Estradiol + Norethisterone


Concise Prescribing Info
Indications/Uses
Listed in Dosage.
Dosage/Direction for Use
Adult : PO Menopausal hormone replacement therapy; Prophylaxis of postmenopausal osteoporosis Continuous combined therapy: Each tab contains estradiol 0.5 mg and norethisterone 1 mg, or estradiol 1 mg and norethisterone 0.5 mg: 1 tab/day w/o interruption. Continuous sequential therapy: Each tab contains estradiol 1 mg and norethisterone 1 mg, or estradiol 2 mg and norethisterone 1 mg: 1 tab once daily from pack, as directed. Transdermal Menopausal hormone replacement therapy; Prophylaxis of postmenopausal osteoporosis As patch releasing estradiol 0.05 mg and norethisterone 0.14 mg, estradiol 0.05 mg and norethisterone 0.17 mg, or estradiol 0.05 mg and norethisterone 0.25 mg per day: Continuous combined therapy:1 patch worn continuously and changed twice wkly. Continuous sequential therapy: 1 patch for 14 days following a 14-day estradiol-only regimen. Change patches twice wkly.
Dosage Details
Oral
Menopausal hormone replacement therapy, Prophylaxis of postmenopausal osteoporosis
Adult: Available preparations:
Continuous combined therapy
Estradiol 0.5 mg and norethisterone 1 mg tab
Estradiol 1 mg and norethisterone 0.5 mg tab
1 tab daily w/o interruption, preferably at the same time each day.

Continuous sequential therapy
Estradiol 1 mg and norethisterone 1 mg tab
Estradiol 2 mg and norethisterone 1 mg tab
1 tab once daily from pack, as directed.

Transdermal
Menopausal hormone replacement therapy, Prophylaxis of postmenopausal osteoporosis
Adult: Available preparations:
Estradiol 0.05 mg and norethisterone 0.14 mg per day patch
Estradiol 0.05 mg and norethisterone 0.17 mg per day patch
Estradiol 0.05 mg and norethisterone 0.25 mg per day patch

Continuous combined therapy
1 patch worn continuously and changed twice wkly. Apply patches to the trunk, below the waist. Do not apply on or near the breasts.

Continuous sequential therapy
1 patch for 14 days following a 14-day estradiol-only regimen. Change patches twice wkly. Begin a new cycle w/o break. Apply patches to the trunk, below the waist. Do not apply on or near the breasts.
Hepatic Impairment
Contraindicated.
Administration
Should be taken with food.
Contraindications
Known, suspected, or history of breast cancer and oestrogen-dependent malignant tumours (e.g. endometrial cancer), current or history of venous thromboembolism (e.g. DVT, pulmonary embolism), undiagnosed genital bleeding, endometrial hyperplasia, thrombophilic disorders (e.g. protein C, protein S or antithrombin deficiency), active or recent arterial thromboembolic disease (e.g. angina, MI), porphyria. Hepatic impairment. Pregnancy and lactation.
Special Precautions
Patient w/ risk factors for thromboembolic disorders (e.g. major surgery, prolonged immobilization, obesity, postpartum period, cancer) and oestrogen-dependent tumours (e.g. 1st degree heredity for breast cancer); history of cholestatic jaundice, history or current leiomyoma (uterine fibroids) or endometriosis, HTN, liver disorders (e.g. liver adenoma), DM, cholelithiasis, migraine or severe headache, SLE, history of endometrial hyperplasia, epilepsy, asthma, otosclerosis, hereditary angioedema and mastopathy; cardiac dysfunction, hypertriglyceridaemia, hypoparathyroidism. Smokers. Renal impairment. This combination drug is indicated for non-hysterectomised women. Not indicated for prevention of CV disease or dementia.
Adverse Reactions
Significant: Irregular or breakthrough bleeding, spotting, increased risk of coronary artery disease, ischaemic stroke, probable dementia and gall bladder disease, endometrial hyperplasia, exacerbation of endometriosis, venous thromboembolism, angioedema, fluid retention; increased levels of circulating total thyroid hormone, corticosteroids, and sex steroids and other plasma proteins (e.g. angiotensin or renin substrate, α-1-antitrypsin, ceruloplasmin). Rarely, increased risk of invasive breast cancer, endometrial cancer, ovarian cancer, chloasma, vision abnormalities (e.g. retinal vascular thrombosis); contact sensitisation (transdermal).
Nervous: Headache, dizziness, insomnia, depression, nervousness, affect lability, asthenia, malaise.
CV: Peripheral oedema, HTN.
GI: Nausea, abdominal distension, diarrhoea, dyspepsia, abdominal pain, flatulence.
Genitourinary: Dysmenorrhoea, menstrual disorder, menorrhagia, genital discharge, irregular vaginal bleeding, uterine spasms, vaginal infection.
Endocrine: Wt gain, libido disorder; breast pain, tenderness, or enlargement.
Musculoskeletal: Back pain, pain in extremity, arthralgia, myalgia.
Dermatologic: Acne, rash, pruritus, dry skin.
Others: Pain, application site reactions (transdermal).
Patient Counseling Information
Ensure adequate intake of Ca and vit D when used for prevention of osteoporosis.
MonitoringParameters
Monitor BP, changes in breasts and signs of endometrial cancer, vision abnormalities (e.g. loss of vision, migraine) and of thromboembolic disorders. Perform Papanicolaou smear and mammogram. Assess need for hormonal replacement therapy at 3-6 mth intervals. When used for prophylaxis of postmenopausal osteoporosis, measure bone density.
Overdosage
Symptoms: Breast tenderness, nausea, vomiting and/or metrorrhagia, depressive mood, fatigue, acne and hirsutism. Management: Symptomatic treatment. Consider gastric lavage.
Drug Interactions
Decreased pharmacological effect and changes in the uterine bleeding profile w/ CYP inducers (e.g. phenytoin, rifampicin, bosentan). May decrease exposure and seizure control of lamotrigine. May decrease folic acid absorption.
Food Interaction
Decreased pharmacological effect and changes in the uterine bleeding profile w/ St. John’s Wort. Alcohol increases risk of breast cancer and of osteoporosis. Avoid alcohol.
Lab Interference
Reduced response to metyrapone test. May interfere w/ tests for coagulation factors, binding proteins, glucose tolerance, lipids.
Action
Description: Estradiol is a synthetic sex hormone similar to endogenous oestrogen. During menopause, estradiol substitutes for oestrogen production and alleviates its symptoms. Estradiol also prevents bone loss following menopause or ovariectomy. Norethisterone reduces the estradiol-induced risk of endometrial hyperplasia in non-hysterectomised women.
Pharmacokinetics:
Absorption: Estradiol: Well absorbed from the GI tract and from the skin. Bioavailability: 53% (oral). Time to peak plasma concentration: 5-8 hr (oral); W/in 21 hr (transdermal).
Norethisterone: Well absorbed from the GI tract and from the skin. Bioavailability: 100% (oral). Time to peak plasma concentration: 0.5-1.5 hr (oral); approx 37 hr (transdermal).
Distribution: Estradiol: Plasma protein binding: 60-65% to albumin, 35-45% to sex hormone binding globulin (SHBG).
Norethisterone: Plasma protein binding: 61% to albumin, 36% to SHBG.
Metabolism: Estradiol: Undergoes extensive first-pass metabolism mainly in the liver and in the gut and other target organs mainly by CYP enzyme system to oestrone, oestriol and several oestrogen glucuronides and sulfates.
Norethisterone: Undergoes first-pass metabolism in the liver mainly by CYP enzyme system to isomers of 5α-dihydro-norethisterone and of tetrahydro-norethisterone.
Excretion: Estradiol: Mainly via urine (90-95%, as inactive glucuronide and sulfate conjugates); faeces (5-10%, as unconjugated form). Elimination half-life: 12-14 hr (oral).
Norethisterone: Mainly via urine, as glucuronide and sulfate conjugates; faeces. Elimination half-life: 8-11 hr (oral); approx 15 hr (transdermal).
Chemical Structure

Chemical Structure Image
Estradiol

Source: National Center for Biotechnology Information. PubChem Database. Estradiol, CID=5757, https://pubchem.ncbi.nlm.nih.gov/compound/Estradiol (accessed on Jan. 22, 2020)


Chemical Structure Image
Norethisterone

Source: National Center for Biotechnology Information. PubChem Database. Norethindrone, CID=6230, https://pubchem.ncbi.nlm.nih.gov/compound/Norethindrone (accessed on Jan. 22, 2020)

Storage
Tab: Store between 20-25°C.
Wear gloves during receiving, unpacking, and placing in storage.
References
Amabelz (Lupin Pharmaceuticals, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 04/08/2017.

Anon. Estradiol and Norethindrone. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 04/08/2017.

CombiPatch 0.05 mg/0.25 mg (Novartis Pharmaceuticals Corp). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 04/08/2017.

Joint Formulary Committee. Estradiol with Norethisterone. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 04/08/2017.

Disclaimer: This information is independently developed by MIMS based on Estradiol + Norethisterone from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2020 MIMS. All rights reserved. Powered by MIMS.com
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