Patient leaflets and SmPCs, drug interaction checker, official dosages and NHS pharmacy opening hours — all in one place.
Patient leaflets and SmPCs, drug interaction checker, official dosages and NHS pharmacy opening hours — all in one place.
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.
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
2.
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 had a premature menopause the risk of using HRT may be different. Talk to your doctor about the risks. Make sure that you:
–
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:
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:
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:
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:
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.
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:
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.
Putting a patch on Do not use a patch if its protective pouch is already open. Step 1: Open and Peel
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
Peel an edge of the patch smoothly away from the skin
Everyday activities
If you stop using Evorel Conti If you have any further questions on the use of this medicine, ask your doctor. 4.
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:
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)
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)
Uncommon (affects less than 1 in100 people)
Being sick Skin discoloration Abnormal liver function tests
Rare (affects less than 1 in 1,000 people)
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.
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.
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
The active substance in Evorel Conti is estradiol hemihydrate, norethisterone acetate.
Medicines with the same active substance, strength and form include: Evorel Sequi. They are interchangeable only if your prescriber or pharmacist says so.
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.
Whether a medicine is available over the counter or on prescription only depends on its licence. Check the leaflet, or ask your pharmacist — they can tell you straight away.
The text above reproduces the patient information leaflet approved for this medicine, restructured for easier reading.
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.
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.
- 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
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.
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.
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.
There are no known data on the effects of Evorel Conti on the ability to drive or use machinery.
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.
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.
Ask anything about Evorel Conti. The assistant answers only from this leaflet — if the leaflet does not cover it, it will say so. It does not give medical advice.
Answers come from the patient leaflet published on the electronic medicines compendium (emc). They are not medical advice. Ask a pharmacist or your GP if you are unsure. For urgent help call NHS 111, or 999 in an emergency.
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