SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

FemSeven Sequi,

50 micrograms/10 micrograms/24 hours, transdermal patch

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Phase 1:

Each patch contains 1.5 mg of estradiol hemihydrate in a patch size of 15 cm , releasing 50 micrograms of estradiol per 24 hours.

Phase 2:

Each patch contains 1.5 mg of estradiol hemihydrate and 1.5 mg of levonorgestrel in a patch size of 15 cm², releasing 50 micrograms of estradiol and 10 micrograms of levonorgestrel per 24 hours.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Transdermal patch

Octagonal, transparent, flexible, rounded-edge transdermal matrix patch located on an oversized removable protective liner.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in postmenopausal women.

Experience of treating women older than 65 years is limited.

4.2 Posology and method of administration

For transdermal use.

Apply FemSeven Sequi once a week, i.e. replace each patch every 7 days. FemSeven Sequi is a continuous sequential hormone replacement therapy (HRT) without a treatment-off phase: as one patch is removed, the next is applied immediately.

Each treatment cycle with FemSeven Sequi consists of the successive application of two transdermal patches containing estradiol (phase 1) and then two transdermal patches containing estradiol and levonorgestrel (phase 2).

Accordingly, the following treatment cycle should be observed:

-    one phase 1 patch once a week for the first two weeks

-    then one phase 2 patch once a week for the following two weeks.

In women who are not taking HRT or women who switch from a continuous combined HRT product, treatment may be started on any convenient day.

In women transferring from a sequential HRT regimen, treatment should begin the day following completion of the prior regimen.

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.

Method of administration

FemSeven Sequi should be applied to clean, dry, healthy skin (which is neither irritated nor grazed), free from any cream, lotion or other oily product.

FemSeven Sequi should be applied to an area of skin without major skin folds, e.g. the buttocks or hips, and not subject to chafing by clothing (avoid the waist and also avoid wearing tight clothing that could loosen the transdermal patch).

FemSeven Sequi must not be applied either on or near the breasts. It is

advisable to avoid applying the patch to the same site twice. At least one week should be allowed to elapse between applications to the same site.

After opening the sachet, peel off one-half of the protective foil, being careful not to touch the adhesive part of the transdermal patch with the fingers. Apply directly to the skin. Now peel off the other half of the protective foil and press the patch on firmly with the palm of the hand for at least 30 seconds, concentrating on the edges. The pressure and the warmth of the hand are essential to ensure maximal adhesive strength of the patch.

It is possible to take a shower or have a bath without removing the transdermal patch.

Should a patch detach prematurely, before 7 days (due to vigorous physical activity, excessive sweating, abnormal chafing of clothing), it should be removed and a new patch of the same phase applied. To aid compliance it is recommended the patient then continues to change the patch on the usual day and according to the initial treatment cycle. This advice also applies if a patient forgets to change the patch on schedule. Forgetting a patch may increase the likelihood of break-through bleeding or spotting.

Once applied, the transdermal patch should not be exposed to sunlight.

Removal of the transdermal patch should be carried out slowly to avoid irritating the skin. In the event of some of the adhesive remaining on the skin, this can usually be removed by gently rubbing with a cream or an oily lotion. After use, fold FemSeven Sequi in two (with the adhesive surface to the inside) and dispose of it with normal household solid waste.

4.3 Contraindications

Known, past or suspected breast cancer ;

-    Known or suspected oestrogen-dependent malignant tumours (e.g. endometrial cancer) ;

-    Undiagnosed genital bleeding ;

-    Untreated endometrial hyperplasia ;

-    Previous or current venous thromboembolism (deep venous thrombosis, pulmonary embolism) ;

-    Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency, see section 4.4);

-    Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction) ;

-    Acute liver disease or a history of liver disease as long as liver function tests have failed to return to normal ;

-    Known hypersensitivity to the active substances or to any of the excipients ;

-    Porphyria.

4.4 Special warnings and precautions for use

•    For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.

•    Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women.

Medical examination/follow-up

•    Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by 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 appropriate imaging tools, e.g. mammography, should be carried out in accordance with currently accepted screening practices, modified according 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 FemSeven Sequi, in particular:

-    Leiomyoma (uterine fibroids) or endometriosis

-    Risk factors for thromboembolic disorders (see below)

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

-    Hypertension

-    Liver disorders (e.g. liver adenoma)

-    Diabetes mellitus with or without vascular involvement

-    Cholelithiasis

-    Migraine or (severe) headache

-    Systemic lupus erythematosus

-    A history of endometrial hyperplasia (see below)

-    Epilepsy

-    Asthma

-    Otosclerosis.

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 risk may remain elevated for at least 10 years.

•    The addition of a progestagen cyclically for at least 12 days per month/28 day cycle or continuous combined oestrogen-progestagen therapy in non-hysterectomised women prevents the excess risk associated with oestrogen-only HRT.

•    Break-through bleeding and spotting may occur during the first months of treatment. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

Breast cancer

The overall evidence suggests an increased risk of breast cancer in women taking combined oestrogenprogestagen and possibly also oestrogen-only HRT, that is dependent on the duration of taking HRT.

• The randomised placebo-controlled trial the Women’s Health Initiative study (WHI), and epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined oestrogen-progestagen for HRT that becomes apparent after about 3 years (see Section 4.8).

The excess risk becomes apparent within a few years of use but returns to baseline within a few (at most five) years after stopping treatment.

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

Ovarian cancer

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

Venous thromboembolism

•    HRT is associated with a 1.3-3 fold risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT than later (see Section 4.8).

•    Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients (see section 4.3).

•    Generally recognised risk factors for VTE include, use of oestrogens, older age, major surgery, prolonged immobilisation, obesity (BMI > 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.

As in all postoperative patients prophylactic measures need be considered to prevent VTE following surgery. If prolonged immobilisation is to follow elective surgery temporarily stopping HRT 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilised.

•    In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age, screening may be offered after careful 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 chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

•    If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).

Coronary artery disease (CAD)

• There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined oestrogen-progestagen or oestrogen-only HRT.

The relative risk of CAD during use of combined oestrogen+progestagen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to oestrogen+progestagen use is very low in healthy women close to menopause, but will rise with more advanced age.

Ischaemic stroke

• Combined oestrogen-progestagen and oestrogen-only therapy are associated with an up to 1.5-fold increase in risk of 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).

Other conditions

•    Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed.

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

•    Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).

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

4.5 Interaction with other medicinal products and other forms of interaction

The metabolism of oestrogens and progestagens 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).

Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones. Herbal preparations containing St John's wort (Hypericum Perforatum) may induce the metabolism of oestrogens and progestagens.

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

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

4.6 Fertility, Pregnancy and lactation

Pregnancy :

FemSeven Sequi is not indicated during pregnancy. If pregnancy occurs during medication with FemSeven Sequi, treatment should be withdrawn immediately.

Clinically, data on a large number of exposed pregnancies indicate no adverse effects of levonorgestrel on the fetus.

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

Lactation :

FemSeven Sequi is not indicated during lactation.

4.7 Effects on ability to drive and use machines

No effects on ability to drive and use machines have been observed.

4.8 Undesirable effects

The most frequently reported undesirable effects (> 10 %) in clinical trials during treatment with FemSeven Sequi were application site reactions. They usually disappeared 2 - 3 days after patch removal.

Other potential systemic undesirable effects are those commonly observed with oestrogen and progestin treatments.

Organ system	Common ADRs > 1/100, < 1/10	Uncommon ADRs > 1/1000, < 1/100	Rare ADRs > 1/10.000, < 1/1000
Body as a whole	Headache, Mastodynia	Fluid retention/oedema/weight increase/loss, fatigue, dizziness, leg cramps, migraine
Gastrointestinal	Nausea, Vomiting	Bloating, abdominal cramps	Cholelithiasis, cholestatic jaundice
Cardio-vascular		Hypertension
Reproductive	Breakthrough bleeding, spotting	Dysmenorrhoea, endometrial hyperplasia, benign breast tumours	Increase in size of uterine fibrosis

Psychiatric

Increase/ decrease in libido

Depression

Breast cancer risk

An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestagen therapy for more than 5 years. Any increased risk in users of oestrogen-only therapy is substantially lower than that seen in users of oestrogen-progestagen combinations.

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

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

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

years’ use___

Age range (years)	Additional cases per 1000 never-users of HRT over a 5 year period1	Risk ratio & 95%CI#	Additional cases per 1000 HRT users over 5 years (95%CI)
Oestroge	n only HRT
50-65	9-12	1.2	1-2 (0-3)
Combined oestrogen-progestagen
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.

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

Age range (yrs)	Incidence per 1000 women in placebo arm over 5 years	Risk ratio & 95%CI	Additional cases per 1000 HRT users over 5 years (95%CI)
CEE oestrogen-only
50-79	21	0.8 (0.7 - 1.0)	-4 (-6 - 0)2
CEE+MPA oestrogen & progestagen^
50-79	14	1.2 (1.0 - 1.5)	+4 (0 - 9)

JWhen 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 risk Postmenopausal women with a uterus

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

In women with a uterus, use of oestrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4).

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

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

Ovarian cancer

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

Risk of venous thromboembolism

HRT is associated with a 1.3-3-fold increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of using HT (see section 4.4). Results of the WHI studies are presented:

WHI Studies - Additional risk of VTE over 5 years’ use

Age range (years)	Incidence per 1000 women in placebo arm over 5 years	Risk ratio and 95%CI	Additional cases per 1000 HRT users
Oral oestrogen-only3
50-59	7	1.2 (0.6-2.4)	1 (-3-10)
Oral combined oestrogen-progestagen
50-59	4	2.3 (1.2-4.3)	5 (1-13)

Risk of coronary artery disease

The risk of coronary artery disease is slightly increased in users of combined oestrogen-progestagen HRT over the age of 60 (see section 4.4).

Risk of ischaemic stroke

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

This relative risk is not dependent on age or on duration of use, but as the baseline risk is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age, see section 4.4.

WHI studies combined - Additional risk of ischaemic stroke⁴ over 5 years’ use

Age range (years)	Incidence per 1000 women in placebo arm over 5 years	Risk ratio and 95%CI	Additional cases per 1000 HRT users over 5 years
50-59	8	1.3 (1.1 1.6)	3 (1-5)

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

-    Gall bladder disease.

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

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

4.9 Overdose

The mode of administration makes significant overdose unlikely. Signs of an overdose are generally breast tenderness, swelling of the abdomen/pelvis, anxiety, irritability, nausea and vomiting. Removal of the transdermal patches is all that is required should it occur.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group:

Progestogens and oestrogens for sequential administration

ATC code: G03FB 09 Transdermal route.

Estradiol: the active ingredient, synthetic 17P-estradiol is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of oestrogen production in postmenopausal women, and alleviates menopausal symptoms.

Levonorgestrel: as oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer. The addition of levonorgestrel, a synthetic progestin, greatly reduces the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

Under treatment with FemSeven Sequi, relief of menopausal symptoms was achieved during the first weeks of treatment.

At the end of one year treatment, 82.7% of women with bleeding reported regular withdrawal bleeding. The day of onset was rather constant 1 - 2 days before the end of the cycle with a mean duration of 4 - 5 days. The percentage of women with breakthrough bleeding and/or spotting was 17.3%. During the 13 cycles of therapy, 19.4% of women treated presented with amenorrhoea.

5.2 Pharmacokinetic properties

With transdermal administration there is no hepatic first-pass effect as observed with oral administration; estradiol reaches the bloodstream in unchanged form and in physiological amounts. Therapeutic estradiol concentrations are comparable to those observed in the follicular phase.

After application of the transdermal system containing estradiol alone (phase 1), therapeutic concentrations of estradiol are achieved within 4 hours; these concentrations are maintained throughout the entire application period of the transdermal patch (7 days). When estradiol is administered simultaneously with levonorgestrel (phase 2), the pharmacokinetics of estradiol are unaltered by levonorgestrel.

Peak plasma concentrations of estradiol (C_max) range from 58 to 71 pg/ml, average plasma concentration (C_av) is between 29 to 33 pg/ml and trough plasma concentration (Cpre) is about 21 pg/ml during both treatment phases. After removal of the transdermal patch, estradiol concentrations return to their baseline values within 12 to 24 hours.

After application of the transdermal system containing estradiol and levonorgestrel at a dose of 10 pg/day (phase 2), the maximum plasma concentration of levonorgestrel (C_max) range from 156 to 189 pg/ml and is reached within 63 to 91 hours (t_max). The average plasma concentration of levonorgestrel (C_av) during a 7-day period is between 121 and 156 pg/ml and the trough plasma concentration (C_pre) levels are 118 pg/ml. The half-life of levonorgestrel after transdermal application is approximately 28 hours (minimum: 16 hours, maximum: 42 hours).

After percutaneous absorption, levonorgestrel is bound to plasma proteins, i.e. albumin (50%), and SHBG (47.5%). Affinity to SHBG is higher than for other commonly used progestogens.

5.3 Preclinical safety data

Animal studies with estradiol and levonorgestrel have shown expected estrogenic and gestagenic effects.

There are no preclinical data of relevance to the prescriber that are additional to those already included in other sections of the SPC (see notably section 4.6).

6 PHARMACEUTICAL PARTICULARS

Transparent polyethylene terephthalate (PET) foil Styrene-isoprene-styrene block copolymer, glycerine esters of completely hydrogenated resins Siliconized transparent polyethylene terephthalate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Do not store above 30°C

6.5 Nature and contents of container

Each phase 1 or phase 2 transdermal patch is contained in an individual sachet (Paper/PE/aluminium/ethylene copolymer). Each carton contains 4 or 12 sachets consisting of 2 x phase 1 patches and 2 x phase 2 patches or 6 x phase 1 patches and 6 x phase 2 patches.

Not all pack sizes may be marketed.

10

1

Taken from baseline incidence rates in developed countries

2

Study in women with no uterus

⁴ No differentiation was made between ischaemic and haemorrhagic stroke.