Drugs List

Therapeutic Indications

Uses

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

All strengths
Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in postmenopausal women at least 6 months since last menses (sequential therapy) or 12 months after last menses (continuous therapy).

Products containing at least 1 mg of estradiol
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.

Contraindications

Suspected hormone dependent neoplasm
Abnormal liver function test
Acute hepatic disorder
Breast cancer
Breastfeeding
Deep vein thrombosis
Galactosaemia
History of breast cancer
History of thromboembolic disorder without anticoagulant therapy
History of venous thromboembolism
Oestrogen dependent neoplasm
Porphyria
Pregnancy
Recent arterial thromboembolic disorder
Thrombophilia
Uncontrolled endometrial hyperplasia
Undiagnosed gynaecological haemorrhage
Venous thromboembolism

Precautions and Warnings

Body mass index above 30kg per square metre
Family history of breast cancer
Patients over 65 years
Predisposition to thromboembolic disease
Prolonged immobilisation
Recent surgery
Severe headache
Asthma
Cardiac impairment
Cholelithiasis
Diabetes mellitus
Endometrial hyperplasia
Endometriosis
Epileptic disorder
Glucose-galactose malabsorption syndrome
Hepatic disorder
History of endometrial hyperplasia
History of thromboembolic disorder
Hypertension
Hypertriglyceridaemia
Lactose intolerance
Meningioma
Migraine
Otosclerosis
Renal impairment
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
Contains lactose
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
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
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 thrombophlebitis or thromboembolism
Discontinue if first occurrence or worsening of migraine/severe headache
Discontinue if jaundice or other evidence of hepatic impairment occurs
Discontinue if pre-existing uterine fibroids increase in size
Discontinue if significant rise in blood pressure 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.

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 Women's 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. 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.
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 CAD during use of combined oestrogen-progestogen HRT is slightly increased. As the baseline 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. 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.

Pregnancy and Lactation

Pregnancy

Hormone replacement therapy is contraindicated during pregnancy.

Should pregnancy occur, treatment should be discontinued immediately.

Oestrogens has been associated with cardiovascular defects, eye and ear abnormalities and hypospadias in the newborn when having been exposed to these in the womb. However, some studies have failed to find a relationship between oestrogens and cardiovascular defects (Briggs, 2015).

Administration of gestagens during pregnancy does not warrant the termination of the foetus, but an ultrasound should be considered (Schaefer, 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 (Briggs, 2015).

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 ).

Lactation

Hormone replacement therapy is contraindicated during breastfeeding.

Estradiol has been used to suppress postpartum breast engorgement in patients who do not desire to breastfeed (Briggs, 2015).

Hale (2014) suggests that although small amounts of estradiol passes in to breast milk, there seems to be little impact on the nursing infant. Use of oestrogens in the initial weeks of breastfeeding may reduce the volume of milk produced and its protein content, thus it is advisable women wait until breastfeeding is well established before taking oestrogens.

The American Academy of Pediatrics classifies estradiol as compatible with breastfeeding (Briggs, 2015)

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

Side Effects

"Spotting" bleeding
Abdominal distension
Abdominal pain
Abnormal vaginal bleeding
Allergic skin reactions
Angioedema
Asthenia
Back pain
Breakthrough bleeding
Breast enlargement
Breast pain
Breast tenderness
Cervical erosion
Change in amount of cervical secretion
Changes in libido
Chloasma
Cholestatic jaundice
Cystitis-like syndrome
Deep vein thrombosis (DVT)
Depression
Dizziness
Dysmenorrhoea
Dyspepsia
Erythema nodosum
Exacerbation of varicose veins
Fatigue
Flatulence
Gallbladder disease
Haemolytic anaemia
Headache
Hypersensitivity reactions
Hypertension
Increased risk of breast cancer
Increased risk of endometrial cancer
Increased size of uterine fibroids
Intolerance to contact lenses
Irregular menstruation
Jaundice
Leg cramps
Liver function disturbances
Malaise
Melasma
Meningioma
Menorrhagia
Metrorrhagia
Migraine
Myocardial infarction
Nausea
Nervousness
Pancreatitis
Pelvic pain
Peripheral oedema
Peripheral vascular disorders
Premenstrual-like syndrome
Pruritus
Pulmonary embolism
Rash
Steepening of corneal curvature
Thromboembolic disorders
Urticaria
Vaginal candidiasis
Vascular purpura
Venous thrombosis
Vomiting
Weight changes

Presentation

Oral formulations containing estradiol and dydrogesterone (continuous and sequential therapies)

Drugs List

Therapeutic Indications

Uses

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

All strengths
Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in postmenopausal women at least 6 months since last menses (sequential therapy) or 12 months after last menses (continuous therapy).

Products containing at least 1 mg of estradiol
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.

Dosage

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

Adults

Additional Dosage Information

Contraindications

Suspected hormone dependent neoplasm
Abnormal liver function test
Acute hepatic disorder
Breast cancer
Breastfeeding
Deep vein thrombosis
Galactosaemia
History of breast cancer
History of thromboembolic disorder without anticoagulant therapy
History of venous thromboembolism
Oestrogen dependent neoplasm
Porphyria
Pregnancy
Recent arterial thromboembolic disorder
Thrombophilia
Uncontrolled endometrial hyperplasia
Undiagnosed gynaecological haemorrhage
Venous thromboembolism

Precautions and Warnings

Body mass index above 30kg per square metre
Family history of breast cancer
Patients over 65 years
Predisposition to thromboembolic disease
Prolonged immobilisation
Recent surgery
Severe headache
Asthma
Cardiac impairment
Cholelithiasis
Diabetes mellitus
Endometrial hyperplasia
Endometriosis
Epileptic disorder
Glucose-galactose malabsorption syndrome
Hepatic disorder
History of endometrial hyperplasia
History of thromboembolic disorder
Hypertension
Hypertriglyceridaemia
Lactose intolerance
Meningioma
Migraine
Otosclerosis
Renal impairment
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
Contains lactose
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
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
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 thrombophlebitis or thromboembolism
Discontinue if first occurrence or worsening of migraine/severe headache
Discontinue if jaundice or other evidence of hepatic impairment occurs
Discontinue if pre-existing uterine fibroids increase in size
Discontinue if significant rise in blood pressure 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.

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 Women's 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. 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.
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 CAD during use of combined oestrogen-progestogen HRT is slightly increased. As the baseline 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. 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.

Pregnancy and Lactation

Pregnancy

Hormone replacement therapy is contraindicated during pregnancy.

Should pregnancy occur, treatment should be discontinued immediately.

Oestrogens has been associated with cardiovascular defects, eye and ear abnormalities and hypospadias in the newborn when having been exposed to these in the womb. However, some studies have failed to find a relationship between oestrogens and cardiovascular defects (Briggs, 2015).

Administration of gestagens during pregnancy does not warrant the termination of the foetus, but an ultrasound should be considered (Schaefer, 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 (Briggs, 2015).

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 ).

Lactation

Hormone replacement therapy is contraindicated during breastfeeding.

Estradiol has been used to suppress postpartum breast engorgement in patients who do not desire to breastfeed (Briggs, 2015).

Hale (2014) suggests that although small amounts of estradiol passes in to breast milk, there seems to be little impact on the nursing infant. Use of oestrogens in the initial weeks of breastfeeding may reduce the volume of milk produced and its protein content, thus it is advisable women wait until breastfeeding is well established before taking oestrogens.

The American Academy of Pediatrics classifies estradiol as compatible with breastfeeding (Briggs, 2015)

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

Counselling

Tablets should be taken continuously without a break between packs.

If a dose has been forgotten, it should be taken as soon as possible. When more than 12 hours have elapsed, it is recommended to continue with the next dose without taking the forgotten tablet. The likelihood of breakthrough bleeding or spotting may be increased.

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

Advise patients that changes in their breasts should be reported to a doctor or nurse.

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 to seek advise at the first signs of pregnancy.

Patients should be advised of the increased risks of diagnosis of breast cancer versus the benefits of HRT, and the need to review treatment regularly.

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

Side Effects

"Spotting" bleeding
Abdominal distension
Abdominal pain
Abnormal vaginal bleeding
Allergic skin reactions
Angioedema
Asthenia
Back pain
Breakthrough bleeding
Breast enlargement
Breast pain
Breast tenderness
Cervical erosion
Change in amount of cervical secretion
Changes in libido
Chloasma
Cholestatic jaundice
Cystitis-like syndrome
Deep vein thrombosis (DVT)
Depression
Dizziness
Dysmenorrhoea
Dyspepsia
Erythema nodosum
Exacerbation of varicose veins
Fatigue
Flatulence
Gallbladder disease
Haemolytic anaemia
Headache
Hypersensitivity reactions
Hypertension
Increased risk of breast cancer
Increased risk of endometrial cancer
Increased size of uterine fibroids
Intolerance to contact lenses
Irregular menstruation
Jaundice
Leg cramps
Liver function disturbances
Malaise
Melasma
Meningioma
Menorrhagia
Metrorrhagia
Migraine
Myocardial infarction
Nausea
Nervousness
Pancreatitis
Pelvic pain
Peripheral oedema
Peripheral vascular disorders
Premenstrual-like syndrome
Pruritus
Pulmonary embolism
Rash
Steepening of corneal curvature
Thromboembolic disorders
Urticaria
Vaginal candidiasis
Vascular purpura
Venous thrombosis
Vomiting
Weight changes

Effects on Laboratory Tests

The density of mammographic images is increased in patients taking HRT, especially oestrogen-progestogen combined treatment. This may adversely affect the radiological detection of breast cancer.

Overdosage

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 ).

Further Information

Last Full Review Date: May 2017

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.

Joint Formulary Committee. British National Formulary. 73rd ed. London: BMJ Group and Pharmaceutical Press; 2017.

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

Summary of Product Characteristics: Femoston-conti 1mg/ 5mg film-coated tablets. Mylan Products Limited. Revised August 2016.
Summary of Product Characteristics: Femoston-conti 0.5mg/2.5mg. Mylan Products Limited. Revised August 2016.
Summary of Product Characteristics: Femoston 1/10mg. Mylan Products Limited. Revised November 2016.
Summary of Product Characteristics: Femoston 2/10mg. Mylan Products Limited. Revised November 2016.

US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available. at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Estradiol Last revised: 11 April 2017
Last accessed: 20 April 2017