Drugs List

Therapeutic Indications

Uses

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

Contraindications

Abnormal liver function test
Acute hepatic disorder
Angina
Breast cancer
Breastfeeding
Deep vein thrombosis
Familial conjugated hyperbilirubinaemias
History of breast cancer
History of hormone dependent neoplasm
History of thromboembolic disorder
Lupus anticoagulant
Myocardial infarction
Oestrogen dependent neoplasm
Porphyria
Pregnancy
Protein C deficiency disease
Protein S deficiency disease
Pulmonary embolism
Thromboembolic disorder
Uncontrolled endometrial hyperplasia
Undiagnosed gynaecological haemorrhage

Precautions and Warnings

Family history of breast cancer
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
Gall bladder disorder
Hepatic disorder
History of breast nodules
History of chloasma
History of thromboembolic disorder without anticoagulant therapy
Hypertension
Hypertriglyceridaemia
Hypocalcaemia
Malignant melanoma
Migraine
Multiple sclerosis
Otosclerosis
Renal impairment
Sickle cell disease
Uterine fibroids

Risk of pancreatitis in individuals with hypertriglyceridaemia
Add progestogen for 12-14 days each cycle for those with an intact uterus
Assess family medical history prior to commencing treatment
Exclude breast cancer before treatment
Exclude oestrogen dependent neoplasm before treatment
Increased risk of endometrial carcinoma with unopposed oestrogens
Not all available brands are licensed for all indications
Some formulations contain propylene glycol
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 hepatic impairment
Regular breast examination advisable
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
Discontinue at the onset of severe depression
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 abnormal neurological signs develop
Discontinue if cerebrovascular disorders occur
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 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

For the treatment of menopausal symptoms the benefits of short-term HRT are considered to outweigh the risks in the majority of women.
In all cases, it is good practice to use the lowest effective dose for the shortest possible time and to review the need to continue treatment at least annually.
For postmenopausal women over 50 years who are at an increased risk of bone fracture, HRT should be used to prevent osteoporosis only in those who are intolerant of, or contraindicated for, other osteoporosis therapies.

Physical examination should be guided by this and a knowledge of the contraindications and precautions and warnings for use of the product. Investigations including mammography should be carried out in accordance with currently accepted screening practices, modified according to the clinical needs of the individual.

There is an increased risk of breast cancer in women currently or recently using Hormone Replacement Therapy (HRT). The risk of breast cancer increases with the duration of treatment and returns to normal after 5 years of stopping treatment.

Examinations to rule out endometrial abnormalities should be undertaken at regular intervals. Prolonged monotherapy with oestrogens increases the risk of endometrial hyperplasia and carcinoma in postmenopausal women unless supplemented by administration of a progestogen to protect the endometrium. Unless there is a previous diagnosis of endometriosis it is not recommended to add a progestogen in hysterectomised women.

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 oestrogens 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

"Spotting" bleeding
Abdominal cramps
Abdominal pain
Aggravation of porphyria
Anxiety
Blood lipid changes
Breakthrough bleeding
Breast enlargement
Breast pain
Breast tenderness
Change in menstrual flow
Changes in libido
Chloasma
Cholestatic jaundice
Deep vein thrombosis (DVT)
Dementia
Depression
Dizziness
Dysmenorrhoea
Endometrial hyperplasia
Erythema multiforme
Erythema nodosum
Exacerbation of epilepsy
Exacerbation of hypocalcaemia
Exacerbation of otosclerosis
Exacerbation of pre-existing asthma
Fibrocystic breast changes
Fluid retention
Gallbladder disease
Headache
Hypertension
Increase in plasma triglyceride concentration
Increased risk of breast cancer
Increased risk of endometrial cancer
Increased risk of oestrogen-dependent neoplasms
Increased risk of ovarian cancer
Increased size of uterine fibroids
Intolerance to contact lenses
Irritability
Liver function disturbances
Migraine
Mood changes
Myocardial infarction
Nausea
Oedema
Pancreatitis
Premenstrual-like syndrome
Pulmonary embolism
Rash
Reduced carbohydrate tolerance
Skin irritation
Stroke
Thrombophlebitis
Vaginal candidiasis
Vascular purpura
Venous thrombosis
Vomiting
Weight changes

Presentation

Gel containing estradiol (as estradiol hemihydrate)

Drugs List

Therapeutic Indications

Uses

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

Dosage

Adults

Elderly

Additional Dosage Information

Contraindications

Abnormal liver function test
Acute hepatic disorder
Angina
Breast cancer
Breastfeeding
Deep vein thrombosis
Familial conjugated hyperbilirubinaemias
History of breast cancer
History of hormone dependent neoplasm
History of thromboembolic disorder
Lupus anticoagulant
Myocardial infarction
Oestrogen dependent neoplasm
Porphyria
Pregnancy
Protein C deficiency disease
Protein S deficiency disease
Pulmonary embolism
Thromboembolic disorder
Uncontrolled endometrial hyperplasia
Undiagnosed gynaecological haemorrhage

Precautions and Warnings

Family history of breast cancer
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
Gall bladder disorder
Hepatic disorder
History of breast nodules
History of chloasma
History of thromboembolic disorder without anticoagulant therapy
Hypertension
Hypertriglyceridaemia
Hypocalcaemia
Malignant melanoma
Migraine
Multiple sclerosis
Otosclerosis
Renal impairment
Sickle cell disease
Uterine fibroids

Risk of pancreatitis in individuals with hypertriglyceridaemia
Add progestogen for 12-14 days each cycle for those with an intact uterus
Assess family medical history prior to commencing treatment
Exclude breast cancer before treatment
Exclude oestrogen dependent neoplasm before treatment
Increased risk of endometrial carcinoma with unopposed oestrogens
Not all available brands are licensed for all indications
Some formulations contain propylene glycol
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 hepatic impairment
Regular breast examination advisable
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
Discontinue at the onset of severe depression
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 abnormal neurological signs develop
Discontinue if cerebrovascular disorders occur
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 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

For the treatment of menopausal symptoms the benefits of short-term HRT are considered to outweigh the risks in the majority of women.
In all cases, it is good practice to use the lowest effective dose for the shortest possible time and to review the need to continue treatment at least annually.
For postmenopausal women over 50 years who are at an increased risk of bone fracture, HRT should be used to prevent osteoporosis only in those who are intolerant of, or contraindicated for, other osteoporosis therapies.

Physical examination should be guided by this and a knowledge of the contraindications and precautions and warnings for use of the product. Investigations including mammography should be carried out in accordance with currently accepted screening practices, modified according to the clinical needs of the individual.

There is an increased risk of breast cancer in women currently or recently using Hormone Replacement Therapy (HRT). The risk of breast cancer increases with the duration of treatment and returns to normal after 5 years of stopping treatment.

Examinations to rule out endometrial abnormalities should be undertaken at regular intervals. Prolonged monotherapy with oestrogens increases the risk of endometrial hyperplasia and carcinoma in postmenopausal women unless supplemented by administration of a progestogen to protect the endometrium. Unless there is a previous diagnosis of endometriosis it is not recommended to add a progestogen in hysterectomised women.

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 oestrogens 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

Apply gel to clean, dry, intact areas of skin such as lower trunk, arms or thighs, using right and left sides on alternate days.

The gel should not be applied to the breasts, vulval region, face or on irritated skin, and avoid contact with the eyes.

The application surface should be 1 to 2 times the size of the hand, or, where the a template is provided in the pack, the size of the template. The gel should be allowed to dry for five minutes before covering with clothing.

The application site should not be washed for at least one hour.

Avoid skin contact with other persons (particularly male) for at least one hour.

Advise patient of the increased risk of breast cancer vs benefits of HRT.
Advise patient that changes in their breasts should be reported to Dr/nurse.
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 women of child bearing potential that HRT does not provide contraceptive cover and non-hormonal contraception should be used during treatment.
Advise patient to seek advise at first indications of pregnancy.
Advise patient to discontinue therapy if abnormal neurological signs develop.
Advise patient of thromboembolic symptoms and to report them if they occur (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).
Advise patient that the ability to drive or operate machinery may be affected by side effects.

Side Effects

"Spotting" bleeding
Abdominal cramps
Abdominal pain
Aggravation of porphyria
Anxiety
Blood lipid changes
Breakthrough bleeding
Breast enlargement
Breast pain
Breast tenderness
Change in menstrual flow
Changes in libido
Chloasma
Cholestatic jaundice
Deep vein thrombosis (DVT)
Dementia
Depression
Dizziness
Dysmenorrhoea
Endometrial hyperplasia
Erythema multiforme
Erythema nodosum
Exacerbation of epilepsy
Exacerbation of hypocalcaemia
Exacerbation of otosclerosis
Exacerbation of pre-existing asthma
Fibrocystic breast changes
Fluid retention
Gallbladder disease
Headache
Hypertension
Increase in plasma triglyceride concentration
Increased risk of breast cancer
Increased risk of endometrial cancer
Increased risk of oestrogen-dependent neoplasms
Increased risk of ovarian cancer
Increased size of uterine fibroids
Intolerance to contact lenses
Irritability
Liver function disturbances
Migraine
Mood changes
Myocardial infarction
Nausea
Oedema
Pancreatitis
Premenstrual-like syndrome
Pulmonary embolism
Rash
Reduced carbohydrate tolerance
Skin irritation
Stroke
Thrombophlebitis
Vaginal candidiasis
Vascular purpura
Venous thrombosis
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: October 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.

Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. Accessed on 02 October 2014.

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

Summary of Product Characteristics: Sandrena 0.5 mg gel. Orion pharma UK ltd. Revised June 2018.
Summary of Product Characteristics: Sandrena 1.0 mg gel. Orion pharma UK ltd. Revised June 2018.
Summary of Product characteristics: Oestrogel Pump-Pack Gel. Besins Healthcare (UK) Ltd. Revised June 2019.

The Renal Drug Handbook. 3rd edition. (2009) ed. Ashley, C and Currie, Radcliffe Publishing Ltd, Abingdon.

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