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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Oestrogel Pump-Pack

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Oestrogel contains 17p-estradiol as active ingredient, 0.06% w/w. For the full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Transdermal gel

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

•    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.

4.2 Posology and method of administration

Posology

Oestrogel is an oestrogen-only product. Oestrogel should be administered daily on a continuous basis.

Menopausal symptoms:

Each measure from the dispenser is 1.25 g of Oestrogel. The usual starting dose is two measures (2.5 g which contains 1.5 mg estradiol) 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 measures (5 g which contains 3.0 mg eastradiol) of Oestrogel daily.

Prevention of osteoporosis:

The minimum effective dose is 2.5 g of Oestrogel once daily for most patients.

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 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-progestagen combinedHRT:

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 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 at least 750 cm2. One measure 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.

Washing the skin or contact with other skin products should be avoided until at least one hour after application of Oestrogel.

Missed dose advice

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.

4.3 Contraindications

-    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, see section 4.4);

-    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

4.4 Special warnings and precautions for use

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 (see section 4.8). After stopping treatment risk may remain elevated for at least 10 years.

•    The addition of a progestagen cyclically for at least 12 days per month/28 day cycle or continuous combined oestrogen-progestagen 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 progestagens 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-progestagen 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-progestagen combinations (see section 4.8).

Combined oestrogen-progestagen 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-progestagen for HRT that becomes apparent after about 3 years (see Section 4.8).

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-progestagen 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 . Long-term (at least 5-10 years) use of oestrogen only HRT products has been associated with an slightly increased risk of ovarian cancer (see section 4.8). Some studies, including the WHI trial suggest that the long-term use of combined HRTs may confer a similar, or slightly smaller risk (see section 4.8).

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 (see Section 4.8).

• 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 (see section 4.3).

• 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-progestagen or oestrogen-only HRT.

Oestrogen-only:

Randomised controlled data found no increased risk of CAD in hysterectomised women using oestrogen-only therapy.

Combined oestrogen-progestagen therapy:

The relative risk of CAD during use of combined oestrogen+progestagen 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+progestagen use is very low in healthy women close to menopause, but will rise with more advanced age.

Ischaemic Stroke

Combined oestrogen-progestagen 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 (see section 4.8).

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.

4.5 Interaction with other medicinal products and other forms of interaction

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 progestagens may lead to decreased effect and changes in the uterine bleeding profile.

4.6 Fertility, Pregnancy and lactation

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.

4.7 Effects on ability to drive and use machines

None known.

4.8 Undesirable effects

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:

Sy	Common ADR’s	Uncommon ADR’s	Rare ADR’s
ste	>1/100 ; <1/10	>1/1000 ; <1/100	>1/10000 ;
m			<1/1000
Me			Glucose
tab			intolerance
oli
sm
an

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

-    Gall bladder disease.

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

-    Probable dementia over the age of 65 (see section 4.4).

Breast cancer risk

•    An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestagen 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-progestagen combinations.

•    The level of risk is dependent on the duration of use (see section 4.4).

•    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

Age range (years)	Additional cases per 1000 never-users of HRT over a 5 year period*1	Risk ratio & 95%CI#	Additional cases per 1000 HRT users over 5 years (95%CI)
		Oestrogen only HRT
50-65	9-12	1.2	1-2 (0-3)
		Combined oestrogen-progestagen
50-65	9-12	1.7	6 (5-7)
#Overal increasi Note: Si the num proporti	risk ratio. The risk ratio is not constant but will increase with ng duration on use nce the background incidence of breast cancer differs by EU country, ber of additional cases of breast cancer will also change onately.

*1: Taken from baseline incidence rates in developed countries US WHI studies - additional risk of breast cancer after 5 years’ use

Age range (years)	Incidence per 1000 women in placebo arm over 5 years	Risk ratio & 95%CI#	Additional cases per 1000 HRT users over 5 years (95%CI)
		CEE oestrogen only
50-79	21	0.8 (0.7 1.0)	-4 (-6 - 0)*2
		CEE +M	PA oestrogen-progestagen}
50-79	17	1.2 (1.0 - 1.5)	+4 (0 - 9)

{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.

*2: 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 (see section 4.4).

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 progestagen 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

Long-term use of oestrogen-only and combined oestrogen-progestagen HRT has been associated with a slightly increased risk of ovarian cancer. In the Million Women Study 5 years of HRT resulted in 1 extra case per 2500 users.

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 (see section 4.4). Results of the WHI studies are presented:

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

Age range	Incidence per 1000 women in	Risk ratio &	Additional cases per
(years)	placebo	95%CI	1000 HRT users
	arm over
	5 years

Oral combined oestrogen-progestagen
50-59	4	2.3 (1.2 -4.3)	5 (1 - 13)

3 *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-progestagen HRT over the age of 60 (see section 4.4).

Risk of ischaemic stroke

The use of oestrogen-only and oestrogen + progestagen 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 HRT will increase with age, see section 4.4.

WHI studies combined - Additional risk of ischaemic stroke*4 over 5 years’ use

Age range (years)	Incidence per 1000 women in placebo arm over 5 years	Risk ratio & 95%CI	Additional cases per 1000 HRT users over 5 years
50-59	8	1.3	3 (1 - 5)
		(11-
		1.6)

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

4.9 Overdose

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC Code: G03CA03.

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

The active ingredient, 173-estradiol, is chemically and biologically identical to endogenous human estradiol. 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 progestagen - 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.

5.2 Pharmacokinetic properties

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 2.5 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 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 (C_max) 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.

5.3 Preclinical safety data

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

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

-Ethanol -Carbomer -Triethanolamine -Purified water

6.2 Incompatibilities

None known

6.3 Shelf life

36 months

6.4 Special precautions for storage

Do not store above 25°C

6.5 Nature and contents of container

Rigid plastic container enclosing a LDPE bag fitted with a metering valve and closed with a polypropylene cap, containing 80 g.

6.6 Special precautions for disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

Besins Healthcare Avenue Louise, 287

B-1050 Brussels Belgium

8    MARKETING AUTHORISATION NUMBER(S)

PL 28397/0002

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

01/11/1997 / 30/08/2002

10 DATE OF REVISION OF THE TEXT

23/12/2013