Oestrogel

/ CTS

Oestrogel is an oestrogen-only product indicated only for women without a uterus. Oestrogel should be administered daily on a continuous basis. The minimum effective dose should be recommended for 24-28 consecutive days each month or three weeks of every four. The dose should be adjusted during the second and/ or third cycle, depending on the response.
In women with an intact uterus it is recommended to add a progestogen (e.g. a progesterone) for at least 12 days of each month, in accordance with the manufacturers’ recommendations.
Menopausal and postmenopausal symptoms:
2.5 g of Oestrogel once daily (1.5 mg Estradiol) is the usual starting dose, which in the majority of women will provide effective relief of symptoms. If after one month’s treatment effective relief is not obtained, the dosage may be increased accordingly to a maximum of four pumps (5 g) of Oestrogel daily (3.0 mg Estradiol). The lowest effective dose should be used for maintenance therapy.
For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration should be used.
Postmenopausal osteoporosis:
The minimum effective dose is 2.5 g of Oestrogel once daily for most patients.
Use with progestogen:
In women with an intact uterus the recommended dose of a progestogen should be administered for at least 12 days of each month, in accordance with the manufacturers recommendations. Oestrogel should be administered daily on a continuous sequential basis.
Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestogen in hysterectomised women.
Initiation of treatment:
Women who have never taken HRT and are post-menopausal or have very infrequent menstrual cycles:
Treatment with Oestrogel can be started on any day.
Switching from a continuous oestrogen-progestogen combined HRT: treatment with Oestrogel can be started on any day of the cycle.
Switching from a cyclic or continuous sequential HRT treatment: finish the therapeutic sequence before beginning treatment with Oestrogel.
The correct dose of gel should be dispensed and applied to clean, dry, intact areas of skin e.g. on the arms and shoulders, or inner thighs.
See prescribing information for full details.

Hormonal replacement therapy for the treatment of symptoms associated with estrogen deficiency in menopausal women.
Prevention of postmenopausal osteoporosis in women with an increased risk for osteoporotic fractures and presenting intolerance or a contraindication to others treatments indicated in the prevention of osteoporosis.

Known, past or suspected breast cancer;
Known or suspected oestrogen-dependent malignant tumours (e.g. endometrial cancer).
Undiagnosed genital bleeding.
Untreated endometrial hyperplasia.
Previous or current venous thromboembolism (e.g. deep venous thrombosis, pulmonary embolism).
Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency).
Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction).
Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal.
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.
Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women.
Medical Examination and 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 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” below). Investigations, including appropriate imaging tools, e.g. 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. It should be taken into account that these conditions may recur or be aggravated during treatment with Oestrogel, in particular:
• Leiomyoma (uterine fibroids) or endometriosis
• Risk factors for thromboembolic disorders (see below)
• Risk factors for oestrogen 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 erythematosus (SLE)
• A history of endometrial hyperplasia
• Epilepsy
• Asthma
• Otosclerosis
Reasons for immediate withdrawal of therapy
Therapy should be discontinued in case a contraindication is discovered and in the following situations:
• Jaundice or deterioration in liver function
• Significant increase in blood pressure
• New onset of migraine-type headache
• Pregnancy
Endometrial hyperplasia and carcinoma
• In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among oestrogen-only users varies from 2-to 12-fold greater compared with non-users, depending on the duration of treatment and oestrogen dose . After stopping treatment risk may remain elevated for at least 10 years.
• The addition of a progestogen cyclically for at least 12 days per month/28 day cycle or continuous combined oestrogen- progestogen therapy in non- hysterectomised women prevents the excess risk associated with oestrogen-only HRT.
• 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 oestrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestogens to oestrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis if they are known to have residual endometriosis.
Breast cancer
The overall evidence suggests an increased risk of breast cancer in women taking combined oestrogen-progestogen and possibly also oestrogen-only HRT, that is dependent on the duration of taking HRT.
Oestrogen-only therapy
The WHI trial found no increase in the risk of breast cancer in hysterectomised women using oestrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is substantially lower than that found in users of oestrogen-progestogen combinations.
Combined oestrogen-progestogen therapy
The randomised placebo-controlled trial, the Women’s Health Initiative study (WHI), and epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined oestrogen-progestogen for HRT that becomes apparent after about 3 years.
The excess risk becomes apparent within a few years of use but returns to baseline within a few (at most five) years after stopping treatment.
HRT, especially oestrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
Ovarian cancer
Ovarian cancer is much rarer than breast cancer. Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women oestrogen-only or combined oestrogen-progestogen HRT which becomes apparent within 5 years of use and diminishes over time after stopping.
Some other studies, including the WHI trial suggest that use of combined HRTs may be associated with a similar, or slightly smaller risk .
Venous thromboembolism
• HRT is associated with a 1.3 – 3 fold risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT than later.
Coronary Artery Disease (CAD)
There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined oestrogen- progestogen or oestrogen-only HRT.
Oestrogen-only:
Randomised controlled data found no increased risk of CAD in hysterectomised women using oestrogen-only therapy.
Combined oestrogen-progestogen therapy:
The relative risk of CAD during use of combined oestrogen+progestogen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to oestrogen+progestogen use is very low in healthy women close to menopause, but will rise with more advanced age.
Ischaemic Stroke
Combined oestrogen-progestogen and oestrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age- dependent, the overall risk of stroke in women who use HRT will increase with age.
Potential Oestrogel transfer to children
Children and others shouldn’t supposed to come into contact with the exposed area of the skin and to cover the application site with clothing if needed. In case of contact the child’s skin should be washed with soap and water as soon as possible.
to consult a physician in case of signs and symptoms (breast development or other sexual changes) in a child that may have been exposed accidentally to Oestrogel.
Other conditions
* Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed.
* Women with pre-existing hypertriglyceridaemia should be followed closely during oestrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.
* Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.
* Oestrogens 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. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).
ALT elevations
Caution is warranted for co-administration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir and also the regimen glecaprevir/pibrentasvir.

Headache, Nausea, Breast pain, Infection, Pain, Vaginitis.
See prescribing information for full details.

Treatment with surface active agents (e.g. sodium lauryl sulphate), or other drugs which alter barrier structure or function, could remove drug bound to the skin, altering transdermal flux. Therefore, patients should avoid the use of strong skin cleansers and detergents (e.g. benzalkonium or benzothonium chloride products), skin care products of high alcoholic content (astringents, sunscreens) and keratolytics (e.g. salicylic acid, lactic acid).
The use of any concomitant skin medication which alters skin production (e.g. cytotoxic drugs) should be avoided.
The metabolism of oestrogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and anti- infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).
Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones. Herbal preparations containing St John’s wort (Hypericum perforatum) may induce the metabolism of oestrogens.
At transdermal administration, the first-pass effect in the liver is avoided and thus, transdermally applied oestrogens HRT might be less affected than oral hormones by enzyme inducers.
Clinically, an increased metabolism of oestrogens and progestogens may lead to decreased effect and changes in the uterine bleeding profile.
Effect of HRT with oestrogens on other medicinal products
Hormone contraceptives containing oestrogens have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered due to induction of lamotrigine glucuronidation.
This may reduce seizure control. Although the potential interaction between hormone replacement therapy and lamotrigine has not been studied, it is expected that a similar interaction exists, which may lead to a reduction in seizure control among women taking both medicinal products together.
Pharmacodynamic interactions
Caution is warranted for co-administration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir and also the regimen with glecaprevir/pibrentasvir.

At transdermal administration, the first-pass effect in the liver is avoided and, thus, transdermally applied oestrogens HRT might be less affected than oral hormones by enzyme inducers.

See prescribing information for full details.

Pregnancy
Oestrogel is not indicated during pregnancy. 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 oestrogens indicate no teratogenic of foetotoxic effects.
Lactation
Oestrogel is not indicated during lactation.

Symptoms
Overdosage is unlikely with transdermal applications.
Overdoses of oestrogen may cause breast tenderness, nausea and withdrawal bleeding. These signs disappear when the treatment is stopped or when the dose is reduced.
Treatment
There are no specific antidotes and treatment should be symptomatic.