Janssen-Cilag Ltd

Evorel 50 micrograms per 24 hours Transdermal Patch

3.2 mg estradiol hemihydrate per patch, releasing a nominal 50 micrograms (µg) estradiol per 24 hours.

For a full list of excipients, see Section 6.1.

Transdermal patch.

Description of the product

Patches are square with rounded corners and are 0.1 mm thick. Patches are made of a flat, two-layer laminate. The outer layer is a flexible, translucent and nearly colourless backing film. The inner layer is a monolayer adhesive film (matrix) composed of acrylic adhesive and guar gum, which contains the active ingredients. This adhesive layer is protected by a polyester foil release liner, which is removed prior to application of the patch to the skin. The polyester foil used is coated with silicone on both sides. It has an S-shaped incision to facilitate its removal prior to use. Each patch is individually enclosed in a protective, hermetically sealed, labelled pouch.

Evorel 50 is marked on the outer side with 'CE50', and has a surface area of 16 cm².

Hormone replacement therapy (HRT) for the symptomatic relief of estrogen deficiency.

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)

For treatment of post-menopausal symptoms, the lowest effective dose should be used.

For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see also Section 4.4) should be used.

Adults

Hysterectomised women

- Treatment of estrogen deficiency symptoms

Evorel can be initiated any time after the manifestation of estrogen deficiency symptoms (e.g. hot flushes). Therapy should be started with Evorel 50. The dose may be adjusted after the first month if necessary depending on efficacy and signs of over-estrogenisation (e.g. breast tenderness). For maintenance therapy, the lowest effective dose should be used. A dose of 100μg of estradiol/24 hours should not be exceeded.

The switch from another estrogen-only therapy in post-menopausal women to Evorel may occur any time; the recommended starting dose is Evorel 50.

If there is a previous diagnosis of endometriosis, the addition of a progestagen to Evorel may also be considered for hysterectomised women.

- Prevention of post-menopausal osteoporosis

Therapy should be started with Evorel 50. The dose may be adjusted depending on efficacy and signs of over-estrogenisation (e.g. breast tenderness). Note, however, that the efficacy of Evorel 25 for the prevention of post-menopausal osteoporosis has not been demonstrated. For maintenance therapy, the lowest effective dose should be used. A dose of 100μg of estradiol/24 hours should not be exceeded.

Women with an intact uterus

- Treatment of estrogen deficiency symptoms

Evorel 50 in conjunction with a progestagen (see below) can be initiated any time after the initial manifestation of estrogen deficiency symptoms (e.g. hot flushes). Therapy should be started with Evorel 50. The dose may be adjusted after the first month if necessary depending on efficacy and signs of over-estrogenisation (e.g. breast tenderness). For maintenance therapy, the lowest effective dose should be used. A dose of 100μg of estradiol/24 hours should not be exceeded.

- Prevention of post-menopausal osteoporosis

Therapy should be started with Evorel 50. Evorel 50 in conjunction with a progestagen (see below) can be initiated any time. The dose may be adjusted if necessary depending on signs of over-estrogenisation (e.g. breast tenderness). Note, however, that the efficacy of Evorel 25 for the prevention of post-menopausal osteoporosis has not been demonstrated.

Switching from other HRT

Women on a continuous combined regimen wishing to switch from another estrogen to Evorel may do so at any time. Women on a cyclic or continuous sequential regimen wishing to switch from another estrogen to Evorel may do so at the end of a cycle of the current therapy.

Progestagen use

A progestagen must be added to Evorel for the prevention of adverse endometrial effects, e.g. hyperplasia and cancer. The regimen may be either cyclic or continuous sequential, that is, the progestagen is used on at least 12 consecutive days out of a cycle of 28 days. Only progestagens approved for addition to estrogen treatment may be prescribed (e.g. oral norethisterone, 1mg/day or medroxyprogesterone acetate, 2.5mg/day).

Children

Evorel is not indicated in children.

Elderly

Data are insufficient in regard to the use of Evorel in the elderly (>65 years old).

Administration

Patches should be applied to the trunk, below the waist. Patches should be changed twice a week, i.e. every three to four days. Application of a new patch should be to a site different from the previous application site.

If a patch detaches partially or completely prior to a scheduled change, it should be replaced immediately. However, the day of changing patches should be maintained. Women with an intact uterus on combination HRT, wearing a patch for more than 4 days or any period without a patch may increase the likelihood of break-through bleeding or spotting.

It is not necessary to remove the patch during bathing or showering.

Method of administration

Transdermal.

- 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), thrombophlebitis

- 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

- Severe renal disease

- 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 re-instituting 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' below). 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. It should be taken into account that these conditions may recur or be aggravated during treatment with Evorel, in particular:

- Leiomyoma (uterine fibroids) or endometriosis

- A history of, or risk factors for, thromboembolic disorders (see below)

- Risk factors for estrogen dependent tumours, e.g. 1^st degree heredity for breast cancer

- Hypertension

- Liver disorders (e.g. liver adenoma)

- Kidney disorders

- Diabetes mellitus with or without vascular involvement

- Cholelithiasis

- Migraine or (severe) headache

- Systemic lupus erythematosus.

- A history of endometrial hyperplasia (see below)

- Epilepsy

- Asthma

- Otosclerosis

- Mastopathy.

Reasons for immediate withdrawal of therapy:

Therapy should be discontinued in case a contra-indication 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

The risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods (see Section 4.8). The addition of a progestagen for at least 12 days per cycle in non-hysterectomised women greatly reduces this risk.

Evorel 75 and 100 are not recommended, as the endometrial safety of added progestagens have not been studied for transdermal doses of estradiol above 50 μg/day.

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 a progestagen 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.

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 oestrogens, oestrogen-progestagen combinations or tibolone for HRT for several years (see Section 4.8, Undesirable Effects). For all HRT, an excess risk becomes apparent within a few years of use and increases duration of intake but returns to baseline within a few (at most five) years after stopping treatment.

In the MWS, the relative risk of breast cancer with conjugated equine oestrogens (CEE) or estradiol (E2) was greater when a progestagen was added, whether sequentially or continuously, and regardless of type of progestagen. There was no evidence of a difference in risk between the different routes of administration.

In the WHI study, the continuous combined conjugated equine oestrogen and medroxyprogesterone acetate (CEE +MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.

HRT, especially oestrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Venous thromboembolism

HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. One randomised controlled trial and epidemiological studies found a two- to threefold higher risk for users compared with non-users. For non-users, it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate =4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate =9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later.

Generally recognised risk factors for VTE include a personal history or family history, severe obesity (BMI > 30 kg/m²) and systemic lupus erythematosus (SLE). There is no consensus about the possible role of varicose veins in VTE.

Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. The women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

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 (eg, painful swelling of a leg, sudden pain in the chest, dyspnoea).

Coronary artery disease (CAD)

There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated 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 examining effects in cardiovascular morbidity or mortality without evidence of ischaemic heart disease. Nevertheless a trend towards an increased cardiac event risk has been observed in postmenopausal women with angiographically proven ischaemic heart disease treated with transdermal estrogens.

Stroke

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.

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 HRT confers 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.

Women with pre-existing hypertriglyceridaemia should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition.

Oral 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 unchanged. 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). With transdermal administration, stimulation of the liver by the first-pass effect is avoided and thus, transdermally applied estrogens might affect hormone binding proteins and other liver products less than oral hormones.

There is no conclusive evidence for improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using combined CEE and MPA after the age of 65. It is unknown whether the findings apply to younger post-menopausal women or other HRT products.

Evorel is not to be used for contraception.

Evorel should be kept away from children and pets.

The metabolism of estrogens and progestagens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as barbiturates, phenylbutazone, meprobamate, anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz) and also bosentan.

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 estrogens and progestagens.

Clinically, an increased metabolism of estrogens may lead to decreased effect and changes in the uterine bleeding profile.

With transdermal administration, the first-pass effect in the liver is avoided and thus, transdermal estrogens might be less affected by enzyme inducers than oral hormones.

Estrogen-containing oral contraceptives 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 estrogen-containing 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 drugs together. Therefore, dose adjustment of lamotrigine may be necessary.

Pregnancy

Evorel is not indicated during pregnancy. If pregnancy occurs during use of Evorel, treatment should be withdrawn immediately.

There are no clinical data on exposed pregnancies.

Studies in animals have not shown reproductive toxicity.

The results of most epidemiological studies to date relevant to inadvertent fetal exposure to combinations of estrogens and progestagens indicate no teratogenic or foetotoxic effect.

Lactation

Evorel is not indicated during lactation.

In normal use, Evorel would not be expected to have any effect on ability to drive or use machinery.

Information on undesirable effects was obtained in two clinical trials comparing Evorel 100 and Evorel 50 to placebo. Of the just over 100 women in each group, one half (with a uterus) were followed for up to three years, the other half (hysterectomised) for up to 24 months. 21 % of women on Evorel 100 followed for up to three months reported at least one drug related adverse event. During follow-up for up to 24 months, the proportion was 26%. Of women on Evorel 50, 18% of those followed for up to three months and 29% of those followed for up to 24 months reported at least one drug related adverse event. Breast pain, reported by 17% of women on Evorel 100 was the most frequent adverse event.

Other side effects reported in the clinical trials with a frequency below 10% are listed in the table below.

*Breast Cancer

According to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women's Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users.

For oestrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which>80% of HRT use was oestrogen-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), respectively.

For oestrogen plus progestagen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with oestrogens alone.

The MWS reported that, compared to never users, the use of various types of oestrogen-progestagen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88-2.12) than use oestrogens alone (RR = 1.0, 95% CI: 1.21-1.40) or use of tibolone (RR =1.45; 95% CI 1.25-1.68).

The WHI trial reported a risk estimate of 1.24 (95% CI: 1.01-1.54) after 5.6 years of use of oestrogen-progestagen combined HRT (CEE +MPA) in all users compared with placebo.

The absolute risks calculated from the MWS and the WHI trial are presented below:

The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:

The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 70 years, an additional 8 cases of invasive breast cancer would be due to oestrogen-progestagen combined HRT (CEE + MPA) per 10 000 women years.

According to calculations from the trial data, it is estimated that:

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) (see section 4.4).

Endometrial Cancer

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed oestrogens. 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. Depending on the duration of treatment and oestrogen dose, the reported increase in endometrial cancer risk among unopposed oestrogen users varies from 2- to 12-fold greater compared with non-users. Adding a progestagen to oestrogen-only therapy greatly reduces this increased risk.

The frequency of estrogen-related adverse events (e.g. breast pain) is expected to increase with the dosage of estradiol transdermal systems.

The adverse event profile, their frequencies and severity in women with a uterus, treated with Evorel in conjunction with a progestagen, is expected to vary with the nature and the dose of the progestagen used concomitantly with Evorel.

Adverse events which have been reported in association with estrogen/progestagen treatment are:

- Estrogen-dependent neoplasms benign and malignant, e.g. endometrial cancer

- **Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone HRT users than among non-users. For further information see Section 4.3 Contraindications and 4.4 Special warnings and precautions for use

- Myocardial infarction and stroke

- Galactorrhoea

- Aggravation of epilepsy

- Gall bladder disease, liver adenoma

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

- Probable dementia (see section 4.4).

By virtue of the mode of administration of Evorel, overdosage is unlikely, but effects can if necessary be reversed by removal of the patch. The most commonly observed symptoms of overdose with estrogen therapy are breast tenderness, nausea and break-through bleeding.

ATC code: G03CA03

Estradiol hemihydrate

The active ingredient, estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of estrogen production in menopausal women, and alleviates menopausal symptoms. Estrogens prevent bone loss following menopause or ovariectomy.

Clinical trial information

Relief of menopausal symptoms was achieved to a similar degree during the first few weeks of treatment with Evorel 50 and Evorel 100.

Prevention of osteoporosis

Estrogen deficiency at menopause is associated with increasing bone turnover and decline in bone mass. The effect of estrogens on the bone mineral density (BMD) is dose-dependent; the relationship is not linear, however. Protection appears to be effective as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar 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 that is limited.

In a clinical trial of two years duration comparing Evorel 50 and 100 to placebo, the increase in lumbar spine bone mineral density (BMD) with Evorel 50 was 4.46 ± 4.04 % (mean±SD). With Evorel 100, the gain in lumbar spine bone density was 5.93 ± 4.34 %.

The percentage of women who maintained or gained BMD in the lumbar spine with Evorel 50 was 84% and with Evorel 100, 92.5%.

Evorel also had an effect on hip BMD. The increase in BMD in the femoral neck with Evorel 50 was 1.26 ± 2.86 % and with Evorel 100, 1.61±0.53 %. The percentage of women maintaining or gaining BMD in the femoral neck was 65 and 63.5 %, respectively. In the total hip, the increase in BMD was 2.17 ± 2.33 % with Evorel 50 and 2.82±0.51 % with Evorel 100. The percentage of women maintaining or gaining BMD in the total hip was 93 and 82.5 %, respectively.

The estradiol hemihydrate of the patch is taken up through the skin as estradiol. Estradiol is metabolised primarily in the liver to estrone, which has weak estrogenic activity. Estrone is either conjugated with glucuronic or sulphuric acid or reconverted to estradiol. Conjugates are excreted mainly by the kidneys. In contrast to oral preparations, the estradiol/estrone ratio on use of Evorel is in the physiological range below 2, similar to that in pre-menopausal women. Estradiol circulates in the blood bound to sex hormone binding globulin (35-45%) and albumin (60-65%).

Estradiol is metabolised mainly in the liver by the P450 enzyme system. While the amounts of circulating estradiol/estrone are not considered clinically relevant modifiers of the activity of the P450 enzyme system, other drugs metabolised through the same pathway might inhibit or increase the metabolism of the hormones (see Section 4.5 Interactions).

Due to the transdermal administration, there is no noticeable first-pass effect.

Pharmacokinetic parameters for Evorel 50 patches are shown in the following table.

Estradiol, which has been used in clinical practice worldwide for many years, is the subject of monographs in a number of major pharmacopoeias, has a well-established medicinal use and has recognised efficacy and an acceptable level of safety. Estradiol is the natural estrogen in humans and animals. Preclinical effects were observed at exposures considered sufficiently in excess of the maximum human exposure, or were related to an exaggerated pharmacological effect, or were related to differences between species regarding hormonal regulation/metabolism and indicate little relevance to clinical use.

Subchronic skin irritation studies in rabbits and dermal sensitisation tests in guinea pigs have been performed.

The studies show that the estradiol transdermal patch is an irritant and that estradiol contributes to the irritancy. It is recognised that test studies on rabbits over-predict skin irritation which occurs in humans.

The dermal sensitisation test shows that Evorel is not a skin sensitiser.

Adhesive acrylic polymer (Duro-Tak 387-2287)

Guar Gum (Meyprogat 90)

Hostaphan MN19 (polyester film: removed before application)

Not applicable

3 years.

Do not store above 25°C. Store within the original sachet and box.

Each Evorel 50 patch is presented in a sealed protective sachet. The polyester film (Hostaphan MN19) is removed before application. The sachets are packed in a cardboard box, in packs of 8 patches.

Not applicable

Janssen-Cilag Ltd

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

PA 748/4/4

Date of first authorisation: 10 June 1999

Date of last renewal: 10 June 2009

9 April 2010