Oestradiol

Registered South African indications:

• Hormone replacement therapy in hysterectomised women

Contraindications 

• Hypersensitivity to the active ingredient or any of its excipients
• Hepatic impairment
  - Acute liver disease
  - History of liver disease (as long as liver function tests have failed to return to normal)
• Porphyria
• Known, past or suspected breast cancer
• Known or suspected oestrogen-dependent malignant tumours
  - Endometrial cancer
• Undiagnosed genital bleeding
• Untreated endometrial hyperplasia
• Presence or history of venous thromboembolism
  - Deep vein thrombosis
  - Pulmonary embolism
• Thrombophilic disorders
  - Protein C deficiency
  - Protein S deficiency
  - Antithrombin deficiency
• Active arterial thromboembolic disease
  - Angina
  - Myocardial infarction

Cautions 

• Renal impairment
• Elderly
• Leiomyoma (uterine fibroids)
• Endometriosis
• Risk factors for thromboembolic disorders
  - Use of oestrogens
  - Older age
  - Major surgery
  - Prolonged immobilisation
  - Obesity (BMI >30kg/m²)
  - Pregnancy/post-partum period
  - Systemic lupus erythematosus
  - Cancer
• Risk factors for oestrogen-dependant tumours
  - 1st degree heredity for breast cancer
• Hypertension
• Liver disorders
  - Liver adenoma
• Diabetes mellitus with or without vascular involvement
• History of endometrial hyperplasia
• Cholelithiasis
• Migraine or severe headaches
• Systemic lupus erythematosus
• Epilepsy
• Asthma
• Otosclerosis
• Hereditary angioedema
• Prolonged administration
• Pre-existing hypertriglyceridaemia
• First degree relative with a history of thrombosis at a young age
• Pre-existing anti-coagulant treatment
• Cardiac dysfunction
• History of chloasma gravidarum
• Fructose intolerance
• Glucose-galactose malabsorption
• Sucrose-isomaltase insufficiency
• Galactose intolerance
• Lapp lactase deficiency

Forms avail. in SA and covered in this monograph: tab

Hormone replacement therapy for oestrogen deficiency in peri- and postmenopausal women

• Oral (tab): Initial: 1mg, dly; Titrate to 1-2mg, dly as necessary

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It does not matter at what time of day the patient takes her tablet, but once she has selected a particular time, she should keep to it every day. Treatment is continuous, which means that the next pack follows immediately without a break

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

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If the patient forgets to take a tablet at the usual time, she may take it within the following 12 hours

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If >12 hours late, the forgotten tablet should NOT be taken and the remaining tablets should be taken at the usual time on the right days. A missed dose may lead to breakthrough bleeding or spotting

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In women with an intact uterus, a progestogen should be added to oestradiol 2mg for at least 12-14 days each month/28 day cycle. Unless there is a previous diagnosis of endometriosis, it is not recommended to add progestogen in hysterectomised women

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See additional prescribing points for how to initiate patients on oestradiol tabs

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Prevention of osteoporosis in postmenopausal women
- Who are at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis

• Oral (tab): 2mg, dly

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In women with an intact uterus, a progestogen should be added to oestradiol 2mg for at least 12-14 days each month/28 day cycle. Unless there is a previous diagnosis of endometriosis, it is not recommended to add progestogen in hysterectomised women

Not indicated for use in children

Pregnancy

• Not indicated for use in pregnancy
• Oestradiol is not indicated during pregnancy. If pregnancy occurs during medication with oestradiol treatment should be withdrawn immediately
• The results of most epidemiological studies to date relevant to inadvertent foetal exposure to oestrogens indicate no teratogenic or foetotoxic effects

Breastfeeding

• Not indicated for use in breastfeeding
• Oestradiol is not indicated during breastfeeding

Renal Impairment

• Caution; no dose adjustment recommended
  Has not been studied, no information available

Hepatic Impairment

• Contraindicated

Elderly

• Caution; no dose adjustment recommended
  Assess the benefits and risks of treatment in patients >65 years

Porphyria Information

• Possibly porphyrinogenic (PSP)
  Postmenopausal women have a lower endogenous hormone level and a reduced risk of having an acute porphyric attack compared to women of fertile age. However, we cannot exclude the possibility that systemic estradiol treatment, i.e. peroral tablets and transdermal patches, might elicit an acute attack since the exposure of the liver is higher. These forms of administration are therefore classified as possibly porphyrinogenic.
  Common adverse reactions of estradiol depend on the route of administration. Common side effects that can be confused with an acute porphyric attack are abdominal pains, nausea and diarrhoea. These side effects may potentially be porphyrinogenic if leading to a decrease in carbohydrate intake

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Anxiety
• Depression
• Migraine
• Headache
• Dizziness
• Fatigue
• Chorea
• Stroke
• Ischaemic stroke
• Haemorrhagic stroke
• Probable dementia
• Decreased or increased libido

Cardiovascular Disorders 

• Palpitations
• Myocardial infarction
• Hypertension
• Thrombophlebitis
• Venous thromboembolism
• Oedema
• Coronary artery disease
• Deep vein thrombosis

Respiratory Disorders

• Epistaxis
• Pulmonary embolism

Gastrointestinal Disorders

• Dyspepsia
• Abdominal pain
• Nausea and vomiting
• Bloating
• Flatulence

Hepatobiliary Disorders

• Gallbladder disease
• Cholestasis

Genitourinary Disorders 

• Cystitis-like symptom
• Increased size of uterine fibroids
• Vaginal candidiasis
• Uterine cervical erosions
• Spotting
• Changes in vaginal bleeding pattern
• Abnormal bleeding or flow
• Breakthrough bleeding
• Dysmenorrhoea
• Changes in vaginal secretion
• Premenstrual-like syndrome
• Endometrial cancer
• Breast secretion
• Breast tenderness
• Breast enlargement or pain
• Breast cancer
• Ovarian cancer

Endocrine and Metabolic Disorders 

• Aggravated porphyria
• Increased or decreased weight
• Increased appetite
• Decreased carbohydrate tolerance

Musculoskeletal Disorders

• Muscle cramps
• Leg pain

Skin and Subcutaneous Tissue Disorders 

• Rashes
• Pruritus
• Eczema
• Urticaria
• Acne
• Hirsutism
• Hair loss
• Erythema nodosum
• Erythema multiforme
• Haemorrhagic rash
• Chloasma
• Vascular purpura

Immune, Blood and Lymphatic System Disorders 

• Hypersensitivity reaction
• Exacerbation of hereditary angioedema

Sensory Disorders

• Visual disturbances
• Intolerance to contact lenses

• CYP450 enzyme inducers
• Anticonvulsants
• Barbiturates
• Phenytoin
• Primidone
• Carbamazepine
• Anti-infectives
• Rifampicin
• Rifabutin
• Nevirapine
• Efavirenz
• Felbamate
• Griseofulvin
• Oxcarbazepine
• Topiramate
• Agents with variable effects on the clearance of sex hormones
• HIV protease inhibitors
• Non-nucleoside reverse transcriptase inhibitors
• HCV inhibitors
• Agents decreasing the clearance of sex hormones (enzyme inhibitors)
• CYP3A4 inhibitors
• Azole antifungals
• Fluconazole
• Itraconazole
• Ketoconazole
• Voriconazole
• Verapamil
• Macrolides
• Clarithromycin
• Erythromycin
• Diltiazem

Other interactions

• Herbal remedy
• St. John's Wort (Hypericum perforatum)
• Grapefruit juice

• Blood pressure
• Gynaecological examination
• Breast examination
• Lipid profile
• Thyroid-stimulating hormone levels

Specific cases may require

• Follicle-stimulating hormone levels
• Estradiol levels
• Bone density measurements

Additional observations

• Baseline risk for breast cancer (prior therapy)

How to initiate oestradiol treatment

• If the woman has an intact uterus and is still menstruating: A combination regimen with oestradiol and a progestogen, commencing with the oestrogen phase, should begin on the first day of bleeding. If the menstrual periods are very infrequent or if amenorrhoea is established, she may start at any time provided, if appropriate, pregnancy has been excluded 
• In women transferring from a continuous combined hormone replacement therapy product: Treatment with oestradiol may be started on any day
• In women transferring from cyclic or continuous sequential hormone replacement therapy regimens: The woman should complete the cycle and then change to oestradiol without a break in therapy

Oestradiol contains estradiol valerate, (the valeric-acid ester of the endogenous female oestrogen, estradiol).  The active ingredient estradiol valerate, a prodrug of the synthetic 17ß-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms. Oestrogens prevent bone loss following menopause or ovariectomy. Ovulation is not inhibited during the use of oestradiol, and the endogenous production of hormones is hardly affected.

Tablet 1mg

• Estrofem (Novo Nordisk) originator
• Estro-Pause (Adcock Ingram)
• Progynova (Bayer)

Tablet 2mg

• Estrofem (Novo Nordisk) originator
• Estro-Pause (Adcock Ingram)
• Progynova (Bayer)

Also available in the following forms: Transdermal patch, vaginal tablet, gel and implant.