SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

FemSeven Conti,

50 micrograms / 7 micrograms / 24 hours, transdermal patch

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each patch contains 1    .5 mg of estradiol hem ihydrate and 0.525 mg

levonorgestrel in a patch size of 15 cm2, releasing 50 micrograms of estradiol and 7 micrograms of levonorgestrel per 24 hours.

For the full list of excipients, see 6.1.

3    PHARMACEUTICAL FORM

Transdermal patch

Octagonal, tr ansparent, flex ible, r ounded-edge transder mal 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 more than one year after menopause.

Experience of treating women older than 65 years is limited.

4.2 Posology and method of administration

For transdermal use.

FemSeven C onti has to be appl ied once a wee k, i .e. each pat ch i s repl aced every 7 days. FemSeven Conti is a continuous combined hormone replacement therapy (HRT ) treat ment without a tr eatment-off phase: as one patc h is removed, the n ext is a pplied im mediately. Forgetting to c hange a pa tch on schedule may increase the likelihood of break-through bleeding or spotting.

In women with amenorrhoea and not taking HRT or women transf erring from another continuous co mbined HRT produc t, treatment with FemSeven C onti may be started on any convenient day.

In women transferring from sequential HRT re gimens, treatment should start right after their withdrawal bleeding has ended.

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 Conti should be applied to clean, d ry, he althy s kin (which is neither i rritated no r grazed), fr ee f rom any c ream, l otion or ot her oily product.

FemSeven Conti should be applied to an ar ea of skin without major sk in folds, i.e. the buttocks or hips, and not subject to chafing by clothing (avoid the wai st and al so av oid weari ng t ight clothin g that could loosen the transdermal patch).

FemSeven Conti m ust not be a pplied e ither on or n ear the b reasts. It is advisable to avoid applying the patch to the same site twice running. At least one week should be allowed to elapse between applications to the same site.

After opening the sachet, one-half of the protective foil is peeled off, b eing careful not to touch th e adhesive part of the tra nsdermal pa tch with the fingers. The n the p atch must be applied dire ctly to the s kin. After tha t the other hal f of the p rotective foil is p eeled off, an d the p atch must be fi rmly pressed with the palm of the hand for at least 3 0 seconds, concentrating on the ed ges. Pressure and t he warmt h of t he hand are essent ial t o ensure maximal adhesive strength of the patch.

It is possible to take a shower or have a bath without removing the transdermal patch. In the event th at the transd ermal patc h should become deta ched prematurely, i.e. befo re the seventh da y (du e to vig orous ph ysical a ctivity, excessive sweatin g, abn ormal chafing of clothing), a new pat ch should be applied (to aid compliance it is recommended that the patient then continues to change the patch on the original scheduled day).

Once applied, the transdermal patch has to be covered b y clothes to avoid direct exposure to sunlight.

Removal o f the transd ermal patch should be c arried out slowl y 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, FemSeven Conti is to be folded in two (with the adhesive surface to the inside) and disposed of with normal household solid waste.

4.3 Contraindications

Known, past or suspected breast cancer;

-    Known o r suspected oestrogen-dependent malignant tum ours (e .g. endometrial cancer);

-    Undiagnosed genital bleeding;

-    Untreated endometrial hyperplasia;

-    Previous idiopathic or current venous thro mboembolism (d eep 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 l iver di sease, or a hi story of l iver di sease as l ong as l iver fun ction tests have failed to return to normal;

- Known h ypersensitivity to the ac tive substa nces or to a    ny 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 ris ks an d benefits s hould be und ertaken at least a nnually and HRT should only be continued as long as the benefit outweighs the risk. Evidence re garding t he ri sks associ ated wi th HR T i n t he t reatment of premature menopause is lim ited. Due to th e lo w level of absolute ris k in younger women, howev er, the balance of ben efits and risk s for these wom en may be more favourable than in older women.

Medical examination/follow-up

Before initia ting or re instituting HRT, a c omplete pe rsonal a nd famil y medical histor y should be tak en. P hysical (includin g pelvic and bre ast) examination should be guided b y this and by the c ontraindications and warnings for use. Durin g treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised wh at ch anges in their b reasts should be reported to their doctor or nurse (see " Breast can cer" bel ow). Investigations, includin g appropri ate imaging tools, e. g mammography, should be c arried out in accordan ce with currently accepted screening practices, modified to the clinical needs of the individual.

Conditions which need supervision

If an y of t he fol lowing condi tions are pres ent, have o ccurred p reviously, and/or have b een a ggravated du ring p regnancy o r previous hor mone treatment, the patient sh ould be closel y supervised. It should be taken i nto account that thes e condi tions m ay r ecur or be aggravated du ring treat ment with Fem7 Conti, in particular:

-    Leiomyoma (uterine fibroids) or endometriosis

-    Risk factors for, thromboembolic disorders (see below)

-    Risk factors f or o estrogen-dependent t umours, e.g. 1^st d egree he redity f or 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 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 and carcinoma

• In women with a n intact uterus, the risk of endometrial hyperplasia and carcinoma i s i ncreased when oest rogens are administrated al one for prolonged periods.. the reported increase in endometrial cancer risk among oestrogen-only users varies from 2-to 12-fold greater compared with nonusers, dependin g on the duration of treatment and oestro gen dose (se e 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 months/28 day cycle or continuous combined oestrogen-progestagen therapy in non-hysterectomised wo men prevent s t he ex cess ri sk associ ated wi th oestrogen-only HRT.

•    Break-through bleeding and spotting may occur during the first months of treatment. If break-through bleeding or spottin g appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investig ated, which m ay include a n endom etrial biops y to exclude endometrial malignancy.

Breast cancer

The ove rall evi dence suggests an i ncreased ri sk of b reast cancer i n hysterectomised w omen u sing o estrogen-progestagen a nd p ossibly also oestrogen-only HRT, that is dependant on the duration of taking HRT.

The randomised placebo-controlled trial the Women's Health Initiative Study (WHI) and epi demiological 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 ex cess ri sk beco mes apparent wi thin a few years of use but ret urns to baseline within a few (at most five) years after stopping treatment.

HRT, especi ally oest rogen/progestagen combined t reatment, i ncreases t he density of mammographic images which may adversely affect the radiological detection of breast cancer.

Ovarian cancer

Ovarian c ancer i s mu ch rare r t han br east can cer. Long t erm (at l east 5-10 years) use of oestrogen-only HRT products has been associated with a slightly increased risk of ovari an cancer (s ee section 4.8). Some studies includin g the WHI trial suggest that the long-term use of c ombined HRTs may confer a similar or slightly smaller risk (see section 4.8).

Venous thromboembolism

•    HRT is associated w ith a 1.3-3 fo ld_risk of developin g veno us thromboembolism (VTE), i.e. de ep vein th rombosis or pul monary 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 th is risk. HRT is therefore contraindicated in thes e patients (see section 4.3).

•    Generally recognised risk factors for VTE include, use of o estrogens, older age, major surgery, prolonged immobilisation, obesity (BMI > 30 kg /m2), pregnancy/postpartum p eriod, s ystemic lupus e rythematosus (S LE) and cancer. There is no cons ensus about the possible role of va ricose veins in VTE.

As in all postoperative patients, prophylactic measures need be consider ed to prevent VTE following surgery, if prolonged immobilisation is to follow elective sur gery te mporarily stoppin g HRT for 4 to 6 week s e arlier i s recommended. Tr eatment should not be r estarted until the wo man is completely mobilised.

•    In women with no perso nal history of VTE but with a first-de gree relative with a history of thrombosis at young age, screening may be offered after careful counsellin g reg arding its limitations (onl y a proportion of thrombophilic defects are identified by screening).

If a thrombophilic defect is identified which s egregates 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 alread y on c hronic anticoa gulant tr eatment require c areful consideration of the benefit-risk of use of HRT.

• If VTE develops after initiating therapy, the dru g should be discontinued. Patients should b e 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 infa rction i n wom en with or wit hout ex isting CAD wh o 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 a ge, the number of extra cas es of CAD due to oestro gen +progestagen use is very low in health y wo men close to m enopause, but will rise with more advanced age.

•

Ischaemic stroke

• Combined oest rogen-progestagen and o estrogen-only t herapy are associated with an up to 1.5-fold increase in risk in ischaemic stroke. The relative risk does not ch ange with age or time since menopause. However, as the bas eline risk of stroke is stro ngly age-dependant, the ov erall 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 la rge increases of pla sma triglycerides leading to pa ncreatitis have been reported with oestrogen therapy in this condition.

•    Oestrogens increase thyroid binding globulin (TBG), leading to inc reased

circulating total th yroid horm one, as m easured b y protein-bound iodine (PBI), T4 lev els (by column or by radio-immunoassay) or T3 lev els (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and fre e T3 concentr ations ar e unaltered. Othe r bindin g proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex horm one-binding globulin (S HBG) leading to i ncreased ci rculating corticosteroids a nd sex st eroids, resp ectively. Free or bi ological a ctive hormone con centrations ar e unch anged. Other plasma proteins may be increased (a ngiotensinogen/renin substra te, a lpha-I-antitrypsin, ceruloplasmin).

•    HRT use does not im prove cognitive function. T here is some evidence o f

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 oe strogens and pr ogestagens m ay be i ncreased by concomitant use of subs tances known to induce drug-metabolising enzymes, specifically cytochrome P 450 enzymes, such as anticonvuls ants ( e.g. phenobarbital, phenytoin, carbamazepine) and antiinfectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

Ritonavir and nelfinavir, althou gh k nown as stron g inhibitors, b y cont rast exhibit inducing properties when used concomitantly with steroid hormones.

Herbal prep arations containing St John’s wort (H ypericum Perforatum) may induce the metabolism of oestrogens and progestagens.

At transdermal administration, the first-pass effect in the liver is avoided and, thus, transdermall y appli ed oestro gens and pro gestagens HRT m ight 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 Conti is not indicated during pregnancy. If pregnancy occurs during treatment with FemSeven Conti, treatment should be withdrawn immediately.

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

The re sults of most e pidemiological studie s to da te tha t a re re levant to inadvertent fo etal ex posure to co mbination of oestro gens + pro gestagens indicate no teratogenic or foetotoxic effect.

Lactation

FemSeven Conti 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 rep orted undesirabl e effects (> 10 %) in clinical tri als during treatment with FemSeven Conti were application site reactions, breast tenderness a nd bl eeding or spottin g. The a pplication site re actions were mostly mild s kin re actions and usuall y disappeared 2 - 3 days after patch removal. In the majority of cases breast tenderness was reported as mild or moderate and tends to decrease during treatment time.

Other potential systemic undesirable effects are those commonly observed with oestrogen and progestin treatments. ¹

Organ s ystem class (e .g. MedDRA SOC level)	Common ADRs > 1/100, < 1/10	Uncommon ADRs > 1/1000, < 1/100	Rare ADRs > 1/10.000, < 1/1000
General disorders	F	luid retention/ oedema/weight increase/loss, fatigue, leg cramps
Nervous system disorders	Headache Di	zziness, migraine
Gastro intestinal disorders	Dyspepsia Bloati	ng , abdominal cr amps, nausea	Cholelithiasis, cholestatic jaundice
Cardiovascula r disorders	H	ypertension
Reproductive system a nd breast disorders	Mastodynia End(	>m etrial hyperplasia, benign breast tissue changes,	Increase i n si ze of uterine fibrosis
Psychiatric disorders	Depression

Breast cancer risk

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

Age range (years)	Additional cases per 1000 nev er-users of HRT over a 5 year-period12	Risk ra tio & 95%CI#	Additional cases per 1 000 HRT users over 5 years (95%CI)
Oestrogen only HRT
50-65	9-12	1.2	1-2 (0-3)
Combined oestrogen-progestagen
50-65	9-12	1.7	6 (5-7)
#Overall risk ratio. The risk ra tio is not constant but will inc rease with inc reasing duration on use Note: S ince the bac kground incidence of br east cance r differs b y EU c ountry, 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 ra tio & 95%CI	Additional cases per 1 000 HRT users over 5 years (95%CI)
CEE oestrogen-only
50-79	21	0.8 (0.7 - 1.0)	-4 (-6 - 0)13
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 prio r to the st udy t here w as no i ncreased risk app arent duri ng t he fi rst 5 years of treatment: after 5 years the risk was higher than in non-users.

2    ¹Taken from baseline incidence rates in developed countries

3    ¹WHI 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 endo metrial c ancer risk is about 5 in eve ry 1000 wo men 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 ca ncer in e pidemiology studie s varie d from b etween 5 and 55 extra cases dia gnosed in every 1000 wo men between the ages of 50 and 65.

Adding a progestagen to oestrogen-only therapy for at least 12 da ys per cycle can prevent this in creased risk. In the Million Women Study the use of five years of co mbined (s equential or c ontinuous) HRT did not increase risk of endometrial cancer (RR of 1.0 (0.8-1.2)).

Ovarian cancer

Long-term use of oestro gen-only and co mbined 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 throm boembolism (VTE), i.e. de ep vein throm bosis 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 ra nge (years)	Incidence per 1000 women in placebo arm over 5 years	Risk ra tio a nd 95%CI	Additional cases per 1000 HRT users
Oral oestrogen-only*4
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 ri sk of co ronary artery disease i s sl ightly increased i n users of combined oestrogen-progestagen HRT over the age of 60 (see section 4.4).

Risk of ischaemic stroke

• The use of oestro gen-only and oestro gen + pro gestagen the rapy is associated with an up to 1.5 fold in creased 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*5 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 ov er 5 years
50-59	8	1.3 (1.1 1.6)	3 (1-5)

4 *Study in women with no uterus

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

Other adve rse re actions have been re ported in a ssociation with oestrogen/progestagen treatment:

-    Gall bladder disease.

-    Skin a nd subc utaneous disorde rs: c hloasma, ery thema m ultiforme, erythema nodosum, vascular purpura.

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

4.9 Overdose

The method 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:

Progestagens and oestr ogens, co mbinations, le vonorgestrel and oestro gen ATC code: G03F A11

FemSeven Conti contain s a continuous combined combination of o estrogen and pro gestagen fo r co ntinuous use, com bining estr adiol hem ihydrate and levonorgestrel.

□Estradiol: The active ingredient, synthetic 17P-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of oestro gen produ ction in m enopausal women, and alleviates menopausal symptoms.

□ Levonorgestrel: As oe strogens pro mote th e growth of th e endo metrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer. The addition of levonorg estrel greatly reduces the oestro gen-induced risk of endometrial hyperplasia in non-hysterectomised women.

Clinical trial information

Relief of oestrogen-deficiency symptoms and bleeding patterns:

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

•    FemSeven Conti is a continuous-com bined HRT given with the intent of avoiding t he regular withdrawal bl eeding as sociated wi th c yclic o r sequential HRT.

Amenorrhoea was seen in 59-68 % of the women during months 10-12 of treatment. Irregular_bleeding and/or spotting appeared in 28 -39 % of the women during the first three months of treatment and in 37 % durin g months 10-12 of treatment.

5.2 Pharmacokinetic properties

By transdermal administration there is no hepatic first-pass effect as observed with oral administration; estradiol reaches the bloodstream in unchanged form and in ph ysiological am ounts. Ther apeutic estradiol concentr ations are comparable to those observed in the follicular phase.

After continuous appl ication of FemSeven Conti, m aximum pl asma concentration of e stradiol (C _max) reaches 82 pg/ml and ave rage pl asma concentration (C_av) is about 34 pg/ml. Trough plasma concentration (Ctr_ough) at the e nd of a 7 -day wearing p eriod is 27 p g/ml. Aft er removal o f the transdermal pa tch, e stradiol c oncentrations re turn to the ir ba seline va lues within 12 to 24 hours.

The maximum plasma concentration of levonorgestrel is reached after three to four days and C _max is approx imately 113 pg/ml at stead y state. Th e average plasma concentration of levonorgestrel during a 7-day period is approximately 88 pg/ml and trough plasma concentration (C_trough) reaches 72 pg/ml.

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

5.3 Preclinical safety data

In experimental animals estradiol displayed an embryolethal effect already at relatively low doses; malformations of the urogenital tract and feminisation of male foetuses were observed. Levonorgestrel displayed an embryolethal effect in animal experiments and, in high doses, a virilising effect on female fetuses. Because of marked differences between animal species and b etween animals and humans, preclinical results are of limited predictive value for the treatment of humans with oestrogens.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Backing layer: Polyethylene terephthalate (PET) foil.

Adhesive matrix:    Styrene-isoprene-styrene block copol ymer, glycerine

esters of completely hydrogenated resins.

Protective liner:    Siliconized polyethylene terephthalate (PET) foil.

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

Sachet (Paper/PE/aluminium/ethylene copolymer). Carton of 4 or 12 sachets.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Teva UK Limited Brampton Road Hampden Park Eastbourne East Sussex BN22 9AG

8    MARKETING AUTHORISATION NUMBER(S)

PL 00289/1802

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

5 November 2002/ 5 November 2007

10 DATE OF REVISION OF THE TEXT

06/03/2013

1

   An up to 2 -fold increased risk of havin g breast cancer diagnosed is reported in women ta king co mbined oestro gen-progestagen ther apy for more than 5 years.

•    Any inc reased ris k in users of oest rogen-only the rapy is substa ntially 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 lar gest r andomised placebo-controlled trial ( WHI-study) and largest epidemiological study (MWS) are presented.