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Estradiol and norethisterone combination and sequential transdermal patches

Updated 2 Feb 2023 | Oestrogens and HRT


Transdermal patches containing estradiol and norethisterone (continuous combined and sequential therapies).

Drugs List

  • estradiol 50microgram/24hour twice weekly patch with norethisterone acetate 170microgram/24hour and estradiol 50microgram/24hour twice weekly patch
  • estradiol with norethisterone acetate 50microgram+170microgram/24hour twice weekly patch
  • EVOREL CONTI patch
  • EVOREL SEQUI patch
  • Therapeutic Indications


    Replacement therapy for oestrogen deficiency symptoms
    Secondary prophylaxis of postmenopausal osteoporosis where risk of fracture

    Hormone replacement therapy for the treatment of oestrogen deficiency symptoms. The sequential treatment is used for peri- and post-menopausal women. The combination treatment is used in post-menopausal women more than 6 months past the menopause (or 18 months since last period).

    Prevention of osteoporosis in postmenopausal women at a high risk of fractures and who are intolerant or contraindicated for drugs indicated for the prevention of osteoporosis.


    For initiation and continuation of hormone replacement therapy, the lowest effective dose for the shortest duration should be used.


    Sequential therapy
    One estradiol transdermal patch to be applied twice weekly for 14 days, followed by one estradiol and norethisterone acetate transdermal patch applied twice weekly for the following 14 days. A subsequent 28 day cycle should follow immediately, without treatment interruption.

    Continuous combined therapy
    One transdermal patch should be applied twice weekly (every 3 to 4 days) on a continuous basis without interruption.

    Additional Dosage Information

    Post-menopausal women with an intact uterus not currently undergoing HRT or those transferring from a continuous combined HRT regimen may begin treatment at any time.

    Post-menopausal women with an intact uterus transferring from a continuous sequential, or cyclical HRT regimen should begin treatment the day after completing the prior treatment course or after a 7 day interval.

    Peri-menopausal women with an intact uterus who are still menstruating should begin treatment within five days of the onset of bleeding. Peri-menopausal women with irregular menstrual cycles, for whom pregnancy has been excluded, can begin treatment at any time.


    Children under 18 years
    Abnormal liver function test
    Acute hepatic disorder
    Breast cancer
    Deep vein thrombosis
    History of breast cancer
    History of venous thromboembolism
    Myocardial infarction
    Oestrogen dependent neoplasm
    Pulmonary embolism
    Recent arterial thromboembolic disorder
    Thromboembolic disorder
    Thrombophilic disorder
    Uncontrolled endometrial hyperplasia
    Undiagnosed gynaecological haemorrhage

    Precautions and Warnings

    Family history of breast cancer
    History of cholestatic jaundice
    History of recurrent spontaneous abortion
    Patients over 65 years
    Predisposition to thromboembolic disease
    Prolonged immobilisation
    Recent surgery
    Recent trauma
    Severe headache
    Cardiac impairment
    Diabetes mellitus
    Endometrial hyperplasia
    Epileptic disorder
    Hepatic adenoma
    Hepatic disorder
    Hepatic impairment
    Hereditary angioneurotic oedema
    History of chloasma
    History of thromboembolic disorder
    Renal impairment
    Systemic lupus erythematosus
    Uterine fibroids

    Risk of pancreatitis in individuals with hypertriglyceridaemia
    Assess family medical history prior to commencing treatment
    Exclude breast cancer before treatment
    Exclude oestrogen dependent neoplasm before treatment
    Avoid the use of creams, oils or lotions as they may reduce patch adhesion
    Do not apply on or near breasts
    Do breast & pelvic exam. before & during treatment if clinically indicated
    Exclude pregnancy prior to initiation of treatment
    Abnormal and/or irregular bleeding should be investigated
    Advise patients of risks/benefits & review need for treatment regularly
    Discontinue treatment if patient develops seizures
    Monitor hepatic function in patients with history of hepatic disease
    Advise patient of thromboembolic symptoms and to report them if they occur
    Advise patient that changes in their breasts should be reported to Dr/nurse
    Avoid immobilisation-treatment may cause increased risk of thromboembolism
    Discontinue at the onset of severe depression
    Increased risk of VTE during travel involving >5hr immobilisation
    Uterine fibroids may increase in size
    May interfere with certain laboratory measurements
    Discontinue 4 - 6 weeks before major surgery
    Advise patient to seek advice at first indications of pregnancy
    Discontinue at first signs of thrombophlebitis or thromboembolism
    Discontinue if cholestasis develops
    Discontinue if first appearance of migraine or severe or frequent headache
    Discontinue if jaundice or other evidence of hepatic impairment occurs
    Discontinue if significant rise in blood pressure occurs
    Discontinue if sudden pain in the chest occurs
    Discontinue if sudden, severe pain in stomach occurs
    Discontinue if symptoms due to endometriosis are exacerbated
    Advise patient not to take St John's wort concurrently
    Female: Not for contraception.Use non-hormonal contraception, if required
    Advise patient of increased risk of breast cancer vs benefits of HRT
    Women with a history of chloasma should avoid exposure to sun/UV light

    Hormone replacement therapy (HRT) should only be considered for patients whose symptoms adversely affect quality of life. An annual careful appraisal of the risks and benefits should be undertaken. When carrying out initial medical examinations of patients, ensure that investigations (including appropriate imaging tools, e.g. mammography) are carried out in accordance with currently accepted screening practices.

    During the first months of treatment, break-through bleeding and spotting may occur. If break-through bleeding or spotting appears after the first few months, or continues after treatment has been discontinued, the reason should be investigated. This may include endometrial biopsy to exclude endometrial malignancy.

    Studies have shown an increased risk of developing breast cancer in women taking oestrogen-progesterone HRT, which usually becomes apparent after 3 years of therapy. The risk of breast cancer returns to normal after about 5 years of stopping treatment.

    Evidence suggests a slight increased risk of ovarian cancer in women taking oestrogen-only or combined oestrogen and progestogen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping.

    The presence of a personal or strong family history of recurrent thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. HRT treatment should be stopped until a definitive diagnosis has been made or anticoagulant treatment initiated.

    Use of HRT in patients with a history of recurrent venous thromboembolism (VTE) or known thrombophilic states already on anticoagulant treatment requires careful consideration of the benefit-risk of use of HRT.

    HRT is associated with a 1.3 to 3 fold risk of developing venous thromboembolism. The occurrence of such an event is most likely during the first year of HRT.

    The relative risk of coronary artery disease during use of combined oestrogen-progestogen HRT is slightly increased. The risk of coronary artery disease is positively correlated with age.

    There is a 1.5 fold increase in risk of ischaemic stroke in patients receiving combined oestrogen-progestogen and oestrogen-only therapy. The relative risk does not change with age or time since menopause.

    In women who start using continuous combined or oestrogen-only HRT after the age of 65, some studies have shown an increased risk of probable dementia.

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

    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 the acceptable range.

    Pregnancy and Lactation


    Estradiol with norethisterone is contraindicated during pregnancy.

    The manufacturer does not recommend using estradiol with norethisterone during pregnancy. Should pregnancy occur, treatment should be discontinued immediately.

    Estradiol has been associated with cardiovascular defects, eye and ear abnormalities and hypospadias in the newborn when having been exposed to these in the womb (Briggs, 2015). However, some studies have failed to find a relationship with cardiovascular defects and non-genital malformations. Down's syndrome has also been associated with oestrogens as a group, but not for estradiol (Schaefer, 2015).

    Exposure to estradiol and progestogen in the womb, has been linked with development alterations in the psychosexual performance of boys. Males who have been exposed to these drugs have demonstrated less heterosexual characteristics and fewer masculine interests than males which have not been exposed to these hormones prenatally (Briggs, 2015).


    Estradiol with norethisterone is contraindicated during breastfeeding.

    The manufacturer does not recommend using estradiol with norethisterone during breastfeeding. Estradiol use in early postpartum may reduce volume of milk produced and protein content (Briggs, 2015). Estradiol has been used to suppress postpartum breast engorgement in patients who do not desire to breastfeed (Hale, 2014).


    Advise patient to discontinue treatment and consult their doctor if they suspect pregnancy.

    It is possible to take a shower or have a bath without removing the transdermal patch. In the event that the transdermal patch should become detached prematurely, a new patch should be applied.

    Forgetting to change a patch on schedule may increase the likelihood of break-through bleeding or spotting.

    Advise patients not to self-medicate with St John's Wort during treatment with HRT.

    Advise patients to contact their doctor if they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).

    Advise patient contact sensitivity may occur.

    Advise patients to avoid the use of creams, gels, lotions or powders on areas of skin where the patch is to be applied, to prevent interference with the adhesive properties of the product.

    Removal of the transdermal patch should be carried out slowly to avoid irritating the skin. In the event of some of the adhesive remaining on the skin, this can usually be removed by gently rubbing, washing with soap and water or an oily lotion.

    After use, fold the patch in two, with the adhesive surface to the inside and dispose of it with normal household solid waste.

    Encourage patients to participate in the national breast cancer screening programme and the national cervical cancer screening programme as appropriate for their age. Breast awareness should also be encouraged and patients advised to report any changes in their breasts to their doctor or nurse.

    Advise patients that patches should never be applied to or near the breast.

    Side Effects

    "Spotting" bleeding
    Abdominal cramps
    Abdominal distension
    Abdominal pain
    Abnormal liver function tests
    Altered glucose tolerance
    Anaphylactic reaction
    Application site reaction
    Back pain
    Blood lipid changes
    Breakthrough bleeding
    Breast enlargement
    Breast fibroadenoma
    Breast pain
    Breast tenderness
    Cerebrovascular accident
    Cervical polyp
    Changes in libido
    Cholestatic jaundice
    Contact lenses may irritate
    Contact sensitisation
    Deep vein thrombosis (DVT)
    Disturbances of appetite
    Endometrial hyperplasia
    Erythema at application site
    Erythematous rash
    Exacerbation of epilepsy
    Exacerbation of varicose veins
    Fibrocystic breast changes
    Fluid retention
    Gallbladder disease
    Gastrointestinal disorder
    Hypersensitivity reactions
    Impaired concentration
    Increased risk of breast cancer
    Irritation at application site
    Leg cramps
    Mood changes
    Peripheral vasodilatation
    Premenstrual-like syndrome
    Pulmonary embolism
    Risk of endometrial carcinoma
    Sodium retention
    Stevens-Johnson syndrome
    Thromboembolic disorders
    Uterine fibroids
    Vaginal candidiasis
    Weight changes
    Weight gain

    Effects on Laboratory Tests

    The use of oestrogen may influence the laboratory results of certain endocrine tests (e.g. glucose tolerance and thyroid function) and liver enzymes.

    Hormone replacement therapy, especially oestrogen-progestogen combined treatment may increase the density of mammographic images and adversely effect the detection of breast cancer.


    It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

    The following number will direct the caller to the relevant local centre (0844) 892 0111

    Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( ) or if this is unavailable at the backup site ( ).

    Further Information

    Last Full Review Date: January 2020

    Reference Sources

    Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 3rd edition (2015) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

    Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition (2015) ed. Briggs, G., Freeman, R. Wolters Kluwer Health, Philadelphia.

    Medications and Mothers' Milk, Sixteenth Edition (2014) Hale, T and Rowe, H, Hale Publishing, Plano, Texas.

    Summary of Product Characteristics: Evorel Conti. Theramex UK Limited. Revised October 2019.

    Summary of Product Characteristics: Evorel Sequi. Theramex UK Limited. Revised October 2019.

    NICE Evidence Services Available at: Last accessed: 13 January 2020

    The Norwegian Porphyria Centre (NAPOS).
    Available at:
    Last accessed: 08 January 2020

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