Estradiol hemihydrate + norethisterone tablets
- Drugs List
- Therapeutic Indications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
Oral formulations containing estradiol hemihydrate and norethisterone (continuous and sequential therapies)
Replacement therapy for oestrogen deficiency symptoms
Secondary prophylaxis of postmenopausal osteoporosis where risk of fracture
Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in postmenopausal women with an intact uterus more than 1 year post menopause.
HRT for oestrogen deficiency symptoms in women 1 year since last menses.
HRT for oestrogen deficiency symptoms in women 6 months since last menses.
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.
Continuous combined therapy
Patients using hormone replacement therapy for the first time:
Commence at least one year after the last natural menstrual period and when pregnancy has been excluded. One tablet daily on a continuous basis, preferably at the same time each day. Tablets should be taken continuously without a break between packs.
Patients changing from a sequential combined hormone replacement therapy:
Women transferring from a cyclical or continuous sequential HRT preparation should complete the current cycle and then begin treatment in accordance with the brand recommendations
One estradiol 2mg tablet to be taken daily for the first 12 days, followed by one estradiol/norethisterone combined tablet daily for the next 10 days, followed by one estradiol 1mg tablet for 6 days. The next 28 day cycle should then commence without a break.
Patients changing from another cyclical hormonal preparation should complete that cycle, then start the new preparation without a break.
Patients who are not menstruating or who are taking continuous hormone replacement therapy may start treatment at any time.
Patients with Renal Impairment
Patients with end stage renal failure need close observation as the levels of circulating estradiol are expected to be increased.
Abnormal liver function test
History of breast cancer
Oestrogen dependent neoplasm
Uncontrolled endometrial hyperplasia
Undiagnosed gynaecological haemorrhage
Precautions and Warnings
Body mass index above 30kg per square metre
Family history of breast cancer
Family history of venous thromboembolism
Patients over 65 years
Predisposition to thromboembolic disease
Glucose-galactose malabsorption syndrome
History of chloasma
History of endometrial hyperplasia
Systemic lupus erythematosus
Assess family medical history prior to commencing treatment
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
Monitor thyroid function where clinically indicated
Advise patient that changes in their breasts should be reported to Dr/nurse
Advise patient to contact a doctor if symptoms of thromboembolism develop
Increased risk of VTE during travel involving >5hr immobilisation
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 jaundice
Discontinue if first occurrence or worsening of migraine/severe headache
Discontinue if liver function deteriorates
Discontinue if pre-existing uterine fibroids increase in size
Discontinue if significant rise in blood pressure occurs
Discontinue if thromboembolism occurs
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
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.
Breakthrough bleeding and spotting may occur during the first months of treatment. If such bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, possibly including endometrial biopsy to exclude endometrial malignancy.
There is little evidence regarding the use of HRT in premature menopause, but due to the lower level of absolute risk in younger women, the benefit to risk ratio may be more favourable for these women compared to older women. The overall evidence suggests an increased risk of breast cancer in women taking combined oestrogen-progestogen (and possibly also oestrogen-only HRT). This increased risk is dependent on the duration of HRT. The Womens Health Initiative study (WHI) and epidemiological studies have both reported an increased risk of breast cancer in women taking combined oestrogen-progestogen for HRT. This increased risk becomes apparent within 3 years of starting treatment but returns to baseline within a few (at most five) years after stopping treatment.
A large meta-analysis suggests there is an increased risk of ovarian cancer in women taking HRT, which becomes apparent after 5 years of use and diminishes over time when therapy has been stopped.
HRT is associated with a 1.3 to 3 fold risk of developing venous thromboembolism. The occurrence of such an event is more likely in the first year of HRT than later. In post-operative patients 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 patient is fully mobilised.
There is little evidence that combined oestrogen-progestogen or oestrogen-only HRT offers any protection against myocardial infarction in women with or without existing coronary artery disease. The relative risk of coronary artery disease during use of combined oestrogen-progestogen HRT is slightly increased. As the baseline absolute risk of coronary artery disease is strongly dependent on age, the number of extra cases of coronary artery disease due to oestrogen+progestogen use is very low in healthy women close to menopause, but will rise with more advanced age. HRT is 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. Fluid retention may be experienced in patients taking oestrogens and thus patients with cardiac or renal dysfunction should be carefully observed. Additionally, as rare cases of increased of plasma triglycerides (leading to pancreatitis) have been reported in women taking oestrogen therapy, patients with pre-existing hypertriglyceridemia should be followed closely. Patients who require thyroid hormone therapy should have their thyroid function monitored regularly whilst on HRT. There is no evidence that HRT improves cognitive function. There is some evidence of increased risk of dementia in women who start using continuous combined or oestrogen-only HRT after the age of 65.
Women with familial hypertriglyceridaemia should be monitored closely due to the increased risk of pancreatitis.
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should minimise exposure to the sun or ultraviolet radiation whilst taking HRT.
The use of a combined oestrogen and progestogen product is not recommended in hysterectomised women unless there is a history of endometriosis.
When changing from sequential therapy, menopausal status may not be known. In some women endogenous oestrogens may still be produced and this could result in unpredictable bleeding patterns.
Pregnancy and Lactation
Hormone replacement therapy is contraindicated during pregnancy.
Should pregnancy occur, treatment should be discontinued immediately.
Estradiol has been associated with cardiovascular defects, eye and ear abnormalities in the newborn when having been exposed to these in the womb. However, some studies have failed to find a relationship with cardiovascular defects and non-genital malformations (Briggs, 2015).
Development alterations in the psychosexual performance of boys have been attributed to exposure to estradiol and progestogen in the womb. Males who have been exposed to estradiol and progestogen have demonstrated a trend to have less heterosexual characteristics and fewer masculine interests than males which have not been exposed to these hormones prenatally.
The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Hormone replacement therapy is contraindicated during breastfeeding.
Estradiol has been used to suppress postpartum breast engorgement in patients who do not desire to breastfeed (Hale, 2014). Oestrogenic agents demonstrate lower infant weight gain, decreased milk production and decreased composition of nitrogen and protein content of human milk (Briggs, 2015). Even though the extent of these changes is low, the changes in milk production and composition may be of nutritional importance in malnourished mothers. Because of the reasons mentioned above the use of this medication during lactation should be avoided.
Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1
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
If a tablet is forgotten, it should be taken as soon as the patient remembers, therapy should then continue as before. If more than one tablet has been missed, only the most recent tablet should be taken - the patient should not take multiple doses. If the tablet is taken more than 12 hours late, the missed tablets should be left in the pack and the next tablet taken at the right time.
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).
Patients should be advised of the increased risks of diagnosis of breast cancer versus the benefits of HRT.
Advise patients not to self-medicate with St John's Wort during HRT.
Advise patients that side effects such as dizziness may affect ability to drive or operate machinery.
Altered serum lipid profile
Change in amount of cervical secretion
Change in carbohydrate metabolism
Changes in libido
Decreased glucose tolerance
Deep vein thrombosis (DVT)
Exacerbation of varicose veins
Increase in plasma triglyceride concentration
Increased risk of breast cancer
Increased risk of endometrial cancer
Increased risk of ovarian cancer
Increased size of uterine fibroids
Intolerance to contact lenses
Lability of affect
Liver function disturbances
Effects on Laboratory Tests
The use of HRT may have an impact on certain laboratory test results, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of carrier proteins, parameters of carbohydrate metabolism, and parameters of coagulation and fibrinolysis. These changes generally remain within the normal laboratory range.
Combined oestrogen and progesterone HRT preparations may increase the density of mammographic images which may 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 ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Last Full Review Date: May 2017
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.
Summary of Product Characteristics: Elleste Duet Conti. Meda Pharmaceuticals. Revised April 2016.
Summary of Product Characteristics: Kliofem film-coated tablets. Novo Nordisk Limited. Revised March 2016.
Summary of Product Characteristics: Kliovance. Novo Nordisk Ltd. Revised March 2016.
Summary of Product Characteristics: Nuvelle Continuous. Bayer plc. Revised March 2017.
Summary of Product Characteristics: Trisequens. Novo Nordisk Ltd. Revised March 2022.
NICE Evidence Services Available at: www.nice.org.uk Last accessed: 06 December 2022
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Medscape UK | Univadis prescription drug monographs & interactions are based on FDB Multilex Content
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