Oestrogel contains estradiol as active ingredient, 0.06% w/w.
Estradiol gel contains 0.06% estradiol in an absorptive hydroalcoholic gel base formulated to provide a controlled release of the active ingredient. 1.25 g contains 0.75 mg of estradiol.
Excipients/Inactive Ingredients: Carbomer, Triethanolamine, Ethanol, Purified water q.s. 30 g, 80 g, and 100 g.
Pharmacotherapeutic group: ESTROGENS (genito-urinary system and sexual hormones). ATC classification: G03CA03.
Pharmacology: Pharmacodynamics: Estradiol gel belongs to the group of natural, physiological estrogens. The active ingredient is chemically and biologically identical to human endogen estradiol. The pharmaceutical form enables the systemic administration of 17β-estradiol by applying it to healthy skin. Estradiol gel substitutes for the loss of estrogens production in post-menopausal or ovariectomised women.
The most active form of estrogens is estradiol which is mainly produced by the ovarian follicles throughout the child-bearing period of women's life.
The transdermal administration of Estradiol gel enables to avoid the hepatic first pass effect which induces an increase in the synthesis of angiotensin, VLDL lipoproteins (triglycerides) and certain coagulation factors.
Pharmacokinetics: Pharmacokinetic studies indicate that, when applied topically to a large area of skin in a volatile solvent, approximately 10% of the estradiol is percutaneously absorbed into the vascular system, regardless of the age of the patient. Daily application of 2.5g or 5g Oestrogel over a surface area of 400-750cm2 results in a gradual increase in Estrogen blood levels to steady state after approximately 3-5 days and provides circulating levels of both estradiol and estrone equivalent in absolute concentrations and in their respective ratio to those obtained during the early-mid follicular phase of the menstrual cycle.
Oestrogel was administered to 17 postmenopausal women once daily on the posterior surface of one arm from wrist to shoulder for 14 consecutive days.
Maximum serum concentrations (Cmax) of estradiol and estrone on Day 12 were 117 pg/ml and 128 pg/ml, respectively.
The time-averaged serum estradiol and estrone concentrations (Caverage) over the 24 hour dose interval after administration of 2.5 g of Oestrogel on Day 12 were 76.8 pg/ml and 95.7 pg/ml, respectively.
Metabolism of estradiol takes place mainly in the liver under oestriol, estrone and their conjugated metabolites (glucuronides, sulphates). These metabolites also undergo enterohepatic recirculation.
When treatment is stopped, estradiol and urinary conjugated estradiol concentrations return to baseline in about 76 hours.
Toxicology: Preclinical safety data: Long-term continuous administration of estrogen, with and progestin, in women, with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer.
Long-term, continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis and liver.
Hormone replacement therapy (HRT) for Estrogen deficiency symptoms in postmenopausal women.
Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis.
Posology: Oestrogel is an estrogen-only product.
Oestrogel should be administered daily on a continuous basis.
For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration should be used.
Use with progestagen: In women with an intact uterus the recommended dose of a progestagen should be administered for at least 12 days of each month, in accordance with the manufacturers recommendations. Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestagen in hysterectomised women.
Initiation of Therapy: In women who are not currently taking HRT, treatment with estradiol gel can be initiated at once. In women who are currently taking HRT, treatment with estradiol gel can be initiated after completion of the current therapy.
Menopausal symptoms: The usual starting dose is a single ruler measure (2.5g) of Oestrogel once daily (containing 1.5mg estradiol). In the majority of women this dose will provide effective relief of menopausal symptoms. If after one month's treatment effective relief is not obtained, the dosage may be increased accordingly to a maximum of two ruler measures (5g) of Oestrogel daily (containing 3.0mg estradiol).
Prevention of osteoporosis: The minimum effective dose is 2.5g of Oestrogel once daily for most patients.
Method of administration: The gel should be applied by the patient herself to clean, dry, intact areas of skin, e.g. on the abdomen, arms, shoulders and/or inner thighs in the morning or in the evening. The area of application should be as large as possible. Gel does not need to be massaged into skin. Estradiol gel must not be applied to the breasts or mucous surfaces such as the vulval region.
Estradiol gel should be allowed to dry for 2 minutes before covering the skin with clothing.
If the patient forgets to apply a dose, then they should apply it as soon as possible and apply the next dose at the normal time. Forgetting a dose may increase the likelihood of break-through bleeding and spotting.
Serious ill effects have not been reported following acute ingestion of large doses of oral estrogen-containing products by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females.
Known, past or suspected breast cancer; Known or suspected estrogen-dependent malignant tumours (e.g endometrial cancer); Undiagnosed genital bleeding; Untreated endometrial hyperplasia; Previous idiopathic or current venous thromboembolism (deep venous thrombosis, pulmonary embolism); Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction, stroke); Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal; Known hypersensitivity to the active substances or to any of the excipients; Porphyria.
For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.
Medical examination/follow-up: Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman.
Women should be advised what changes in their breasts should be reported to their doctor or nurse (see Breast cancer as follows).
Investigations, including mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.
Conditions which need supervision: If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised: Leiomyoma (uterine fibroids) or endometriosis; Risk factors for, thromboembolic disorders; Risk factors for estrogen dependent tumours, e.g. 1st degree heredity for breast cancer; Hypertension; Liver disorders (e.g. liver adenoma); Diabetes mellitus with or without vascular involvement; Cholelithiasis; Migraine or (severe) headache; Systemic lupus erythematous; A history of endometrial hyperplasia (see as follows); Epilepsy; Asthma; Otosclerosis.
Reasons for immediate withdrawal of therapy: Therapy should be discontinued if a contraindication is discovered and in the following situations: Jaundice or deterioration in liver function; Significant increase in blood pressure; New onset of severe migraine-type headache; Pregnancy.
Cardiovascular Disorders: Coronary Heart Disease and Stroke: There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated and Estrogens and medroxyprogesterone acetate (MPA). Two large clinical trials (WHI and HERS i.e. Heart and Estrogen/progestin Replacement Study) showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products there are only limited data from randomised controlled trials to date examining effects in cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.
Venous Thromboembolism (VTE): Oral estrogen and estrogen/progestin therapy has been associated with an increased risk of venous thrombosis and pulmonary embolism.
The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all postoperative patients, scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4 to 6 weeks earlier, if possible. Treatment should not be restarted until the woman is completely mobilised.
If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g., painful swelling of a leg, sudden pain in the chest, dyspnea).
Carcinoma: Breast cancer: A randomised placebo-controlled trial, the Women's Health Initiative study (WHI), and epidemiological studies, including the Million Women Study (MWS), have reported an increased risk of breast cancer in women taking estrogens, estrogen-progestagen combinations or tibolone for HRT for several years (see Adverse Reactions).
A postmenopausal woman without a uterus who requires estrogen should receive estrogen-alone therapy, and should not be exposed unnecessarily to progestins.
HRT, especially Estrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
Endometrial cancer: The risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods (see Adverse Reactions). The addition of a progestagen for at least 12 days per cycle in non-hysterectomised women greatly reduces this risk. Break-through bleeding and spotting may occur during the first months of treatment. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy. Unopposed estrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestagens to estrogen replacement therapy is should be considered in women who have undergone hysterectomy because of endometriosis if they are known to have residual endometriosis.
Ovarian cancer: Long-term (at least 5-10 years) use of Estrogen only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRTs confers to a different risk than Estrogen-only products.
Other conditions: Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed.
Women using hormonal replacement therapy (HRT) sometimes experience increased blood pressure. Blood pressure should be monitored with HRT use. Elevation of blood pressure in previously normotensive or hypertensive patients should be investigated and HRT therapy may have to be discontinued. Clinical trials have shown that percutaneously administered 17β-estradiol (0.06%) does not affect renin substrate and has no significant effect on blood pressure in normotensive patients.
Rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oral estrogen therapy and therefore women with pre-existing hypertriglyceridaemia should be followed closely during estrogen replacement or hormone replacement therapy.
A worsening of glucose tolerance has been observed in a significant percentage of peri- and post-menopausal patients. Therefore, diabetic patients or those with a predisposition to diabetes should be observed closely to detect any alterations in carbohydrate metabolism.
Estrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). 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 (CBG), sex hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.
Symptoms and physical findings associated with a previous diagnosis of endometriosis may reappear or become aggravated with estrogen use. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.
Abnormal vaginal bleeding, due to its prolongation, irregularity or heaviness, occurring during therapy should prompt diagnostic measures like hysteroscopy, endometrial biopsy or curettage to rule out the possibility of uterine malignancy and the treatment should be re-evaluated.
Pre-existing uterine leiomyoma may increase in size during estrogen use. Growth, pain or tenderness of uterine leiomyoma requires discontinuation of medication.
Photosensitivity/Photoallergy: increased sensitivity to direct exposure to the sun on areas of OESTROGEL application has not been evaluated.
Effect of sunscreen application: the effects of concomitant application of OESTROGEL and a sunscreen lotion have not been evaluated.
Estradiol Transfer: the effect of estradiol transfer was evaluated in 24 healthy postmenopausal women who topically applied 1.25 g of estradiol gel once daily on the posterior surface of one arm from wrist to shoulder for a period of 14 consecutive days. On each day, one hour after gel application, a cohort of 24 non-dosed healthy postmenopausal females directly contacted the dosed cohort at the site of gel application for 15 minutes. No change in endogenous mean serum concentrations of estradiol was observed in the non-dosed cohort after direct skin-to-skin contact with subjects administered estradiol gel.
Effects on ability to drive and use machines: The effect of estrogens has not been assessed.
Oestrogel is not indicated during pregnancy and lactation. If pregnancy occurs during medication with Oestrogel, treatments should be withdrawn immediately.
The results of most epidemiological studies to date, relevant to inadvertent foetal exposure to Estrogens indicate no teratogenic of foetotoxic effects.
Skin: Irritation, reddening of the skin or mild and transient erythema at the site of application have been occasionally reported. In this instance a different site of application should be used, but if the topical side-effects continue, consideration should be given to discontinuation of treatment.
CNS: headache, migraine and mood changes.
Gastrointestinal tract: nausea.
Genito-urinary tract: increase in the size of uterine fibromyomata, excessive production of cervical mucus.
Breast: pain, enlargement and secretion.
Coronary Heart disease: see Cardiovascular Disorders: Coronary Heart disease and Stroke under Precautions.
Stroke: See Cardiovascular Disorders: Coronary Heart Disease and Stroke under Precautions. One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated estrogens and MPA. For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 11 per 1000 women aged 60-69 years. It is estimated that for women who use conjugated estrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate = 1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.
Venous Thromboembolism (VTE): see Venous Thromboembolism (VTE) under Precautions.
Pulmonary embolus: Breast cancer (see Carcinoma under Precautions): For estrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which >80% of HRT use was estrogen-only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95%CI 1.21 - 1.49) and 1.30 (95%CI 1.21 - 1.40).
For estrogen plus progestagen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with estrogens alone. In the recent cohort E3N study, the risk was significantly greater (p<0.01) with HRT containing synthetic progestagens than with HRT containing micronized progesterone, the RRs being 1.4 (1.2-1.7).
The WHI trial reported a risk estimate of 1.26 (95%CI 1.00-1.59) after 5.6 years of use of estrogen-progestagen combined HRT (CEE + MPA) in all users compared with placebo. The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to estrogen-progestagen combined HRT (CEE + MPA) per 10,000 women years. The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65).
Endometrial cancer: According to data from epidemiological studies, the best estimate of the risk is that for women not using HRT. About 5 in every 1000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. Most studies show no significant increased risk associated with use of estrogens for less than one year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.
Ovarian cancer: Long-term (at least 5-10 years) use of estrogen-only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRTs confers to a different risk than estrogen-only products.
Dementia: There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined oral CEE and MPA after the age of 65.
Drug-Drug interaction: Drug interactions have not been assessed for estradiol gel. Nevertheless, with transdermal administration, the first-pass effect in the liver is avoided and, thus, transdermally applied estrogens might be less affected than oral hormones by enzyme inducers.
In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism.
Inducers of CYP3A4 such as St. John's Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, efavirenz and rifampicin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile.
Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in undesirable effects.
Instructions for use and handling: Close the tube after use to avoid alcohol evaporation.
Incompatibilities: Not applicable.
Store at temperatures not exceeding 30°C.
Shelf-life: 36 months.
G03CA03 - estradiol ; Belongs to the class of natural and semisynthetic estrogens used in estrogenic hormone preparations.
Oestrogel transdermal gel 600 mcg/g
80 g x 1's
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