This information is intended for use by health professionals

1. Name of the medicinal product

EVOREL SEQUI

International non-proprietary names

estradiol

norethisterone acetate

2. Qualitative and quantitative composition

EVOREL SEQUI is a transdermal therapy comprising

a) 4 EVOREL 50 TDSs, each containing:

3.2 mg of estradiol hemihydrate

b) 4 EVOREL CONTI TDSs, each containing:

3.2 mg of estradiol hemihydrate

11.2 mg of norethisterone acetate

3. Pharmaceutical form

EVOREL SEQUI is composed of EVOREL 50 and EVOREL CONTI. Both EVOREL 50 and EVOREL CONTI are a Transdermal Delivery System (TDS), or transdermal patch, composed of a flat two-layer laminate which is 0.1 mm in thickness. The first layer is a flexible, translucent, and nearly colourless backing film. The second layer is a monolayer adhesive film (matrix) composed of acrylic adhesive and guar gum and contains the hormones. This system is protected by a polyester foil release liner, which is affixed to the adhesive matrix and is removed prior to application of the patch to the skin. The polyester foil used is coated with silicone on both sides. The release liner has an S-shaped opening to facilitate its removal prior to use. Each TDS is enclosed in a protective, hermetically-sealed sachet.

EVOREL CONTI has a surface area of 16 sq cm and contains 3.2 mg of estradiol corresponding to a nominal release of 50 micrograms of estradiol per 24 hours and 11.2 mg of norethisterone acetate corresponding to a nominal release of 170 micrograms of norethisterone acetate per 24 hours. Each EVOREL Conti patch is marked in the centre of the lower margin on the outside of the backing film: CENI.

EVOREL 50 has a surface area of 16 sq cm and contains 3.2 mg of estradiol corresponding to a nominal release of 50 micrograms of estradiol per 24 hours. The release liner of EVOREL 50 is aluminised on one side. Each EVOREL 50 patch is marked in the centre of the lower margin of the outside of the backing film: CE50.

4. Clinical particulars
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 also Section 4.4)

The experience treating women older than 65 years is limited.

4.2 Posology and method of administration

Adults

Evorel Sequi is a continuous sequential HRT preparation. Patches are applied to the skin twice weekly.

One Evorel Sequi patch should be worn at all times, without interruptions. 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.

Guidance on how to start therapy:

Any previous therapy with HRT must be stopped prior to starting Evorel Sequi.

Post-menopausal women currently not on HRT may start Evorel Sequi at any time.

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

Switching from other HRT

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

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

Method of Administration

A treatment cycle with Evorel Sequi is 28 days. During the first 14 days, one estradiol-only (Evorel 50) patch should be worn at all times, without interruption. During days 15-28, one estradiol + norethisterone (Evorel Conti) patch should be worn at all times, without interruption. A subsequent treatment cycle should follow immediately, without a treatment free interval.

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. The patch 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.

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.

Wearing a patch for more than 4 days by mistake or any period without a patch may increase the likelihood of breakthrough bleeding or spotting.

Children

Evorel Sequi is not indicated in children.

Elderly

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

Route of administration

Transdermal use.

4.3 Contraindications

Known, 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

Untreated endometrial hyperplasia

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 (listed in section 6.1)

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 contra-indications 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 Evorel Sequi, 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 if 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 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 the risk remains elevated for at least 10 years. The addition of a progestogen for 12-14 days per 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.

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.

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 (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).

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 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 1.3-3 fold risk of developing venous thrombo-embolism (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)

Generally recognised risk factors for VTE include a personal history or family history, use of oestrogens, older age, major surgery, prolonged immobilisation, severe obesity (BMI > 30 kg/m2), pregnancy/ postpartum period, systemic lupus erythematosus (SLE) and cancer. 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. HRT is therefore contraindicated in these patients (see section 4.3).

In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age or recurrent spontaneous abortion, screening may be offered after careful counselling 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 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-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. 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.

Ishaemic Stroke

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. 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).

Hypothyroidism

Patients who require thyroid hormone replacement therapy should have their thyroid function monitored regularly while on HRT to ensure that thyroid hormone levels remain in an acceptable range.

Angioedema

Oestrogens may induce or exacerbate symptoms of angioedema, in particular in women with hereditary angioedema.

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 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-l-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.

Contact sensitisation is known to occur with all topical applications. Although it is extremely rare, women who develop contact sensitisation to any of the components of the patch should be warned that a severe hypersensitivity reaction may occur with continuing exposure to the causative agent.

Evorel Sequi 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, telaprevir 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.Some laboratory tests may be influenced by oestrogen therapy, such as tests for glucose tolerance or thyroid function.

4.6 Fertility, pregnancy and lactation

Pregnancy

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

Data on a limited number of exposed pregnancies indicate adverse effects of norethisterone on the foetus. At doses higher than normally used in oral contraceptives and HRT formulations, masculinisation of female foetuses was observed.

The results of most epidemiological studies to date, relevant to inadvertent foetal exposure to combinations of oestrogens and progestogens indicate no teratogenic or foetotoxic effect.

Breast Feeding

Evorel Sequi is not indicated during breast feeding.

4.7 Effects on ability to drive and use machines

There are no known data on the effects of Evorel Sequi on the ability to drive or use machinery.

4.8 Undesirable effects

The safety of Evorel Sequi was evaluated in 165 subjects who participated in 2 clinical trials. Based on safety data from these clinical trials, the most commonly reported (≥5% incidence) adverse drug reactions (ADRs) were (with % incidence): application site reaction (14.6%), headache (7.9%), breast pain (6.1%), and depression (5.5%).

Including the above-mentioned ADRs, the following table displays ADRs that have been reported with the use of Evorel Sequi from either clinical trial or post-marketing experiences, and additional ADRs that have been reported with the use of Evorel (estradiol alone) from clinical trial data. 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

Uncommon

Candidiasis

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Uncommon

Breast cancer, fibroadenoma of breast

Frequency not known

Endometrial cancer

Immune System Disorders

Uncommon

Hypersensitivity

Psychiatric disorders

Common

Depression, Insomnia, Affect lability, Nervousness

Uncommon

Libido decreased, Libido increased

Frequency not known

Mood swings

Nervous system disorders

Common

Migraine, Headache

Uncommon

Dizziness, Paraesthesia, Disturbance in attention

Frequency not known

Cerebrovascular accident, Epilepsy*

Cardiac disorders

Uncommon

Palpitations

Vascular disorders

Common

Hypertension

Frequency not known

Deep vein thrombosis, Thrombosis*

Respiratory, Thoracic and Mediastinal Disorders

Frequency not known

Pulmonary embolism

Gastrointestinal disorders

Common

Abdominal pain, Gastrointestinal disorder, Diarrhoea*, Flatulence*, Nausea

Frequency not known

Abdominal distension

Hepato-biliary disorders

Frequency not known

Cholelithiasis

Skin and subcutaneous tissue disorders

Common

Pruritus, Rash erythematous

Frequency not known

Rash*, Stevens-Johnson syndrome

Musculoskeletal and Connective Tissue Disorders

Common

Arthralgia, Back pain, Myalgia*

Reproductive system and breast disorders

Common

Breast pain, Dysmenorrhoea, Menorrhagia, Menstrual disorder

Uncommon

Breast enlargement, Endometrial hyperplasia, Metrorrhagia

General disorders and administration site conditions

Very Common

Application site erythema, Application site pruritus, Application site rash, Application site reaction

Common

Pain*, Oedema, Malaise

Uncommon

Generalised oedema*, Fatigue

Frequency not known

Oedema peripheral*, Application site oedema*

Investigations

Common

Weight increased

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

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

Nervous system disorders

Uncommon

Vertigo

Vascular disorders

Uncommon

Varicose veins

Gastrointestinal disorders

Common

Dyspepsia

Uncommon

Vomiting

Hepatobiliary disorders

Rare

Gallbladder disorder

Very rare

Cholestatic jaundice

Skin and subcutaneous tissue disorders

Common

Acne, Dry skin

Uncommon

Skin discoloration

Frequency not known

Alopecia

Musculoskeletal and connective tissue disorders

Common

Pain in extremity

Rare

Myasthenia

Reproductive system and breast disorders

Very common

Breast tenderness

Common

Genital discharge, Uterine spasms, Vaginal infection

Rare

Uterine leiomyoma, Fallopian tube cysts, Cervical polyps

Investigations

Uncommon

Transaminases increased

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 (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*

Risk ratio #

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-progestogen

50-65

9-12

1.7

6 (5 - 7)

# Overall risk ratio. The risk ratio is not constant but will increase with increasing duration on use.

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 developed countries.

US WHI studies - additional risk of breast cancer after 5 year's 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)*

CEE + MPA oestrogen & progestogens

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.

* 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 a 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 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 (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.

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 - Additional risk of VTE 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

Oral, oestrogen-only*

50-59

7

1.2 (0.6 - 2.4)

1 (-3 - 10)

Oral combined, oestrogen -progesterone

50-59

4

2.3 (1.2 - 4.3)

5 (1 - 13)

* 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 (see section 4.4).

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 HRT will increase with age (see section 4.4).

WHI studies combined - Additional risk of ischaemic stroke* 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 (1.1 – 1.6)

3 (1 – 5)

* No differentiation was made between ischaemic and haemorrhagic stroke.

Other adverse events 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 Sections 4.3 Contraindications and 4.4 Special Warnings and Special Precautions for use.

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 (see section 4.4)

• Dry eyes

• Tear film composition changes

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

Signs and symptoms

Due to the mode of administration, overdose of oestradiol or norethisterone is unlikely to occur. Symptoms of overdose of oral oestrogen are breast tenderness, nausea, vomiting and /or metrorrhagia. Over dosage of progestogens may lead to a depressive mood, fatigue, acne and hirsutism.

Treatment

There is no specific antidote and treatment should be symptomatic. These symptoms can be reversed by removing the Evorel Sequi patch.

5. Pharmacological properties
5.1 Pharmacodynamic properties

ATC code: G03F B05

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.

Norethisterone:

As oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestogen reduces the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

Clinical trial information:

Relief of oestrogen-deficiency symptoms and bleeding patterns:

Relief of menopausal symptoms was achieved during the first few weeks of treatment with Evorel Sequi.

Regular withdrawal bleeding occurs in over 95% of women using Evorel Sequi. Two thirds of treatment cycles have only one bleeding episode of a median duration of five days. Where secondary bleeding episodes occurred, they were shorter with a median duration of 1.5 days.

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. 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.

Evorel Sequi was not tested for effects on bone mineral density (BMD). However, information is available on the efficacy of the two constituents of Evorel Sequi (Evorel 50 and Evorel Conti).

After two years of treatment with Evorel 50, the increase in lumbar spine bone mineral density (BMD) was 4.46 ± 4.04 % (mean±SD). The percentage of women who maintained or gained BMD in the lumbar zone during treatment was 84%.

Evorel 50 also had an effect on hip BMD. The increase in BMD in the femoral neck was 1.26 ± 2.86 % and the percentage of women maintaining or gaining BMD in the femoral neck was 65%. In the total hip, the increase in BMD was 2.17 ± 2.33 % (mean±SD) with 93% women maintaining or gaining BMD.

After one year of treatment with Evorel Conti, the increase in lumbar spine bone mineral density (BMD) was 2.94 ± 2.62 % (mean±SD). The percentage of women who maintained or gained BMD in the lumbar zone during treatment was 90%.

Evorel Conti also had an effect on hip BMD. The increase in BMD in the femoral neck was 2.42 ± 3.04 % and the percentage of women maintaining or gaining BMD in the femoral neck was 82%. In the total hip, the increase in BMD was 1.73 ± 2.55 % (mean±SD) with 74% women maintaining or gaining in BMD.

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. The estradiol / estrone ratio on use of Evorel 50 and Evorel Conti is close to one, similar to pre-menopausal women. Estradiol circulates in the blood bound to sex hormone binding globulin (35-45%) and albumin (60-65%).

Norethisterone acetate is cleaved immediately on resorption to yield norethisterone. Norethisterone distributes widely in the body and circulates bound to sex hormone binding globulin (about 36%) and albumin (about 61%). It is metabolised mainly in the liver. Metabolites are conjugated with glucuronic or sulfuric acid. Conjugates are excreted in faeces and urine.

The metabolism of both estradiol and norethisterone in the liver is mediated primarily by the P450 enzyme system. See Section 4.5, Interactions with other medicinal products and other forms of interaction.

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

Estradiol pharmacokinetics

Upon use of an estradiol-only patch (Evorel 50), serum estradiol levels rise within 11 hours (Tmax, multiple application) from pre-treatment levels by an average of 316 pmol/L (86 pg/mL) (Cmax, multiple application). The 95% confidence interval ranges from 150 to 484 pmol/L (42-132 pg/mL). Levels decrease over 3.5 days to an average of 77 pmol/L (21 pg/mL). When patch use is discontinued, serum estradiol levels decrease with a half-life of 6.6 hours. 24 hours after patch removal, pre-treatment levels are again observed.

On use of an estradiol+norethisterone patch (Evorel Conti), serum estradiol levels rise from pre-treatment levels within 21 hours from patch change (Tmax, multiple application) by an average of 121 pmol/L (33 pg/mL) (Cmax, multiple applications). The 95% confidence interval for Cmax ranges from 77 to 165 pmol/L (21 to 45 pg/mL). 24 hours after patch removal, baseline levels are again observed.

Norethisterone pharmacokinetics

On first use of Evorel Conti by post-menopausal women, serum norethisterone levels rise over 37 hours (Tmax, single application) to 706 pmol/L (240 pg/mL)(Cmax, single application) and then decrease to 420 pmol/L (143 pg/mL) at day 3.5. On patch change, levels rise again over 22 hours (Tmax, multiple applications) to 756 pmol/L (257 pg/mL)(Cmax, multiple applications). When patch use is discontinued, norethisterone levels decrease with a half-life of ~15 hours.

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.

Norethisterone, like other progestogens, caused virilisation of female foetuses in rats and monkeys. After high doses of norethisterone embryolethal effects were observed.

Local tolerance studies with Evorel Conti were conducted in rabbits. In this model, Evorel Conti showed a mild irritation potential. It is recognised that the rabbit model is over-predictive of irritation of human skin.

Sensitisation studies with Evorel Conti in guinea pigs showed a weak sensitisation potential. Clinical trial experience with Evorel Conti use for up to two years gave no evidence of a clinically relevant sensitisation potential in humans.

6. Pharmaceutical particulars
6.1 List of excipients

EVOREL 50

Adhesive: acrylate-vinylacetate copolymer (Duro-Tak 387-2287)

Guar gum

Backing film: polyethylene terephthalate foil (Hostaphan MN19)

Release liner: siliconised polyethylene terephthalate foil, is removed before application

EVOREL CONTI

Adhesive: acrylate-vinylacetate copolymer (Duro-Tak 387-2287)

Guar gum

Backing film: polyethylene terephthalate foil (Hostaphan MN19)

Release liner: siliconised polyethylene terephthalate foil, is removed before application

6.2 Incompatibilities

No creams, lotions or powders should be applied to the skin area where the TDS is to be applied to prevent interference with the adhesive properties of EVOREL 50 TDS and EVOREL CONTI TDS.

6.3 Shelf life

EVOREL SEQUI has a shelf-life of 24 months, when stored at or below 25°C. The product can be used until the expiration date mentioned on the container.

6.4 Special precautions for storage

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

Keep out of reach and sight of children. This also applies to used and disposed TDSs.

6.5 Nature and contents of container

Each carton box has 8 TDSs in individual foil-lined sachets. The sachet comprises a 4 layer laminate including:

- surlyn-ionomer film on the inside,

- then aluminium foil,

- then polyethylene film,

- with a layer of bleached reinforced paper on the outside.

One EVOREL SEQUI box contains 4 EVOREL 50 TDS and 4 EVOREL CONTI TDSs.

6.6 Special precautions for disposal and other handling

The EVOREL SEQUI TDS should be placed on a clean, dry area of skin on the trunk of the body below the waist. Creams, lotions or powders may interfere with the adhesive properties of the EVOREL SEQUI TDS. The TDS should not be applied on or near to the breasts. The area of application should be changed, with an interval of at least one week allowed between applications to a particular site. The skin area selected should not be damaged or irritated. The waistline should not be used because excessive rubbing of the TDS may occur.

The TDS should be used immediately after opening the sachet. Remove one part of the protecting foil. Apply the exposed part of adhesive to the application site from the edge to the middle; avoid wrinkling of the TDS. The second part of the protective foil should now be removed and the freshly exposed adhesive applied. Wrinkling should again be avoided and the palm of the hand used to press the TDS onto the skin and to bring the TDS to skin temperature at which the adhesive effect is optimised. Do not touch the adhesive part of the TDS.

When using EVOREL SEQUI for the first two weeks, one of the EVOREL 50 TDSs should be applied and changed twice weekly. During the following two weeks of EVOREL SEQUI, one of the EVOREL CONTI TDSs should be applied, also to be changed twice weekly. The patient then starts again with a new box of EVOREL SEQUI.

To remove the EVOREL TDS, peel away an edge of the patch and pull smoothly away from the skin.

Any gum that remains on the skin after removal of EVOREL TDS may be removed by rubbing it off with the fingers, washing with soap and water or by using baby oil.

The EVOREL TDS should be disposed of in household waste (do not flush down the toilet).

7. Marketing authorisation holder

Janssen-Cilag Ltd

50 -100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

8. Marketing authorisation number(s)

PL 00242/0320

9. Date of first authorisation/renewal of the authorisation

25/09/2006

10. Date of revision of the text

15 June 2016