Drugs List

Therapeutic Indications

Uses

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 more than three years after the menopause with an intact uterus.

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.

Use the lowest effective dose for the shortest possible time and review the need to continue treatment at least annually.

Contraindications

Suspected hormone dependent neoplasm
Abnormal liver function test
Acute hepatic disorder
Breast cancer
Breastfeeding
Deep vein thrombosis
Familial conjugated hyperbilirubinaemias
Galactosaemia
History of breast cancer
History of hormone dependent neoplasm
History of thromboembolic disorder without anticoagulant therapy
History of venous thromboembolism
Lupus anticoagulant
Oestrogen dependent neoplasm
Porphyria
Pregnancy
Protein C deficiency disease
Protein S deficiency disease
Pulmonary embolism
Recent arterial thromboembolic disorder
Severe cardiac disorder
Severe renal impairment
Thromboembolic disorder
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
History of recurrent spontaneous abortion
Patients over 65 years
Predisposition to thromboembolic disease
Prolonged immobilisation
Recent surgery
Recent trauma
Risk factor for oestrogen-dependent neoplasm
Asthma
Breast nodules
Cardiac impairment
Cholelithiasis
Chronic hepatic disorder
Diabetes mellitus
Endometrial hyperplasia
Endometriosis
Epileptic disorder
Fibrocystic breast disorder
Glucose-galactose malabsorption syndrome
Haemoglobinopathies
Hereditary angioneurotic oedema
History of angioedema
History of breast nodules
History of chloasma
History of fibrocystic breast disorder
History of pregnancy-related deterioration in otosclerosis
History of thromboembolic disorder
Hypertriglyceridaemia
Hypocalcaemia
Lactose intolerance
Malignant melanoma
Migraine
Otosclerosis
Renal impairment
Systemic lupus erythematosus
Uterine fibroids

Assess family medical history prior to commencing 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
Discontinue treatment if patient develops seizures
Monitor for signs of haematological and non-haematological toxicity
Monitor hepatic function in patients with hepatic impairment
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
May affect results of some laboratory tests
Discontinue 4 - 6 weeks before major surgery
Advise patient to seek advice at first indications of pregnancy
Discontinue at first signs of jaundice
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 first occurrence or worsening of visual disturbances
Discontinue if severe abdominal symptoms develop
Discontinue if significant rise in blood pressure occurs
Discontinue if sudden pain in the chest 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
Advise patient to discontinue therapy if any disturbances of vision occur
Women with a history of chloasma should avoid exposure to sun/UV light

Hormone replacement therapy should only be initiated in patients with symptoms that adversely affect quality of life. Careful consideration of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefits outweigh the risks. Medical examinations which include appropriate imaging tools, e.g. mammography, should be carried out in accordance with current screening practices and modified to the needs of the individual.

Women should be examined with special care if they have an intact uterus with undiagnosed abnormal bleeding or women with an intact uterus who have previously been treated with unopposed oestrogens. This is in order to exclude malignancy of the endometrium before treatment initiation.

The risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods of time in women with an intact uterus. The increased risk of endometrial cancer, among systemic oestrogen only users, varies from 2 to 12 fold compared with non-users. This is dependant on both duration of treatment and on oestrogen dose. The risk may remain elevated for at least 10 years after withdrawing treatment.

Evidence suggests there is an increased risk of breast cancer in women taking combined oestrogen-progestogen and possibly oestrogen only HRT. In hysterectomised women using oestrogen only HRT, the WHI trial found no increase in risk of breast cancer. The risk of breast cancer increases with the duration of treatment and, after stopping HRT, the risk will decrease with time. When HRT lasts for more than 5 years, the risk may persist for 10 years or more.

An association has been made between long-term (at least 5 to 10 years) use of oestrogen only HRT products and a slightly increased risk of ovarian cancer. The long term use of oestrogen-progesterone combined HRT may confer a similar or slightly smaller risk.

HRT is associated with a 1.3 to 3 fold risk of developing venous thromboembolism (VTE), which is more likely in the first year of HRT than later. In women who have no personal history of VTE, but have a first degree relative with a history of VTE at a young age screening may be offered. The woman should be carefully counselled with regards to the screenings limitations. This should include the information that only a proportion of thrombophilic defects are identified by screening.

There is a 1.5 fold increase in risk of ischaemic stroke in women taking combined HRT and oestrogen only HRT. It should be noted that the relative risk does not change with age or time since menopause but as the baseline risk of stroke is strongly age dependent, the overall risk of stroke in women who use HRT increase with age.

Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, T4 levels or T3 levels. 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 and sex hormone binding globulin leading to increased circulating corticosteroids and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha 1 antitrypsin, ceruloplasmin).

There is some evidence of an increased risk of probable 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.

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, 2011). However, some studies have failed to find a relationship with cardiovascular defects and non-genital malformations. Down's syndrome has also been associated with estrogens as a group, but not for estradiol (Schaefer, 2007).

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 ).

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 (Hale, 2010). Oestrogenic agents demonstrate lower infant weight gain, decreased milk production and decreased composition of nitrogen and protein content of human milk (Briggs, 2011). 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

Side Effects

Abdominal pain
Alopecia
Anxiety
Bloating
Breast enlargement
Breast tenderness
Changes in libido
Chloasma
Cholestasis
Cholestatic jaundice
Contact lenses may irritate
Dementia
Depressed mood
Dizziness
Dyspepsia
Erythema multiforme
Erythema nodosum
Exacerbation of angioedema
Flatulence
Gallbladder disease
Gallstones
Haemorrhagic eruption
Headache
Hirsutism
Hypertension
Increase in plasma triglyceride concentration
Increased risk of oestrogen-dependent neoplasms
Increased size of uterine fibroids
Irregular uterine bleeding
Itching
Leg cramps
Liver function disturbances
Migraine
Mood changes
Myocardial infarction
Nausea
Oedema
Premenstrual-like syndrome
Rash
Sodium/water retention
Steepening of corneal curvature
Stroke
Thromboembolism
Vaginal candidiasis
Vascular purpura
Vomiting
Weight changes

Presentation

Tablets containing estradiol valerate with medroxyprogesterone acetate

Drugs List

Therapeutic Indications

Uses

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 more than three years after the menopause with an intact uterus.

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.

Use the lowest effective dose for the shortest possible time and review the need to continue treatment at least annually.

Dosage

Adults

Elderly

Additional Dosage Information

Contraindications

Suspected hormone dependent neoplasm
Abnormal liver function test
Acute hepatic disorder
Breast cancer
Breastfeeding
Deep vein thrombosis
Familial conjugated hyperbilirubinaemias
Galactosaemia
History of breast cancer
History of hormone dependent neoplasm
History of thromboembolic disorder without anticoagulant therapy
History of venous thromboembolism
Lupus anticoagulant
Oestrogen dependent neoplasm
Porphyria
Pregnancy
Protein C deficiency disease
Protein S deficiency disease
Pulmonary embolism
Recent arterial thromboembolic disorder
Severe cardiac disorder
Severe renal impairment
Thromboembolic disorder
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
History of recurrent spontaneous abortion
Patients over 65 years
Predisposition to thromboembolic disease
Prolonged immobilisation
Recent surgery
Recent trauma
Risk factor for oestrogen-dependent neoplasm
Asthma
Breast nodules
Cardiac impairment
Cholelithiasis
Chronic hepatic disorder
Diabetes mellitus
Endometrial hyperplasia
Endometriosis
Epileptic disorder
Fibrocystic breast disorder
Glucose-galactose malabsorption syndrome
Haemoglobinopathies
Hereditary angioneurotic oedema
History of angioedema
History of breast nodules
History of chloasma
History of fibrocystic breast disorder
History of pregnancy-related deterioration in otosclerosis
History of thromboembolic disorder
Hypertriglyceridaemia
Hypocalcaemia
Lactose intolerance
Malignant melanoma
Migraine
Otosclerosis
Renal impairment
Systemic lupus erythematosus
Uterine fibroids

Assess family medical history prior to commencing 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
Discontinue treatment if patient develops seizures
Monitor for signs of haematological and non-haematological toxicity
Monitor hepatic function in patients with hepatic impairment
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
May affect results of some laboratory tests
Discontinue 4 - 6 weeks before major surgery
Advise patient to seek advice at first indications of pregnancy
Discontinue at first signs of jaundice
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 first occurrence or worsening of visual disturbances
Discontinue if severe abdominal symptoms develop
Discontinue if significant rise in blood pressure occurs
Discontinue if sudden pain in the chest 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
Advise patient to discontinue therapy if any disturbances of vision occur
Women with a history of chloasma should avoid exposure to sun/UV light

Hormone replacement therapy should only be initiated in patients with symptoms that adversely affect quality of life. Careful consideration of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefits outweigh the risks. Medical examinations which include appropriate imaging tools, e.g. mammography, should be carried out in accordance with current screening practices and modified to the needs of the individual.

Women should be examined with special care if they have an intact uterus with undiagnosed abnormal bleeding or women with an intact uterus who have previously been treated with unopposed oestrogens. This is in order to exclude malignancy of the endometrium before treatment initiation.

The risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods of time in women with an intact uterus. The increased risk of endometrial cancer, among systemic oestrogen only users, varies from 2 to 12 fold compared with non-users. This is dependant on both duration of treatment and on oestrogen dose. The risk may remain elevated for at least 10 years after withdrawing treatment.

Evidence suggests there is an increased risk of breast cancer in women taking combined oestrogen-progestogen and possibly oestrogen only HRT. In hysterectomised women using oestrogen only HRT, the WHI trial found no increase in risk of breast cancer. The risk of breast cancer increases with the duration of treatment and, after stopping HRT, the risk will decrease with time. When HRT lasts for more than 5 years, the risk may persist for 10 years or more.

An association has been made between long-term (at least 5 to 10 years) use of oestrogen only HRT products and a slightly increased risk of ovarian cancer. The long term use of oestrogen-progesterone combined HRT may confer a similar or slightly smaller risk.

HRT is associated with a 1.3 to 3 fold risk of developing venous thromboembolism (VTE), which is more likely in the first year of HRT than later. In women who have no personal history of VTE, but have a first degree relative with a history of VTE at a young age screening may be offered. The woman should be carefully counselled with regards to the screenings limitations. This should include the information that only a proportion of thrombophilic defects are identified by screening.

There is a 1.5 fold increase in risk of ischaemic stroke in women taking combined HRT and oestrogen only HRT. It should be noted that the relative risk does not change with age or time since menopause but as the baseline risk of stroke is strongly age dependent, the overall risk of stroke in women who use HRT increase with age.

Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, T4 levels or T3 levels. 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 and sex hormone binding globulin leading to increased circulating corticosteroids and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha 1 antitrypsin, ceruloplasmin).

There is some evidence of an increased risk of probable 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.

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, 2011). However, some studies have failed to find a relationship with cardiovascular defects and non-genital malformations. Down's syndrome has also been associated with estrogens as a group, but not for estradiol (Schaefer, 2007).

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 ).

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 (Hale, 2010). Oestrogenic agents demonstrate lower infant weight gain, decreased milk production and decreased composition of nitrogen and protein content of human milk (Briggs, 2011). 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

Counselling

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 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).

If patient has forgotten to take one tablet, the forgotten tablet is to be discarded. Forgetting a dose may increase the likelihood of breakthrough bleeding and spotting.

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.

Stop treatment immediately if pregnancy is suspected.

Side Effects

Abdominal pain
Alopecia
Anxiety
Bloating
Breast enlargement
Breast tenderness
Changes in libido
Chloasma
Cholestasis
Cholestatic jaundice
Contact lenses may irritate
Dementia
Depressed mood
Dizziness
Dyspepsia
Erythema multiforme
Erythema nodosum
Exacerbation of angioedema
Flatulence
Gallbladder disease
Gallstones
Haemorrhagic eruption
Headache
Hirsutism
Hypertension
Increase in plasma triglyceride concentration
Increased risk of oestrogen-dependent neoplasms
Increased size of uterine fibroids
Irregular uterine bleeding
Itching
Leg cramps
Liver function disturbances
Migraine
Mood changes
Myocardial infarction
Nausea
Oedema
Premenstrual-like syndrome
Rash
Sodium/water retention
Steepening of corneal curvature
Stroke
Thromboembolism
Vaginal candidiasis
Vascular purpura
Vomiting
Weight changes

Effects on Laboratory Tests

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

The use of oestrogen may influence the laboratory results of certain endocrine tests and liver enzymes.

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: July 2014

Reference Sources

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

Medications and Mothers' Milk, 14th Edition (2010) Hale, T. Hale Publishing, Amarillo, Texas.

Summary of Product Characteristics: Indivina 1 mg/2.5 mg tablets. Orion Pharma (UK) Limited. Revised August 2020.
Summary of Product Characteristics: Indivina 1 mg/5 mg tablets. Orion Pharma (UK) Limited. Revised August 2020.
Summary of Product Characteristics: Indivina 2 mg/5 mg tablets. Orion Pharma (UK) Limited. Revised August 2020.

MHRA Drug Safety Update September 2019
Available at: https://www.mhra.gov.uk
Last accessed: 07 January 2020