Oestrogel

Oestrogel Pump-Pack

One gram of gel contains 0.6 mg of the active ingredient, 17β-oestradiol (0.06% w/w).

Each pump actuation delivers 1.25 g of gel which contains 0.75 mg of 17β-oestradiol.

Transdermal gel.

A clear, colourless gel with an odour of alcohol.

- Hormone replacement therapy (HRT) for oestrogen 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. (see also Section 4.4)

The experience treating women older than 65 years is limited.

Posology

Oestrogel is an oestrogen-only product indicated only for women without a uterus. Oestrogel should be administered daily on a continuous basis.

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 symptoms:

Each metered dose (1 pump actuation) from the dispenser is 1.25 g of Oestrogel. The usual starting dose is two pumps (2.5 g which contains 1.5 mg oestradiol) of Oestrogel once daily. 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 four pumps (5 g which contains 3.0 mg oestradiol) of Oestrogel daily.

Prevention of 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. Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestogen in hysterectomised women.

Initiation of treatment:

Women who 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.

Method of Administration

The pump pack will require priming before using a new pump pack for the first time. The first dose dispensed should be discarded.

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. The area of application should be as large as possible at least 750 cm². One pump actuation from the dispenser, or half the prescribed dose, should be applied to each arm/shoulder (or thigh). Oestrogel should NOT be applied on or near the breasts or on the vulval region.

Oestrogel should be allowed to dry for 5 minutes before covering the skin with clothing.

The gel should be applied by the patient herself, not by anyone else, and skin contact, particularly with a male partner, should be avoided for one hour after application. Wash hands with soap and water after applying the gel. Washing the skin or contact with other skin products should be avoided until at least one hour after application of Oestrogel.

) should be used.

For people not being treated with Oestrogel:

In the event of contact with an application area, which has not been washed or is not covered with clothing, wash the area of skin onto which Oestrogel may have been transferred as soon as possible, using soap and water.

If the patient forgets to apply a dose and it is more than 12 hours until the next dose, the missed dose should be applied and normal dosing resumed the next day. If the next dose is less than 12 hours away, it is best just to wait and apply the next dose normally. Patients should be advised not to apply two doses at the same time.

Forgetting a dose may increase the likelihood of break-through bleeding and spotting.

Method of Administration

For transdermal use.

- 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 ;

- 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;

- 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.

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. 1^st 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 (see below)

- 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.

- Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients.

- Generally recognised risk factors for VTE include, use of oestrogens, older age, major surgery, prolonged immobilisation, obesity (BMI > 30kg/m²), pregnancy/postpartum period, systemic lupus erythematosus (SLE) and cancer. There is no consensus about the possible role of varicose veins in VTE. As in all postoperative patients, prophylactic measures need be considered to prevent VTE following surgery. If prolonged immobilisation is to follow elective surgery temporarily stopping HRT 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilised.

- In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age, screening may be offered after careful counseling regarding its limitations (only a proportion of thrombophilic defects are identified by screening).

If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is 'severe' (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT is contraindicated.

- Women already on chronic anticoagulant treatment require careful consideration of the benefit risk of use of HRT.

- 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, dyspnoea).

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.

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.

- 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).

- HRT use does not improve cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined or oestrogen-only HRT after the age of 65.

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, carbamezapin) 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.

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.

Breast-feeding

Oestrogel is not indicated during breast-feeding.

None known.

Summary of the safety profile

The undesirable effects are generally mild and rarely require treatment withdrawal. Undesirable effects, if any, usually occur during the first months of treatment.

Undesirable effects observed with HRT products used in menopause are reported in the table below:

Adverse reactions were categorized as very common (> 1/10), common (> 1/100 to ≤ 1/10), uncommon (> 1/1,000 to ≤ 1/100) or rare (> 1/10,000 to ≤ 1/1,000).

Other adverse reactions have been reported in association with oestrogen/progestogen treatment:

- Gall bladder disease.

- Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura.

- Probable dementia over the age of 65.

Breast cancer risk

- An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestogen therapy for more than 5 years.

- Any increased risk in users of oestrogen-only therapy is substantially lower than that seen in users of oestrogen-progestogen combinations.

- The level of risk is dependent on the duration of use.

- Results of the largest randomised placebo-controlled trial (WHI-study) and largest epidemiological study (MWS) are presented.

Million Women study- Estimated additional risk of breast cancer after 5 years' use

*2: Taken from baseline incidence rates in developed countries

US WHI studies - additional risk of breast cancer after 5 years' use

‡When the analysis was restricted to women who had not used HRT prior to the study there was no increased risk apparent during the first 5 years of treatment: after 5 years the risk was higher than in non-users.

*3: WHI study in women with no uterus, which did not show an increase in risk of breast cancer

Endometrial cancer risk

Postmenopausal women with a uterus

The endometrial cancer risk is about 5 in every 1000 women with an uterus not using HRT.

In women with a uterus, use of oestrogen-only HRT is not recommended because it increases the risk of endometrial cancer.

Depending on the duration of oestrogen-only use and oestrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 women between the ages of 50 and 65.

Adding a progestogen to oestrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study the use of five years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer (RR of 1.0 (0.8-1.2)).

Ovarian cancer

Use of oestrogen-only or combined oestrogen-progestogen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed.

A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.31-1.56). For women aged 50 to 54 years taking 5 years of HRT, this results in about 1 extra case per 2000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5-year period.

Risk of venous thromboembolism

HRT is associated with a 1.3-3-fold increased relative 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 using HT. Results of the WHI studies are presented:

WHI studies combined - Additional risk of VTE over 5 years' use

4 *Study in women with no uterus

Risk of coronary artery disease

The risk of coronary artery disease is slightly increased in users of combined oestrogen- progestogen HRT over the age of 60.

Risk of ischaemic stroke

The use of oestrogen-only and oestrogen + progestogen therapy is associated with an up to 1.5 fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT.

This relative risk is not dependent on age or on duration of use, but as the baseline risk is strongly age-dependent, the overall risk of stroke in women who use

WHI studies combined - Additional risk of ischaemic stroke*5 over 5 years' use

5*no differentiation was made between ischaemic and haemorrhagic stroke.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the website www.mhra.gov.uk/yellowcard

Pain in the breasts or excessive production of cervical mucus may be indicative of too high a dosage, but acute overdosage has not been reported and is unlikely to be a problem. Overdosages of oestrogen may cause nausea, and withdrawal bleeding may occur. There are no specific antidotes and treatment should be symptomatic.

ATC Code: G03CA03.

Sex Hormones and Modulators of the Genital System - Natural and Semisynthetic Oestrogens, plain.

The active ingredient, 17β-oestradiol, is chemically and biologically identical to endogenous human oestradiol. It substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms.

Oestrogel prevents bone loss following menopause or ovariectomy.

Clinical trial information

- Relief of oestrogen deficiency symptoms and bleeding patterns

Relief of menopausal symptoms was achieved during the first few weeks of treatment. The rate of regular withdrawal bleeding or amenorrhoea depends on the individual posology and may vary on the individual patient.

- Prevention of osteoporosis

- Oestrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass.

- The effect of oestrogens on the bone mineral density is dose-dependent. Protection appears to be effective for as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a similar rate to that in untreated women.

- Evidence from the WHI trial and meta-analysed trials shows that current use of HRT, alone or in combination with a progestogen - given to predominantly healthy women- reduces the risk of hip, vertebral, and other osteoporotic fractures. HRT may also prevent fractures in women with low bone density and/or established osteoporosis, but the evidence for this is limited.

Pharmacokinetic studies indicate that, when applied topically to a large area of skin in a volatile solvent, approximately 10% of the oestradiol is percutaneously absorbed into the vascular system, regardless of the age of the patient. Daily application of 2.5 g or 5 g Oestrogel over a surface area of 400-750 cm² results in a gradual increase in oestrogen blood levels to steady state after approximately 3-5 days and provides circulating levels of both oestradiol 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 (C_max) of oestradiol and estrone on Day 12 were 117 pg/ml and 128 pg/ml, respectively.

The time-averaged serum oestradiol and estrone concentrations (C_average) 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 oestradiol 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, oestradiol and urinary conjugated oestradiol concentrations return to baseline in about 76 hours.

No relevant information additional to that already contained in the SPC.

-Ethanol

-Carbomer

-Triethanolamine

-Purified water

Not known.

3 years

Do not store above 25°C.

Metering canister composed of a polypropylene bottle, a LDPE pouch, a polypropylene metering pump and closed with a polypropylene cap, containing 80 g of gel.

No special requirements

Besins Healthcare

Avenue Louise, 287

B-1050 Brussels

Belgium

PL 28397/0002

1 November 1997

22 December 2017