EVOREL 75 - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Evorel 75

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Evorel 75 patch contains estradiol 4.80 mg.

Evorel is a square shaped, transparent, self-adhesive transdermal therapeutic system (patch) to skin. Evorel 75 has a surface area of 16 cm2 and 0.2 mm thickness. It consists of a monolayered adhesive matrix throughout which 17B estradiol is uniformly distributed. The adhesive matrix is protected on the outside surface (from clothes etc.) by a polyethylene teraphthalate backing foil, while the adhesive surface of the patch is covered by a polyester sheet (the release liner) which is removed before placing the patch on the body surface. This release liner has an S-shaped incision which facilitates easy removal from the patch.

4.1 Therapeutic indications

Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in peri- and post-menopausal 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 Section 4.4)

The experience treating women older than 65 years is limited.

4.2 Posology and method of administration

Adults

Evorel is an oestrogen-only HRT patch applied to the skin twice weekly.

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

For women with an intact uterus progestogen should normally be added to Evorel for the prevention of adverse endometrial effects, eg hyperplasia and cancer. The regimen may be either cyclic or continuous sequential.

Only progestogens approved for addition to oestrogen treatment may be prescribed (e.g. oral norethisterone, 1 mg/day or medroxyprogesterone acetate, 2.5 mg/day) and should be added for at least 12–14 days every month/28 day cycle.

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

Treatment of oestrogen deficiency symptoms

Therapy should be started with one Evorel 50 patch (delivering 50 micrograms of estradiol/24 hours) and the dose adjusted after the first month if necessary depending on efficacy and signs of over-oestrogenisation (eg breast tenderness). For maintenance therapy the lowest effective dose should be used; a maximum dose of 100 micrograms of estradiol/24 hours should not be exceeded.

Prevention of post-menopausal osteoporosis

Therapy should be started with Evorel 50. The dose may be adjusted depending on efficacy and signs of over-oestrogenisation (eg 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 100micrograms of estradiol/24 hours should not be exceeded.

Post-menopausal women currently not on HRT may start Evorel at any time. Peri-menopausal women who are still having regular menstrual cycles and are not currently on HRT should start Evorel within 5 days of the start of bleeding. Peri-menopausal women with irregular menstrual cycles, for whom pregnancy has been excluded, can start Evorel at any time.

Switching from other HRT

The switch from another oestrogen-only therapy in post-menopausal women to Evorel may occur at any time.

Women on a continuous combined regimen wishing to switch from another oestrogen to Evorel may do so at any time.

Women on a cyclic or continuous sequential regimen wishing to switch from a sequential combined HRT preparation to Evorel may do so at the end of a cycle of the current therapy or after a 7 day hormone free interval.

Method of Administration

Evorel should be applied to the skin as soon as it is removed from the wrapper. Recommended application sites are on clean, dry, healthy, intact skin and each application should be made to a slightly different area of skin on the trunk below waistline. Evorel should not be applied on or near the breasts.

Evorel should remain in place during bathing and showering. Should it fall off during bathing or showering the patient should wait until cutaneous vasodilation ceases before applying a replacement patch to avoid potential excessive absorption. Should a patch fall off at other times it should be replaced immediately.

Patients can be advised to use baby oil to help remove any gum/glue which may remain on their skin after patch removal.

Missed dose

If the patient forgets to change their patch, they should change it as soon as possible and apply the next one at the normal time. However, if it is almost time for the next patch, the patient should skip the missed one and go back to their regular schedule. Only one patch should be applied at a time.

There is an increased likelihood of break-through bleeding and spotting when a patch is not replaced at the normal time.

Children

Evorel is not indicated in children.

Elderly

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

Route of administration

Transdermal use.

4.3 Contraindications

Known, current or past, or suspected breast cancer

Known or suspected oestrogen-dependent malignant tumours (eg endometrial cancer) or pre-malignant tumours (e.g. untreated atypical endometrial hyperplasia)

Undiagnosed genital bleeding

Previous idiopathic or current venous thrombo-embolism (deep venous thrombosis, pulmonary embolism)

Active or recent past arterial thrombo-embolic disease (eg cerebrovascular accident 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 thrombophilic conditions (e.g.protein C, Protein S or antithrombin deficiency see section 4.4).

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 menopausal 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/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, thrombo-embolic disorders (see below)

– Risk factors for oestrogen dependent tumours, eg 1st degree heredity for breast cancer

– Hypertension

– Liver disorders (eg liver adenoma)

– 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

– Hereditary angioedema

– Mastopathy

Conditions which require monitoring while on oestrogen therapy:

Oestrogens may cause fluid retention. Cardiac or renal dysfunction should be carefully observed

Disturbances or mild impairment of liver function

History of cholestatic jaundice

Pre-existing hypertriglyce­ridaemia. Rare cases of large increases of plasma triglycerides leading

to pancreatitis have been reported with oestrogen therapy in this condition

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

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, the risk may remain elevated for at least 10 years.

Oestrogen-only therapy

from 1 to 5 years in women with a uterus has been estimated to increase the risk of endometrial cancer 3-fold (from a baseline lifetime risk of about 3% for a woman aged 50 years), with effects persisting for several years after oestrogen is stopped. The addition of a progestogen for 12 14 days per cycle or continuous combined oestrogen/pro­gestogen therapy in non-hysterectomised women greatly reduces this risk.

Although progestogen treatment for at least 10 days per cycle reduces the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer, 12–14 days per cycle is recommended to maximise endometrial protection. Such a sequential oestrogen/oestrogen-progestogen regimen results in cyclic bleeding in the majority of women.

For Evorel 75 and 100 the endometrial safety of added progestogens has not been studied.

Break-through bleeding and spotting may occur during the first months of treatment. If breakthrough 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 a progestogen 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 shows an increased risk of breast cancer in women taking combined oestrogen-progestogen or oestrogen-only HRT, that is dependent on the duration of taking HRT.

Combined oestrogen-progestogen therapy:

The randomised placebo-controlled trial the Women's Health Initiative study (WHI), and a metaanalysis of prospective 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 (1–4) years (see Section 4.8).

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 lower than that found in users of oestrogen-progestogen combinations (see Section 4.8).

Results from a large meta-analysis showed that after stopping treatment, the excess risk will decrease with time and the time needed to return to baseline depends on the duration of prior HRT use. When HRT was taken for more than 5 years, the risk may persist for 10 years or more.

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 metaanalysis suggests a slightly increased risk in women taking 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 the use of combined HRTs may be associated with a similar or slightly smaller risk (see Section 4.8).

Venous thrombo-embolism

HRT is associated with a higher relative risk of developing venous thrombo-embolism (VTE), ie 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 combined oral 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, use of oestrogens, older age, severe obesity (BMI > 30 kg/m2), pregnancy/pos­tpartum period, cancer 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 thrombo-embolism 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. 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 thrombo-embolic 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 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-progestogen therapy: The relative risk of CAD during use of combined oestrogen-progestogen HRT is slightly increased. The 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

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 oestrogens and medroxyprogesterone acetate (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 oestrogens 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.

Combined oestrogen-progestogen and oestrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause or duration of use. 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 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 radioimmunoassay) 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).

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should minimise exposure to the sun or ultraviolet radiation whilst taking HRT.

Dementia

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

Evorel is not to be used for contraception. Women of child-bearing potential should be advised to use non-hormonal contraceptive methods to avoid pregnancy.

4.5 Interaction with other medicinal products and other forms of interaction

The metabolism of oestrogens and progestogens 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) 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 raise the metabolism of oestrogens and progestogens.

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

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

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.

4.6 Fertility, Pregnancy and lactation

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 foetal exposure to oestrogens indicate no teratogenic or foetotoxic effect.

Lactation

Evorel is not indicated during lactation.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

The safety of Evorel was evaluated in 2584 subjects who participated in 15 clinical trials and received at least one administration of Evorel. Subjects were also asked about application site signs and symptoms in 8 of the 15 clinical trials (N = 1739 subjects). Based on safety data from these clinical trials, the most commonly reported (>5% incidence) adverse drug reactions (ADRs) were (with % incidence): application site rash (20.8%), application site pruritus (19.8%), application site erythema (8.5%), headache (7.8%), and breast pain (6.6%).

Including the above-mentioned ADRs, the following table displays ADRs that have been reported with the use of Evorel from either clinical trial or post-marketing experiences. The displayed frequency categories use the following convention:

Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available clinical trial data).

Adverse Drug Reactions

Infections and Infestations

Immune System Disorders

Psychiatric disorders

Nervous system disorders

Cardiac disorders

Vascular disorders

* Additional adverse drug reactions reported in clinical trials of Evorel (estradiol only)

The table below reports additional undesirable effects that have been reported in users of other hormone replacement therapy (HRT) by MedDRA system organ classes (MedDRA SOCs).

Skin and subcutaneous tissue

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

Gall bladder disease.

Skin and subcutaneous disorders: chloasma, erythema multiforme,

Vascular purpura.

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

Serious undesirable effects associated with the use of hormone replacement therapy are also mentioned in section 4.4 Special warnings and precautions for use

Breast Cancer

. 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.

The increased risk in users of oestrogen-only therapy is lower than that seen in users of oestrogenproges­tagen combinations.

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

Absolute risk estimations based on results of the largest randomised placebo-controlled trial (WHI-study) and the largest meta-analysis of prospective epidemiological studies are presented below:

Taken from baseline incidence rates in England in 2015 in women with BMI 27 (kg/m2).

Note: since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately.

Taken from baseline incidence rates in England in 2015 in women with BMI 27 (kg/m2)

Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately.

US WHI studies – additional risk of breast cancer after 5 year's use

WHI study in women with no uterus, which did not show an increase of breast cancer.

§ 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.

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 progestogen to oestrogen-only therapy greatly reduces 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 (see Section 4.4).

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.

Adverse events which have been reported in association with oestrogen/ progestogen treatment :

Venous thrombo-embolism, ie 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 Contra-indications and 4.4 Special warnings and precautions for use.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

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 oestrogen therapy are breast pain or tenderness, nausea, vomiting and breakthrough bleeding, abdominal cramps or bloating. There is no specific antidote and treatment should be symptomatic.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC code: G03CA03

Estradiol hemihydrate:

The active ingredient, synthetic 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.

Oestrogens 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

Oestrogen deficiency at menopause is associated with increasing bone turnover and decline in bone mass. The effect of oestrogens 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 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 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.

5.2 Pharmacokinetic properties

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. (see Section 4.5 Interactions).

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

Pharmacokinetic parameters for the four sizes of Evorel patches are shown in the following table.

__________Evorel 25________Evorel 50________Evorel 75__________E­vorel 100

Serum estradiol (pmol/L; mean+/-SD)

5.3 Preclinical safety data

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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Adhesive acrylic polymer (Duro-Tak 387–2287)

Guar gum

Hostaphan MN19 (polyester film – removed before application)

6.2

None known.

6.3

24 months for the product as packed for sale.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

Each Evorel 75 patch is presented in a sealed protective pouch. The pouches are packed in a cardboard carton. Pack sizes: 8, 10, 24, 26, 30, 48, 60.

6.6 Special precautions for disposal

Not applicable.