Oestradiol/ Norethisterone

Registered South African indications:

• Menopausal symptoms
• Osteoporosis

Contraindications

Norethisterone/oestradiol 50μg/170μg (11.2mg/3.2mg)

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Known current or past or suspected breast cancer
• Family history of breast cancer
• Known or suspected estrogen-dependent malignant tumours (e.g. endometrial cancer) or pre-malignant tumours (e.g. untreated atypical endometrial hyperplasia)
• Undiagnosed genital bleeding
• Pregnancy
• Lactation
• Active liver disease or a history of liver disease as long as liver function tests have failed to return to normal
• Previous or current venous thromboembolism (deep venous thrombosis, pulmonary embolism)
• Known thrombophilic conditions
• Active or past arterial thromboembolic disease (e.g. cerebrovascular accident, myocardial infarction)
• Porphyria
• Inherited thrombophilia
• Patients known with inherited genetic mutations: BRCA 1 and BRCA 2 genes
• Early menstrual periods (before age 12 years)
• History of non-cancerous breast diseases (atypical hyperplasia or lobular carcinoma in situ)
• Previous treatment using radiation therapy to the chest or breast
• Previous treatment with diethylstilboestrol (DES)
• Depression not well controlled with treatment
• History of depression with the use of estrogen and/or progesterone/progestogen-containing medicines, irrespective of the indication, dosage formulation, and route of administration

Norethisterone/oestradiol 50μg/140μg, 50μg/250μg

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Known or suspected pregnancy
• Breastfeeding
• Undiagnosed abnormal vaginal bleeding
• Known or suspected breast cancer
• History of breast cancer
• Known or suspected cancer of the endometrium or other oestrogen-dependent neoplasia
• Existing or previous severe hepatic disease
• History of or current venous thromboembolism (e.g. deep vein thrombosis, pulmonary embolism)
• Known thrombophilic disorders or thrombophlebitis
• History of or current arterial thromboembolic disease (e.g coronary heart disease, stroke)
• Porphyria

Cautions

• Renal impairment
• Mild to moderate hepatic impairment
• Elderly
• Leiomyoma 
• Endometriosis
• A history of, or risk factors for, thrombo-embolic disorders
• Risk factors for oestrogen dependent tumours
• Hypertension
• Diabetes mellitus 
• Cholelithiasis
• Migraine or (severe) headache
• Systemic lupus erythematosus
• A history of endometrial hyperplasia 
• Epilepsy
• Asthma
• Otosclerosis
• Mastopathy
• Cardiac impairment
• History of cholestatic jaundice
• Pre-existing hypertriglyceridaemia
• Hypothyroidism
• Intact uterus
• Dementia
• Hereditary angioedema

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

Relief of menopausal symptoms in women 
Prevention of osteoporosis in postmenopausal women 
-with an intact uterus

Fixed dose
Oestradiol/ Norethisterone
50/250 (μg)
3.2/11.2 (mg)

• Topical (pat): Apply 1 patch, every 3-4 days

Sequential dose
Oestradiol/ Norethisterone
3.2/11.2 (mg)

• Topical (pat): Apply the 3.2mg oestradiol patch, twice weekly; Treatment duration: 14 days

THEN

• Topical (pat): Apply the 11.2/3.2mg patch twice weekly; Treatment duration: 14 days

See additional prescribing points for administration directions

Do not continue for longer then 5 years

Not indicated for use in children

Contraindicated in early menstrual periods (before age 12 years) (Norethisterone/oestradiol 50μg/170μg)

Pregnancy 

• Contraindicated
• Norethisterone/Oestrogen is not indicated during pregnancy
• If pregnancy occurs during use of norethisterone/oestrogen, treatment should be withdrawn immediately
• Data on a limited number of exposed pregnancies indicated adverse effects of norethisterone on the foetus. At doses higher than normally used in oral contraceptives and HRT formulations, masculinisation of female foetuses was observed
• The results of most epidemiological studies to date, relevant to inadvertent foetal exposure to combinations of oestrogens and progestogens indicate no teratogenic or foetotoxic effect

Breastfeeding

• Contraindicated

Renal Impairment

• Caution; no dose adjustment recommended

Hepatic Impairment

Norethisterone/oestradiol 50μg/170μg (11.2mg/3.2mg)

• Mild to moderate: Caution; no dose adjustment recommended
• Severe: Caution; no information available
• Active liver disease or a history of liver disease (as long as liver function tests have failed to return to normal): Contraindicated

Norethisterone/oestradiol 50μg/140μg, 50μg/250μg

• Mild to moderate: Caution; no dose adjustment recommended
• Severe: Contraindicated

Elderly

• Caution; no information available

Porphyria Information

• Contraindicated

Central Nervous System Disorders

• Depression
• Insomnia
• Anxiety
• Nervousness
• Decreased libido 
• Mood swings
• Paraesthesia
• Headache
• Migraine
• Epilepsy
• Cerebrovascular accident
• Dizziness
• Fatigue
• Affect lability
• Vertigo

Cardiovascular Disorders

• Palpitations
• Hypertension
• Varicose veins
• Vasodilatation
• Thrombosis
• Deep vein thrombosis

Respiratory Disorders

• Pulmonary embolism

Gastrointestinal Disorders

• Abdominal pain
• Diarrhoea
• Nausea and vomiting
• Dyspepsia
• Flatulence
• Abdominal distension

Hepatobiliary Disorders

• Cholelithiasis
• Gallbladder disorder
• Cholestatic jaundice
• Elevated transaminases

Genitourinary Disorders

• Breast pain
• Cervical polyp
• Endometrial hyperplasia
• Genital discharge
• Dysmenorrhoea
• Menorrhagia
• Menstrual disorder
• Metrorrhagia
• Breast enlargement
• Breast tenderness
• Uterine spasms
• Vaginal infection
• Uterine leiomyoma
• Fallopian tube cysts

Endocrine and Metabolic Disorders

• Increased weight

Musculoskeletal Disorders

• Arthralgia
• Back pain
• Myalgia
• Pain in extremity
• Myasthenia

Skin and Subcutaneous Tissue Disorders

• Erythematous rash
• Pruritus
• Rash
• Stevens-Johnson syndrome
• Acne
• Dry skin
• Skin discolouration
• Alopecia
• Application site erythema
• Application site pruritus
• Application site rash
• Application site reaction
• Oedema
• Application site oedema

Immune, Blood and Lymphatic System Disorders

• Candidiasis
• Breast neoplasms
• Endometrial cancer
• Hypersensitivity

• CYP450 inducers
• Ritonavir
• Telaprevir 
• Nelfinavir
• St. John's wort
• Lamotrigine 

• Breast examination
• Mammogram
• Papanicolaou smear

Specific cases may require

• Endometrial sampling
• Blood glucose
• Lipid profile
• Thyroid function
• Bone density scan

Administration directions

Initiation

• Post-menopausal women currently not on hormone replacement therapy (HRT) may start at any time
• Women on a continuous combined regimen wishing to switch from another oestrogen to Norethisterone/ Oestrogen may do so at any time
• Women on a cyclic or continuous sequential regimen wishing to switch from a sequential combined HRT preparation to Norethisterone/ Oestrogen may do so at the end of a cycle of the current therapy or after a 7 day hormone free interval

Application

• Patch should be applied to clean, dry, healthy, intact skin as soon as it is removed from the sachet
• Each application should be made to a different area of the skin, on the trunk below the waist. The patch should not be applied on or near the breasts
• The patch should remain in place during bathing and showering
• Should a patch fall off, it should be replaced immediately with a new patch. However the usual day of changing patches should be maintained

Missed dose

• If the patient forgets to change their patch, they should change it as soon as possible and apply the next one at the normal time. However, if it is almost time for the next patch, the patient should skip the missed one and go back to their regular schedule
• Only one patch should be applied at a time
• Wearing a patch for more than 4 days by mistake or any period without a patch may increase the likelihood of breakthrough bleeding or spotting

This combination product contains oestradiol hemihydrates which is a synthetically prepared oestrogen and norethisterone acetate, the acetate ester or norethisterone, a synthetic progestin. After application to the skin the transdermal system delivers 17ß-oestradiol, a physiological hormone, transdermally into the systemic circulation and consequently, the 17ß-oestradiol does not undergo first-pass liver metabolism. In postmenopausal women, it raises the oestradiol concentrations to levels similar to those in the early follicular phase and maintain these levels over the application period of 3-4 days. The oestradiol/oestrone ratio in the plasma of post-menopausal women is between 0,2 to 0,5 which increases after the transdermal application of oestradiol to approximately 1 (normal pre-menopausal levels; early follicular phase). Norethisterone acetate, is hydrolysed to norethisterone, a synthetic 19-nortestosterone derivative of the 13-methyl gonane group with potent progestational activity. Transdermal norethisterone acetate administration prevents oestrogen-related endometrial proliferation.

COMBINATION PREPARATIONS

Fixed preparation

Estradiol/ Norethisterone

Patch 50μg/140μg

• Estalis (Novartis) originator

Patch (per 16cm²) 3.2mg/11.2mg

• Evorel conti (Janssen) originator

Sequential preparation

Estradiol/ Norethisterone

Patch (per 16cm²) 3.2mg/11.2mg

• Evorel sequi (Janssen) originator