than in non-users, especially during the first year of taking it. Blood clots can be serious, and if one travels to the lungs, it can cause chest pain, breathlessness, fainting or even death. You are more likely to get a blood clot in your veins as you get older and if any of the following applies to you. Inform your doctor if any of these situations applies to you:

  • You are unable to walk for a long time because of major surgery, injury or illness (see also section 3, If you need to have surgery);
  • You are seriously overweight (BMI >30 kg/m2);
  • You have any blood clotting problem that needs long-term treatment with a medicine used to prevent blood clots;
  • You have a rare illness called SLE (Systemic lupus erythematosus);
  • You have cancer;
  • You are taking medicine containing an oestrogen. For signs of a blood clot, see "Stop taking Evorel Conti and see a doctor immediately". If any of these things apply to you, talk to your doctor to see if you should take HRT. Compare Looking at women in their 50s, on average, over 5 years:
  • In women not taking HRT – between 4 and 7 in 1000 would be expected to get a blood clot
  • In women taking oestrogen-progestogen HRT – 9 and 12 in 1000 would be expected to get a blood clot (an extra 5 cases) If you get painful swelling in your leg, sudden chest pain or have difficulty breathing
  • See a doctor as soon as possible
  • Do not take any more HRT until your doctor says you can These may be signs of a blood clot. Heart disease (heart attack) There is no evidence that HRT will prevent a heart attack. Women over the age of 60 years who use oestrogen-progestogen HRT are slightly more likely to develop heart disease than those not taking any HRT. HRT is not recommended for women who have had heart disease recently. If you have ever had heart disease, talk to your doctor to see if you should be taking HRT. Stroke Research suggests that HRT slightly increases the risk of having a stroke. Other things that can increase the risk of stroke include:
  • Getting older
  • High blood pressure
  • Smoking
  • Drinking too much alcohol
  • An irregular heartbeat If you are worried about any of these things, or if you have had a stroke in the past, talk to your doctor to see if you should take HRT. 7

Compare The risk of getting stroke is about 1.5 times higher in HRT users than in non- users. The number of extra cases of stroke due to use of HRT will increase with age. Looking at women in their 50s, on average, over 5 years:

  • In women not taking HRT – 8 in 1000 would be expected to have a stroke
  • In women taking HRT – 11 in 1000 would be expected to have a stroke (an extra 3 cases) If you get migraine-type headaches which you cannot explain
  • See a doctor as soon as possible
  • Do not take any more HRT until your doctor says you can These headaches may be an early warning sign of a stroke. Other conditions • HRT will not prevent memory loss. There is some evidence of a higher risk of memory loss in women who start using HRT after the age of 65. Speak to your doctor for advice; • If you have brown patches on your face or body (chloasma) or have a history of them, you may need to keep out of the sun or away from sunbeds (these patches may not completely disappear again). Children and adolescents Evorel Conti should not be used by children. Other medicines and Evorel Conti Some medicines may interfere with the effect of Evorel Conti. This might lead to irregular bleeding. This applies to the following medicines:
  • Medicines for epilepsy (such as phenobarbital, phenytoin or carbamazepine);
  • Medicines for tuberculosis (such as rifampicin, rifabutin);
  • Medicines for HIV infection (such us nevirapine, efavirenz, ritonavir or nelfinavir);
  • Medicine for Hepatis C infection, telaprevir;
  • Bosentan – for high blood pressure in the blood vessels of the lungs;
  • Herbal remedies containing St John's Wort (Hypericum perforatum). Taking these medicines with Evorel Conti can stop it from working as well. Because of this you may get some bleeding, like a period, when you are not expecting it. HRT can affect the way some other medicines work:
  • A medicine for epilepsy (lamotrigine), as this could increase frequency of seizures
  • Medicines for Hepatitis C virus (HCV) (such as combination regimens ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin; glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir) may cause increases in liver function blood test results (increase in ALT liver enzyme) in women using CHCs containing ethinylestradiol. Evorel Conti contains estradiol instead of ethinylestradiol. It is not known whether an increase in ALT liver enzyme can occur when using Evorel Conti with this HCV combination regimen. 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. Your doctor will advise you. Operations or tests If you need a blood test, tell your doctor or the laboratory staff that you are taking Evorel Conti, because this medicine can affect the results of some tests.

8

You may need to stop taking HRT about 4 to 6 weeks before the operation to reduce the risk of a blood clot. Your doctor will tell you when you can start taking HRT again. If you visit a hospital or your family doctor for a blood or urine test, tell them that you are taking Evorel Conti. This is because this medicine may affect the results of the tests.

Pregnancy and breast-feeding Do not use this medicine if you are pregnant, think you may be pregnant or might become pregnant. This is because it may affect the baby. Evorel Conti is for use in postmenopausal women only. If you become pregnant, remove the patch and contact your doctor. Do not use this medicine if you are breast-feeding. Ask your doctor or pharmacist for advice before taking any medicine if you are pregnant or breastfeeding. Driving and using machines There is no information about whether Evorel Conti affects your ability to drive or use machines. See how this medicine affects you before you drive or use any tools or machines.

3.

How to take it

Evorel Conti

Always use Evorel Conti exactly as your doctor has told you. Your doctor will aim to prescribe the lowest dose to treat your symptom for as short as necessary. Speak to your doctor if you think this dose is too strong or not strong enough. When to start using Evorel Conti You may put an Evorel Conti patch on at any time if:

  • You have not been using another type of HRT Put an Evorel Conti patch on at the end of a treatment cycle or one week after you finish using another HRT product if:
  • You are changing from an HRT medicine that gives you a withdrawal bleed If you are using another type of HRT:
  • The day you start will depend on the type of HRT you have been using Talk to your doctor if you are not sure which type of HRT you are using. Using the patches The patches need to be changed twice a week. Start a new pack of Evorel Conti as soon as you finish one. Do not leave a break between packs. Changing your patches
  • You must change the patches twice a week to give your body a steady supply of hormones. There is enough hormone in each patch to last for several days
  • Change your patch on the same two days every week. This will mean that one patch is on for three days and the next patch for four days
  • For example, if you apply your first patch on a Monday, change it on Thursday and again on the following Monday. You can work out your two days from the following table, starting from the first day of use: If you put your 9

first patch on: Monday

→

Change on: Thursday

&

Change again on: Monday

Tuesday

→

Friday

&

Tuesday

Wednesday

→

Saturday

&

Wednesday

Thursday

→

Sunday

&

Thursday

Friday

→

Monday

&

Friday

Saturday

→

Tuesday

&

Saturday

Sunday

→

Wednesday

&

Sunday

To help you remember your two "patch change" days, mark them here or on the pack. They are written on the pack like this:

Mon Thur

Tue Fri

Wed Sat

Thur Sun

Fri Mon

Sat Tue

Sun Wed

Where to apply the patch Stick the patch onto a hairless area of skin below the waist. Most women prefer to wear the patch on the thigh or bottom.

  • Do not apply on or near the breasts
  • Do not put it on top of cuts, spots or anywhere the skin is irritated
  • Do not use cream, moisturiser or talc before applying the patch
  • Do not apply the patch on the same area of skin twice in a row
  • It can be worn under loose areas of clothing.
  • Do not wear a patch under elasticated areas or a tight waistband
  • Apply the patch to clean, dry, cool skin as soon as you open the protective pouch

Putting a patch on Do not use a patch if its protective pouch is already open. Step 1: Open and Peel

  • Using the notches as a guide, tear along two

10

•

edges of the pouch. Remove the patch With the protective backing facing you, bend and peel off half the backing. Don't touch the sticky side – it may not stick properly if you do

Step 2: Apply and Press

  • Apply the open half of the patch to your skin
  • Remove the remaining backing and press down the rest of the patch
  • Warm and press the patch down to the skin with the palm of the hand for at least 10 seconds. Pressure and heat by the hand are crucial, to achieve maximum adhesion of the patch Removing a patch •

Peel an edge of the patch smoothly away from the skin

  • Fold the patch in half, so that the sticky side sticks to itself
  • Put it safely out of the reach of children and pets
  • Do not flush used patches down the toilet When you remove the patch some glue may remain on your skin. It will disappear with time, or you can use baby oil to remove it. If a patch falls off Apply a new patch but keep to your original 'patch change' days. If you have just had a bath or shower, wait until your skin cools before applying a new patch. Talk to your doctor if you need more patches. If you forget to use Evorel Conti Change it as soon as you remember and then keep to your original 'patch change' days. You may get some bleeding and spotting like a period during this time. If you use more Evorel Conti than you should It is unlikely that you will have too much of the hormones in Evorel Conti. The most common symptoms of having too much oestrogen or progestogen in your body are:
  • Tender breasts
  • Feeling sick (nausea) or being sick
  • Unexpected vaginal bleeding
  • Feeling depressed
  • Tiredness
  • Acne
  • Growth of body or facial hair Removing the patch can reverse the effects of too much oestrogen. Talk to your doctor or pharmacist before using any more patches. Contraception while using Evorel Conti The levels of hormone from the patches are too low to act as a contraceptive. Use non-hormonal contraceptive methods (such as a condom, diaphragm or coil) until your periods have completely stopped. Everyday activities 11

Everyday activities

  • You can have a bath or shower as normal. Do not scrub too hard as this can loosen the edges of the patch
  • You can go swimming. The patch will not be affected
  • You can exercise and play sports. However, do not wear the patch under tight clothing or waist bands
  • You can sunbathe. However, keep the patch covered, out of direct sunlight If you have any further questions on the use of this product, ask your doctor or pharmacist. If you need to have surgery If you are going to have surgery, tell the surgeon that you are taking Evorel Conti. You may need to stop taking Evorel Conti about 4 to 6 weeks before the operation to reduce the risk of a blood clot (see section 2, Blood clots in a vein). Ask your doctor when you can start taking Evorel Conti again.

If you stop using Evorel Conti If you have any further questions on the use of this medicine, ask your doctor. 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 HRT compared to women not using HRT:

  • breast cancer;
  • abnormal growth 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;
  • probable memory loss if HRT is started over the age of 65; For more information about these side effects, see Section 2. Take off the patch and tell your doctor straight away if you notice or suspect any of the following. You may need urgent medical treatment. • • • • • • • •

Sudden swelling of the face or throat which may cause difficulty in swallowing or breathing, rapid swelling of the hands and feet and stomach cramps Blood clots (thrombosis) (affects less than 1 in 1000 people) or stroke (frequency not known) Yellowing of the skin or whites of the eyes (jaundice), or other liver problems Migraine-type headaches for the first time or more frequent (affects less than 1 in 100 people) An increase in blood pressure (affects less than 1 in 10 people) Breast or ovarian cancer, endometrial cancer or hyperplasia (long, heavy or irregular periods) Widespread rash with peeling skin and blistering in the mouth, eyes and genitals (Stevens-Johnson syndrome) (frequency not known) Convulsions or fits (affects less than 1 in 1,000 people)

Tell your doctor if you notice any of the following side effects while using Evorel Conti: Very common (affects more than 1 in 10 people) 12

•

Irritated, itchy, red skin and rash where the patch is applied

Common (affects less than 1 in 10 people)

  • Allergic reaction (hypersensitivity)
  • Being unable to sleep
  • Feeling depressed, nervous or anxious
  • Headache
  • Being aware of your heartbeat (palpitations)
  • Varicose veins
  • Flushing, skin reddening
  • Breast pain
  • Numb or tingling hands or feet
  • Feeling sick (nausea)
  • Diarrhea
  • Stomach ache
  • Pain including pain in the back or joints
  • Painful periods
  • Discharge from the vagina
  • Irregular, heavy or prolonged bleeding from the vagina, including after sex
  • Water retention or build-up of fluid under the skin (oedema)
  • Feeling tired
  • Weight gain Uncommon (affects less than 1 in 100 people)
  • Vaginal infections such as thrush
  • Less interest in sex than usual
  • Wind
  • Itchy skin
  • Rash
  • Swelling of the hands and feet (peripheral oedema)
  • Muscle pain Frequency not known • • • • •

Mood swings Feeling dizzy Bloated feeling Gallstones Fuller breasts

The following side effects have been reported with other combined HRTs: Very common (affects more than 1 in 10 people)

  • Tender breasts Common (affects less than 1 in 10 people)
  • Mood changes
  • Indigestion
  • Acne
  • Dry skin
  • Pain in extremity (e.g. back pain, arms, legs, wrists, ankles)
  • Severe contractions of the uterus
  • Vaginal infection (white or yellowish discharge from the vagina) 13

Uncommon (affects less than 1 in100 people)

  • Dizziness • • •

Being sick Skin discoloration Abnormal liver function tests

Rare (affects less than 1 in 1,000 people)

  • Gallstones
  • Muscle weakness
  • Benign growths in the uterus smooth muscle
  • Cysts close to the fallopian tube Very Rare (affects less than 1 in 10,000 people)
  • Yellowing of the skin, itching, dark coloured urine Frequency not known •

Hair loss

The following side effects have been reported in association with other HRTs: • •

• • • •

Gall bladder disease Various skin disorders: discoloration of the skin especially of the face or neck known as "pregnancy patches" (chloasma); painful reddish skin nodules (erythema nodosum) rash with target shaped reddening or sores (erythema multiforme) Rash with red or purple coloured spots (vascular purpura) Loss of memory (Dementia) (see section 2) Dry eyes Change to composition of tears

Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard . By reporting side effects you can help provide more information on the safety of this medicine.

5.

How to store it

Evorel Conti

Keep this medicine out of the sight and reach of children. It should be stored at room temperature (at or below 25°C). Keep in the original pouch and carton. Do not use Evorel Conti after the expiry date which is stated on the label. The expiry date refers to the last day of that month. Do not use a patch if the protective pouch is open. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Evorel Conti contains 14

The active substances in Evorel Conti are estradiol hemihydrate and norethisterone acetate. Each Evorel Conti patch contains 3.2 mg of estradiol hemihydrate and 11.2 mg of norethisterone acetate. Each Evorel Conti patch delivers 50 micrograms of estradiol and 170 micrograms of norethisterone acetate a day. The other ingredients are Duro-Tak 387-2287 (this makes the patches sticky), guar gum and Hostaphan MN19 (backing film). What Evorel Conti looks like and contents of the pack Evorel Conti comes in a memory pack containing eight or twenty-four patches (marked CEN1). The patches are square with rounded corners. They are clear with a sticky backing that can be stuck to the skin. Each patch comes in a protective sealed pouch and has a surface area of 16 sq cm. Marketing Authorisation Holder Theramex HQ UK Limited 5th Floor, 50 Broadway London, SW1H 0BL United Kingdom Manufacturer Aesica Pharmaceuticals GmbH Alfred-Nobel-Str. 10 40789 Monheim am Rhein Germany LTS Lohmann Therapie-Systeme AG Lohmannstr.2 56626 Andernach Germany Pharmapac (UK) Limited Unit 22 Valley Road Business Park Bidston Wirral CH41 7EL United Kingdom For information in large print, tape, CD or Braille, telephone 0800 198 5000. This leaflet was last revised in March 2025.

15

Frequently asked questions about Evorel Conti

What is the active substance in Evorel Conti?

The active substance in Evorel Conti is estradiol hemihydrate, norethisterone acetate.

Are there equivalent medicines to Evorel Conti?

Medicines with the same active substance, strength and form include: Evorel Sequi. They are interchangeable only if your prescriber or pharmacist says so.

Where does this information come from?

This leaflet reproduces the patient information leaflet approved for Evorel Conti, as published on the electronic medicines compendium (emc). The version printed inside your medicine’s packaging is the one that applies to you.

Can I get Evorel Conti without a prescription?

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About this leaflet

The text above reproduces the patient information leaflet approved for this medicine, restructured for easier reading.

Medical disclaimer: This page is for information only and does not replace advice from your doctor or pharmacist. Always read the leaflet supplied with your medicine. If you are unwell, call NHS 111; in an emergency, call 999.

Medicines with the same active substance: Estradiol hemihydrate (40 medicines), Estradiol hemihydrate, norethisterone acetate (9 medicines)
See every medicine containing this substance, or browse the full A–Z of active substances.
⚕For healthcare professionals — Summary of Product Characteristics (SmPC)Full SmPC: dosage, interactions, contraindications, warnings+
Technical information intended for healthcare professionals (doctors and pharmacists). The Summary of Product Characteristics (SmPC) is the official document approved by the MHRA/EMA. It does not replace the patient leaflet or a doctor’s advice.

4.1. Therapeutic indications

Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in post-menopausal women more than 6 months post-menopause (or 18 months since last period).

Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis. (See also Section 4.4)

The experience treating women older than 65 years is limited.

4.2. Posology and method of administration

Adults

Evorel Conti is a continuous combined HRT preparation. Patches are applied to the skin twice weekly.

One Evorel Conti patch should be worn at all times, without interruptions. For initiation and continuation of treatment of menopausal symptoms, the lowest effective dose for the shortest duration (see also Section 4.4) should be used.

Guidance on how to start therapy:

Post-menopausal women currently not on HRT may start Evorel Conti at any time.

Switching from other HRT

Women on a continuous combined regimen wishing to switch from another oestrogen to Evorel Conti may do so at any time.

Women on a cyclic or continuous sequential regimen wishing to switch from a sequential combined HRT preparation to Evorel Conti may do so at the end of a cycle of the current therapy or after a 7 day hormone free interval.

Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestogen in hysterectomised women.

Method of Administration

The sachet containing one Evorel Conti patch should be opened and one part of the protective foil removed at the S- shaped incision. The patch should be applied to clean, dry, healthy, intact skin as soon as it is removed from the sachet.

The patient should avoid contact between fingers and the adhesive part of the patch during application. Each application should be made to a different area of the skin, on the trunk below the waist. The patch should not be applied on or near the breasts.

Evorel Conti patch should remain in place during bathing and showering.

Should a patch fall off, it should be replaced immediately with a new patch. However the usual day of changing Evorel Conti patches should be maintained.

Missed dose

If the patient forgets to change their patch, they should change it as soon as possible and apply the next one at the normal time. However, if it is almost time for the next patch, the patient should skip the missed one and go back to their regular schedule. Only one patch should be applied at a time.

Wearing a patch for more than 4 days by mistake or any period without a patch may increase the likelihood of breakthrough bleeding or spotting.

Children

Evorel Conti is not indicated in children.

Elderly

Data are insufficient in regard to the use of Evorel Conti in the elderly (>65 years old).

Route of administration

Transdermal use.

4.3. Contraindications

- Known, past or suspected breast cancer

- Known or suspected oestrogen-dependent malignant tumours (eg endometrial cancer) or pre-malignant tumours (e.g. untreated atypical endometrial hyperplasia)

- Undiagnosed genital bleeding

- Untreated endometrial hyperplasia

- Previous idiopathic or current venous thrombo-embolism (deep venous thrombosis, pulmonary embolism)

- Active or recent past arterial thrombo-embolic disease (eg cerebrovascular accident angina, myocardial infarction)

- Known thrombophilic conditions (e.g. protein C, protein S or antithrombin deficiency, see section 4.4)

- Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal

- Known hypersensitivity to the active substances or to any of the excipients (listed in section 6.1)

- Porphyria

4.4. Special warnings and precautions for use

For the treatment of menopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.

Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women.

Medical examination/follow-up

Before initiating or re-instituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contra-indications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see 'Breast cancer' below). Investigations, including appropriate imaging tools, e.g. mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.

Conditions which need supervision

If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Evorel Conti, in particular:

- Leiomyoma (uterine fibroids) or endometriosis

- A history of, or risk factors for, thrombo-embolic disorders (see below)

- Risk factors for oestrogen dependent tumours, e.g. 1st degree heredity for breast cancer

- Hypertension

- Liver disorders (e.g. liver adenoma)

- Diabetes mellitus with or without vascular involvement

- Cholelithiasis

- Migraine or (severe) headache

- Systemic lupus erythematosus.

- A history of endometrial hyperplasia (see below)

- Epilepsy

- Asthma

- Otosclerosis

- Mastopathy

Conditions which require monitoring while on oestrogen therapy:

• Oestrogens may cause fluid retention. Cardiac or renal dysfunction should be carefully observed

• Disturbances or mild impairment of liver function

• History of cholestatic jaundice

• Pre-existing hypertriglyceridaemia. Rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition

Reasons for immediate withdrawal of therapy:

Therapy should be discontinued in case a contra-indication is discovered and in the following situations:

• Jaundice or deterioration in liver function

• Significant increase in blood pressure

• New onset of migraine-type headache

• Pregnancy.

Endometrial hyperplasia and carcinoma

In women with an intact uterus, the risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among oestrogen-only users, varies from 2 to 12 fold greater compared with non-users, depending on the duration of treatment and oestrogen dose (see Section 4.8). After stopping treatment, the risk may remain elevated for at least 10 years.

The addition of a progestogen for 12-14 days per cycle or continuous combined oestrogen/progestogen therapy in non-hysterectomised women prevents the excess risk associated with oestrogen-only HRT.

Break-through bleeding and spotting may occur during the first months of treatment. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

Breast cancer

The overall evidence shows an increased risk of breast cancer in women taking combined oestrogen-progestogen or oestrogen-only HRT, that is dependent on the duration of taking HRT.

Combined oestrogen-progestogen therapy:

The randomised placebo-controlled trial, the Women's Health Initiative study (WHI), and a meta-analysis of prospective epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined oestrogen-progestogen for HRT that becomes apparent after about 3 (1-4) years (see Section 4.8).

Oestrogen-only therapy:

The WHI trial found no increase in the risk of breast cancer in hysterectomised women using oestrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is lower than that found in users of oestrogen-progestogen combinations (see Section 4.8).

Results from a large meta-analysis showed that after stopping treatment, the excess risk will decrease with time and the time needed to return to baseline depends on the duration of prior HRT use. When HRT was taken for more than 5 years, the risk may persist for 10 years or more.

HRT, especially oestrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Ovarian cancer

Ovarian cancer is much rarer than breast cancer. Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking oestrogen-only or combined oestrogen-progestogen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping. Some other studies, including the WHI trial, suggest that the use of combined HRTs may be associated with a similar or slightly smaller risk (see Section 4.8).

Venous thrombo-embolism

HRT is associated with a 1.3-3 fold risk of developing venous thrombo-embolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT than later (See Section 4.8).

Generally recognised risk factors for VTE include a personal history or family history, major surgery, prolonged immobilisation, severe obesity (BMI > 30 kg/m2), use of oestrogens, older age, pregnancy/ postpartum period, systemic lupus erythematosus (SLE) and cancer. There is no consensus about the possible role of varicose veins in VTE.

Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk, HRT is therefore contraindicated in these patients (see section 4.3).

In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age or recurrent spontaneous abortion, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is 'severe' (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects), HRT is contraindicated.

The women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery.

As in all postoperative patients, scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4 to 6 weeks earlier, if possible. Treatment should not be restarted until the woman is completely mobilised.

If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thrombo-embolic symptom (e.g., painful swelling of a leg, sudden pain in the chest, dyspnoea).

Coronary artery disease (CAD)

There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined oestrogen-progestogen or oestrogen-only HRT.

Oestrogen-only: Randomised controlled data found no increased risk of CAD in hysterectomised women using oestrogen-only therapy.

Combined oestrogen-progestogen therapy: The relative risk of CAD during use of combined oestrogen-progestogen HRT is slightly increased. The absolute risk of CAD is strongly dependent on age. The number of extra cases of CAD due to oestrogen-progestogen use is very low in healthy women close to menopause, but will rise with more advanced age.

Ischaemic Stroke

Combined oestrogen-progestogen and oestrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see Section 4.8).

Hypothyroidism

Patients who require thyroid hormone replacement therapy should have their thyroid function monitored regularly while on HRT to ensure that thyroid hormone levels remain in an acceptable range.

Angioedema

Oestrogens may induce or exacerbate symptoms of angioedema, in particular in women with hereditary angioedema.

Other conditionsOestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed.

Women with pre-existing hypertriglyceridaemia should be followed closely during oestrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.

Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.

Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-l-antitrypsin, ceruloplasmin).

Dementia

HRT use does not improve cognitive function. There is some evidence of increased risk of probable dementia in women who start using continuous combined or oestrogen-only HRT after the age of 65.

ALT elevations

During clinical trials with patients treated for hepatitis C virus (HCV) infections with the combination regimen ombitasvir/paritaprevir/ritonavir and dasabuvir with and without ribavirin, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medicinal products such as CHCs. Additionally, also in patients treated with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, and ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co-administration with the following combination drug regimens: ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir. See section 4.5.

Contact sensitisation is known to occur with all topical applications. Although it is extremely rare, women who develop contact sensitisation to any of the components of the patch should be warned that a severe hypersensitivity reaction may occur with continuing exposure to the causative agent.

Evorel Conti is not to be used for contraception. Women of child-bearing potential should be advised to use non- hormonal contraceptive methods to avoid pregnancy.

4.5. Interaction with other medicinal products and other forms of interaction

The metabolism of oestrogens and progestogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g., phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g., rifampicin, rifabutin, nevirapine, efavirenz) and also bosentan.

Ritonavir, telaprevir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones. Herbal preparations containing St. John's Wort (Hypericum perforatum) may raise the metabolism of oestrogens and progestogens.

With transdermal administration, the first-pass effect in the liver is avoided and thus, transdermally applied oestrogens and progestogens might be less affected by enzyme inducers than oral hormones.

Clinically, an increased metabolism of oestrogens and progestogens may lead to decreased effect and changes in the uterine bleeding profile.

Pharmacodynamic interactions

During clinical trials with the HCV combination drug regimen ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medicinal products such as CHCs. Additionally, also with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, and ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co-administration with the following combination drug regimens: ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section 4.4).

Oestrogen-containing oral contraceptives have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered due to induction of lamotrigine glucuronidation. This may reduce seizure control. Although the potential interaction between estrogen-containing hormone replacement therapy and lamotrigine has not been studied, it is expected that a similar interaction exists, which may lead to a reduction in seizure control among women taking both drugs together. Therefore, dose adjustment of lamotrigine may be necessary.

Some laboratory tests may be influenced by oestrogen therapy, such as tests for glucose tolerance or thyroid function.

4.6. Fertility, pregnancy and lactation

Pregnancy

Evorel Conti is not indicated during pregnancy. If pregnancy occurs during use of Evorel Conti, treatment should be withdrawn immediately.

Data on a limited number of exposed pregnancies indicate adverse effects of norethisterone on the foetus. At doses higher than normally used in oral contraceptives and HRT formulations, masculinisation of female foetuses was observed.

The results of most epidemiological studies to date, relevant to inadvertent foetal exposure to combinations of oestrogens and progestogens indicate no teratogenic or foetotoxic effect.

Breast Feeding

Evorel Conti is not indicated during breast feeding.

4.7. Effects on ability to drive and use machines

There are no known data on the effects of Evorel Conti on the ability to drive or use machinery.

4.8. Undesirable effects

The safety of Evorel Conti was evaluated in 196 subjects who participated in 3 clinical trials and received at least one administration of Evorel Conti. Based on safety data from these clinical trials, the most commonly reported (≥5% incidence) adverse drug reactions (ADRs) were (with % incidence): application site reaction (11.7%), menstrual disorder (7.1%), headache (8.2%), and breast pain (5.1%).

Including the above-mentioned ADRs, the following table displays ADRs that have been reported with the use of Evorel Conti from either clinical trial or post-marketing experiences, and additional ADRs that have been reported with the use of Evorel (estradiol alone) from clinical trial data. The displayed frequency categories use the following convention:

Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available clinical trial data).

Adverse Drug Reactions

Infections and Infestations

Uncommon

Candidiasis

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Frequency not known

Breast neoplasms, Endometrial cancer

Immune System Disorders

Common

Hypersensitivity

Psychiatric disorders

Common

Depression, Insomnia, Anxiety, Nervousness

Uncommon

Libido decreased

Frequency not known

Mood swings

Nervous system disorders

Common

Paraesthesia, Headache

Uncommon

Migraine

Rare

Epilepsy*

Frequency not known

Cerebrovascular accident, Dizziness

Cardiac disorders

Common

Palpitations

Vascular disorders

Common

Hypertension, Varicose vein, Vasodilatation

Rare

Thrombosis*

Frequency not known

Deep vein thrombosis

Respiratory, Thoracic and Mediastinal Disorders

Frequency not known

Pulmonary embolism

Gastrointestinal disorders

Common

Abdominal pain, Diarrhoea*, Nausea

Uncommon

Flatulence*

Frequency not known

Abdominal distension

Hepato-biliary disorders

Frequency not known

Cholelithiasis

Skin and subcutaneous tissue disorders

Common

Rash erythematous

Uncommon

Pruritus, Rash*,

Frequency not known

Stevens-Johnson syndrome

Musculoskeletal and Connective Tissue Disorders

Common

Arthralgia, Back pain

Uncommon

Myalgia*

Reproductive system and breast disorders

Common

Breast pain, Cervical polyp, Endometrial hyperplasia, Genital discharge, Dysmenorrhoea, Menorrhagia, Menstrual disorder, Metrorrhagia

Frequency not known

Breast enlargement

General disorders and administration site conditions

Very Common

Application site erythema, Application site pruritus, Application site rash, Application site reaction

Common

Pain*, Oedema, Application site oedema* Fatigue

Uncommon

Generalised oedema, Oedema peripheral*,

Investigations

Common

Weight increased

* Additional adverse drug reactions reported in clinical trials of Evorel (estradiol only)

The table below reports additional undesirable effects that have been reported in users of other hormone replacement therapy (HRT) by MedDRA system organ classes (MedDRA SOCs).

Psychiatric disorders

Common

Affect lability

Nervous system disorders

Uncommon

Vertigo

Gastrontestinal disorders

Common

Dyspepsia

Uncommon

Vomiting

Hepatobiliary disorders

Rare

Gallbladder disorder,

Very rare

Cholestatic jaundice

Skin and subcutaneous tissue

Common

Acne, Dry skin

Uncommon

Skin discolouration

Frequency not known

Alopecia

Musculoskeletal and connective tissue disorders

Common

Pain in extremity

Rare

Myasthenia

Reproductive system and breast disorders

Very Common

Breast tenderness

Common

Uterine spasms, Vaginal infection

Rare

Uterine leiomyoma, Fallopian tube cysts,

Investigations

Uncommon

Transaminases increase

Breast Cancer Risk

An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen- progestogen therapy for more than 5 years.

- The increased risk in users of oestrogen-only therapy is substantially lower than that seen in users of oestrogen- progestogen combinations.

- The level of risk is dependent on the duration of use (see section 4.4).

- Absolute risk estimations based on results of the largest randomised placebo-controlled trial (WHI-study) and the largest meta-analysis of prospective epidemiological studies are presented.

Largest meta-analysis of prospective epidemiological studies– Estimated additional risk of breast cancer after 5 years' use in women with BMI 27 (kg/m2)

Age at start HRT (years)

Incidence per 1000 never-users of HRT over a 5 year period (50-54 years)*

Risk ratio

Additional cases per 1000 HRT users after 5 years

Oestrogen only HRT

50

13.3

1.2

2.7

Combined oestrogen-progestagen

50

13.3

1.6

8.0

* Taken from baseline incidence rates in England in 2015 in with BMI 27 (kg/m2).

Note: since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer differs by EU country; the number of additional cases of breast cancer will also change proportionately.

Estimated additional risk of breast cancer after 10 years' use in women with BMI 27 (kg/m2)

Age at start HRT

(years)

Additional cases Incidence per 1000 never-users of HRT over a 10 year period (50-59 years) *

Risk ratio

Additional cases per 1000 HRT users after 10 years

Oestrogen only HRT

50

26.6

1.3

7.1

Combined oestrogen-progestagen

50

26.6

1.8

20.8

*Taken from baseline incidence rates in England in 2015 in women with BMI 27 (kg/m2)

Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately.

US WHI studies - additional risk of breast cancer after 5 year's use

Age range (years)

Incidence per 1000 women in placebo arm over 5 years

Risk ratio & 95%CI

Additional cases per 1000 HRT users over 5 years (95% CI)

CEE oestrogen only

50-79

21

0.8 (0.7-1.0)

-4 (-6 - 0)*

CEE + MPA oestrogen & progestagens §

50-79

17

1.2 (1.0-1.5)

+4 (0 - 9)

§ When the analysis was restricted to women who had not used HRT prior to the study there was no increased risk apparent during the first 5 years of treatment: after 5 years the risk was higher than in non-users.

* WHI study in women with no uterus, which did not show an increase of breast cancer.

Endometrial Cancer Risk

Postmenopausal women with a uterus

The endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT. In women with a uterus, use of oestrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4).

Depending on the duration of oestrogen-only use and oestrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 women between the ages of 50 and 65.

Adding a progestogen to oestrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study, the use of five years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer (RR of 1.0 (0.8-1.2)).

Ovarian cancer

Use of oestrogen-only or combined oestrogen-progestogen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed (see Section 4.4).

A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.31-1.56). For women aged 50 to 54 years taking 5 years of HRT, this results in about 1 extra case per 2000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5-year period.

Risk of venous thromboembolism

HRT is associated with a 1.3-3-fold increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of using HT (see section 4.4). Results of the WHI studies are presented:

WHI Studies - Additional risk of VTE over 5 years' use

Age range (years)

Incidence per 1000 women in placebo arm over 5 years

Risk ratio & 95%CI

Additional cases per 1000 HRT users

Oral, oestrogen-only*

50-59

7

1.2 (0.6 - 2.4)

1 (-3 - 10)

Oral combined, oestrogen -progesterone

50-59

4

2.3 (1.2 - 4.3)

5 (1 - 13)

* Study in women with no uterus.

Risk of coronary artery disease

The risk of coronary artery disease is slightly increased in users of combined oestrogen-progestogen HRT over the age of 60 (see section 4.4).

Risk of ischaemic stroke

• The use of oestrogen-only and oestrogen + progestogen therapy is associated with an up to 1.5 fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT.

• This relative risk is not dependent on age or on duration of use, but as the baseline risk is strongly age- dependent, the overall risk of stroke in women who use HRT will increase with age (see section 4.4).

WHI studies combined - Additional risk of ischaemic stroke* over 5 years' use.

Age range (years)

Incidence per 1000 women in placebo arm over 5 years

Risk ratio & 95%CI

Additional cases per 1000 HRT users over 5 years

50-59

8

1.3 (1.1 – 1.6)

3 (1 – 5)

* No differentiation was made between ischaemic and haemorrhagic stroke.

Adverse events which have been reported in association with oestrogen/ progestogen treatment :

Venous thrombo-embolism, ie deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone HRT users than among non-users. For further information see Section 4.3 Contra-indications and 4.4 Special warnings and precautions for use.

Other adverse reactions have been reported in association with oestrogen/progestogen treatment:

• Gall bladder disease

• Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura

• Probable dementia over the age of 65 (see section 4.4)

• Dry eyes

• Tear film composition changes

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9. Overdose

Sign and symptoms

Due to the mode of administration, overdose of oestradiol or norethisterone is unlikely to occur. Symptoms of overdose with oral oestrogens are breast tenderness, nausea, vomiting and/or metrorrhagia. Over dosage of progestogens may lead to a depressive mood, fatigue, acne and hirsutism.

Treatment

These symptoms can be reversed by removing the Evorel Conti patch.

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