Drugs List

Therapeutic Indications

Uses

Atrophic vaginitis - post-menopausal

Contraindications

Abnormal liver function test
Acute hepatic disorder
Angina
Antiphospholipid syndrome
Breast cancer
Breastfeeding
Deep vein thrombosis
History of breast cancer
History of hormone dependent neoplasm
History of thromboembolic disorder
History of venous thromboembolism
Hormone dependent neoplasm
Myocardial infarction
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
Hereditary angioedema
Patients over 65 years
Predisposition to thromboembolic disease
Prolonged immobilisation
Risk factor for oestrogen-dependent neoplasm
Severe headache
Asthma
Cardiac impairment
Cholelithiasis
Diabetes mellitus
Endometrial hyperplasia
Endometriosis
Epileptic disorder
Hepatic adenoma
Hepatic disorder
History of chloasma
Hypertension
Hypertriglyceridaemia
Hypocalcaemia
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
Treat vaginal infections before initiation of therapy
Do breast & pelvic exam. before & during treatment if clinically indicated
Follow up at least annually with physical and gynaecological examination
Investigate persistent or recurrent vaginal bleeding
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
Advise patients to report gynaecological bleeding and/or pelvic pain
Increased risk of VTE during travel involving >5hr immobilisation
May increase baseline risk of ovarian carcinoma
Prolonged use of unopposed oestrogen may incr.risk of endometrial carcinoma
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 hepatic function deteriorates
Discontinue if jaundice or other evidence of hepatic impairment occurs
Discontinue if significant rise in blood pressure occurs
Discontinue if symptoms due to endometriosis are exacerbated
Advise patient not to take St John's wort concurrently
Advise patient of increased risk of breast cancer vs benefits of HRT
Advise patients risk of endometrial cancer and to report relevant symptoms

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 hyperstimulation/malignancy of the endometrium before treatment initiation. There is very little systemic absorption of estradiol during treatment with estradiol vaginal tablets, however, being a HRT product, the following need to be considered, especially in repeated or long term use.

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. As the systemic exposure to oestrogen is within normal postmenopausal range, it is not recommended to add a progestogen with oestrogen products for vaginal application. Endometrial safety of repeated or long term (more than one year) use of vaginally administered oestrogen is uncertain. Therefore, if repeated, it is recommended that treatment is reviewed at least annually. Special consideration should be given to any symptoms of endometrial hyperplasia or carcinoma.

Evidence suggest there is no increased risk of breast cancer in women with no history of breast cancer taking low dose vaginally applied oestrogens. It is unknown if low dose vaginal oestrogens stimulate a recurrence of breast cancer. In hysterectomised women using oestrogen only HRT, the WHI trial found no increase in risk of breast cancer.

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). Vaginal administration of estradiol is associated with minimal systemic absorption and thus is less likely to have pronounced effects on plasma binding proteins than systemic HRT.

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. In women with serious vaginal atrophy, the intravaginal applicator may cause minor local trauma.

Pregnancy and Lactation

Pregnancy

Estradiol is contraindicated during pregnancy.

The manufacturer does not recommend using estradiol during pregnancy. Should pregnancy occur, treatment should be discontinued immediately. The results of most epidemiological studies to date indicate no teratogenic or foetotoxic effects.
In some studies estradiol has been associated with cardiovascular defects and hypospadias in the newborn when having been exposed to estradiol in utero. However, other 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 which 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).

Lactation

Estradiol is contraindicated during breastfeeding.

The manufacturer does not recommend estradiol during breastfeeding.

Estradiol has been used to suppress postpartum breast engorgement in patients who do not desire to breast feed. In women receiving 50 or 100 mg of vaginal estradiol, less than 10% of the dose was expressed in breast milk. The American Academy of Paediatrics classifies estradiol as compatible with breastfeeding (Briggs, 2015).

Side Effects

Abdominal pain
Anaphylactic reaction
Anaphylactic shock
Breast pain
Chloasma
Deep vein thrombosis (DVT)
Diarrhoea
Endometrial hyperplasia
Erythema multiforme
Erythema nodosum
Erythematous rash
Fluid retention
Gallbladder disease
Headache
Hot flushes
Hypersensitivity reactions
Hypertension
Increased risk of breast cancer
Insomnia
Migraine
Nausea
Peripheral oedema
Postmenopausal bleeding
Pruritus
Rash
Risk of endometrial carcinoma
Slight vaginal bleeding
Urticaria
Vaginal candidiasis
Vaginal discharge
Vaginal discomfort
Vaginal haemorrhage
Vaginal irritation
Vaginal pain
Vaginal ulcers
Vaginismus
Vascular purpura
Vulvovaginal infections
Weight gain

Presentation

Vaginal tablets containing estradiol.

Drugs List

Therapeutic Indications

Uses

Atrophic vaginitis - post-menopausal

Dosage

For initiation and continuation of treatment of menopausal symptoms, the lowest effective dose for the shortest duration should be used.

Adults

Contraindications

Abnormal liver function test
Acute hepatic disorder
Angina
Antiphospholipid syndrome
Breast cancer
Breastfeeding
Deep vein thrombosis
History of breast cancer
History of hormone dependent neoplasm
History of thromboembolic disorder
History of venous thromboembolism
Hormone dependent neoplasm
Myocardial infarction
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
Hereditary angioedema
Patients over 65 years
Predisposition to thromboembolic disease
Prolonged immobilisation
Risk factor for oestrogen-dependent neoplasm
Severe headache
Asthma
Cardiac impairment
Cholelithiasis
Diabetes mellitus
Endometrial hyperplasia
Endometriosis
Epileptic disorder
Hepatic adenoma
Hepatic disorder
History of chloasma
Hypertension
Hypertriglyceridaemia
Hypocalcaemia
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
Treat vaginal infections before initiation of therapy
Do breast & pelvic exam. before & during treatment if clinically indicated
Follow up at least annually with physical and gynaecological examination
Investigate persistent or recurrent vaginal bleeding
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
Advise patients to report gynaecological bleeding and/or pelvic pain
Increased risk of VTE during travel involving >5hr immobilisation
May increase baseline risk of ovarian carcinoma
Prolonged use of unopposed oestrogen may incr.risk of endometrial carcinoma
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 hepatic function deteriorates
Discontinue if jaundice or other evidence of hepatic impairment occurs
Discontinue if significant rise in blood pressure occurs
Discontinue if symptoms due to endometriosis are exacerbated
Advise patient not to take St John's wort concurrently
Advise patient of increased risk of breast cancer vs benefits of HRT
Advise patients risk of endometrial cancer and to report relevant symptoms

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 hyperstimulation/malignancy of the endometrium before treatment initiation. There is very little systemic absorption of estradiol during treatment with estradiol vaginal tablets, however, being a HRT product, the following need to be considered, especially in repeated or long term use.

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. As the systemic exposure to oestrogen is within normal postmenopausal range, it is not recommended to add a progestogen with oestrogen products for vaginal application. Endometrial safety of repeated or long term (more than one year) use of vaginally administered oestrogen is uncertain. Therefore, if repeated, it is recommended that treatment is reviewed at least annually. Special consideration should be given to any symptoms of endometrial hyperplasia or carcinoma.

Evidence suggest there is no increased risk of breast cancer in women with no history of breast cancer taking low dose vaginally applied oestrogens. It is unknown if low dose vaginal oestrogens stimulate a recurrence of breast cancer. In hysterectomised women using oestrogen only HRT, the WHI trial found no increase in risk of breast cancer.

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). Vaginal administration of estradiol is associated with minimal systemic absorption and thus is less likely to have pronounced effects on plasma binding proteins than systemic HRT.

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. In women with serious vaginal atrophy, the intravaginal applicator may cause minor local trauma.

Pregnancy and Lactation

Pregnancy

Estradiol is contraindicated during pregnancy.

The manufacturer does not recommend using estradiol during pregnancy. Should pregnancy occur, treatment should be discontinued immediately. The results of most epidemiological studies to date indicate no teratogenic or foetotoxic effects.
In some studies estradiol has been associated with cardiovascular defects and hypospadias in the newborn when having been exposed to estradiol in utero. However, other 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 which 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).

Lactation

Estradiol is contraindicated during breastfeeding.

The manufacturer does not recommend estradiol during breastfeeding.

Estradiol has been used to suppress postpartum breast engorgement in patients who do not desire to breast feed. In women receiving 50 or 100 mg of vaginal estradiol, less than 10% of the dose was expressed in breast milk. The American Academy of Paediatrics classifies estradiol as compatible with breastfeeding (Briggs, 2015).

Counselling

If a dose is forgotten it should be taken as soon as the patient remembers. A double dose should be avoided.

Advise patient not to take St John's wort concurrently.

Advise patients risk of endometrial cancer and to report relevant symptoms.

Advise patient of thromboembolic symptoms and to report them if they occur.

Advise patient to report gynaecological bleeding.

Advise patient to examine their breast(s) regularly and report any changes to their doctor or nurse immediately, due to the risk of breast cancer.

Advise patient to seek advise at the first indications of pregnancy.

Advise patient to participate in the national breast cancer and cervical cancer screening programmes as appropriate for their age.

Advise patient of increased risk of breast cancer versus benefits of treatment.

Side Effects

Abdominal pain
Anaphylactic reaction
Anaphylactic shock
Breast pain
Chloasma
Deep vein thrombosis (DVT)
Diarrhoea
Endometrial hyperplasia
Erythema multiforme
Erythema nodosum
Erythematous rash
Fluid retention
Gallbladder disease
Headache
Hot flushes
Hypersensitivity reactions
Hypertension
Increased risk of breast cancer
Insomnia
Migraine
Nausea
Peripheral oedema
Postmenopausal bleeding
Pruritus
Rash
Risk of endometrial carcinoma
Slight vaginal bleeding
Urticaria
Vaginal candidiasis
Vaginal discharge
Vaginal discomfort
Vaginal haemorrhage
Vaginal irritation
Vaginal pain
Vaginal ulcers
Vaginismus
Vascular purpura
Vulvovaginal infections
Weight gain

Effects on Laboratory Tests

Combined oestrogen and progesterone HRT preparations may increase the density of mammographic images which may 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: November 2020

Reference Sources

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: Gina 10 micrograms vaginal tablets. Novo Nordisk Limited. Revised June 2022.

Summary of Product Characteristics: Vagifem 10mcg vaginal tablets. Novo Nordisk Limited. Revised September 2018.

Summary of Product Characteristics: Vagirux 10mcg vaginal tablets. Gedeon Rickter (UK) Limited. Revised August 2020.

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 17 October 2022