Drugs List

Therapeutic Indications

Uses

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.

Contraindications

Children under 18 years
Abnormal liver function test
Acute hepatic disorder
Angina
Breast cancer
Breastfeeding
Deep vein thrombosis
History of breast cancer
History of venous thromboembolism
Myocardial infarction
Oestrogen dependent neoplasm
Porphyria
Pregnancy
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
Asthma
Cardiac impairment
Cholelithiasis
Diabetes mellitus
Endometrial hyperplasia
Endometriosis
Epileptic disorder
Hepatic adenoma
Hepatic disorder
Hepatic impairment
Hereditary angioneurotic oedema
History of chloasma
History of thromboembolic disorder
Hypertension
Hypertriglyceridaemia
Hypothyroidism
Mastopathy
Migraine
Otosclerosis
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

Pregnancy

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).

Lactation

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).

Side Effects

"Spotting" bleeding
Abdominal cramps
Abdominal distension
Abdominal pain
Abnormal liver function tests
Acne
Alopecia
Altered glucose tolerance
Anaphylactic reaction
Anxiety
Application site reaction
Arthralgia
Back pain
Bloating
Blood lipid changes
Breakthrough bleeding
Breast enlargement
Breast fibroadenoma
Breast pain
Breast tenderness
Cerebrovascular accident
Cervical polyp
Changes in libido
Chloasma
Cholelithiasis
Cholestatic jaundice
Contact lenses may irritate
Contact sensitisation
Deep vein thrombosis (DVT)
Depression
Diarrhoea
Disturbances of appetite
Dizziness
Dysmenorrhoea
Endometrial hyperplasia
Erythema at application site
Erythematous rash
Exacerbation of epilepsy
Exacerbation of varicose veins
Fatigue
Fibrocystic breast changes
Flatulence
Fluid retention
Gallbladder disease
Gastrointestinal disorder
Headache
Hirsutism
Hypersensitivity reactions
Hypertension
Hypoesthesia
Impaired concentration
Increased risk of breast cancer
Insomnia
Irritation at application site
Leg cramps
Malaise
Menorrhagia
Metrorrhagia
Migraine
Mood changes
Myalgia
Nausea
Oedema
Pain
Palpitations
Pancreatitis
Paraesthesia
Peripheral vasodilatation
Premenstrual-like syndrome
Pruritus
Pulmonary embolism
Rash
Risk of endometrial carcinoma
Sodium retention
Stevens-Johnson syndrome
Thromboembolic disorders
Thrombosis
Urticaria
Uterine fibroids
Vaginal candidiasis
Vomiting
Weight changes
Weight gain

Presentation

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

Drugs List

Therapeutic Indications

Uses

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.

Dosage

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

Adults

Additional Dosage Information

Contraindications

Children under 18 years
Abnormal liver function test
Acute hepatic disorder
Angina
Breast cancer
Breastfeeding
Deep vein thrombosis
History of breast cancer
History of venous thromboembolism
Myocardial infarction
Oestrogen dependent neoplasm
Porphyria
Pregnancy
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
Asthma
Cardiac impairment
Cholelithiasis
Diabetes mellitus
Endometrial hyperplasia
Endometriosis
Epileptic disorder
Hepatic adenoma
Hepatic disorder
Hepatic impairment
Hereditary angioneurotic oedema
History of chloasma
History of thromboembolic disorder
Hypertension
Hypertriglyceridaemia
Hypothyroidism
Mastopathy
Migraine
Otosclerosis
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

Pregnancy

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).

Lactation

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).

Counselling

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
Acne
Alopecia
Altered glucose tolerance
Anaphylactic reaction
Anxiety
Application site reaction
Arthralgia
Back pain
Bloating
Blood lipid changes
Breakthrough bleeding
Breast enlargement
Breast fibroadenoma
Breast pain
Breast tenderness
Cerebrovascular accident
Cervical polyp
Changes in libido
Chloasma
Cholelithiasis
Cholestatic jaundice
Contact lenses may irritate
Contact sensitisation
Deep vein thrombosis (DVT)
Depression
Diarrhoea
Disturbances of appetite
Dizziness
Dysmenorrhoea
Endometrial hyperplasia
Erythema at application site
Erythematous rash
Exacerbation of epilepsy
Exacerbation of varicose veins
Fatigue
Fibrocystic breast changes
Flatulence
Fluid retention
Gallbladder disease
Gastrointestinal disorder
Headache
Hirsutism
Hypersensitivity reactions
Hypertension
Hypoesthesia
Impaired concentration
Increased risk of breast cancer
Insomnia
Irritation at application site
Leg cramps
Malaise
Menorrhagia
Metrorrhagia
Migraine
Mood changes
Myalgia
Nausea
Oedema
Pain
Palpitations
Pancreatitis
Paraesthesia
Peripheral vasodilatation
Premenstrual-like syndrome
Pruritus
Pulmonary embolism
Rash
Risk of endometrial carcinoma
Sodium retention
Stevens-Johnson syndrome
Thromboembolic disorders
Thrombosis
Urticaria
Uterine fibroids
Vaginal candidiasis
Vomiting
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.

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: 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: www.nice.org.uk Last accessed: 13 January 2020

The Norwegian Porphyria Centre (NAPOS).
Available at: https://www.drugs-porphyria.org
Last accessed: 08 January 2020