SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Nuvelle™ Continuous

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains:

Estradiol (as hemihydrate)    2.0 mg

Norethisterone acetate    1.0 mg

Excipient with known effect

Lactose monohydrate. Each tablet contains 50.3 mg lactose monohydrate. For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablets Each tablet is pink.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Hormone replacement therapy (HRT) for estrogen deficiency symptoms in postmenopausal women with an intact uterus more than 1 year post menopause.

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

4.2 Posology and method of administration

• Posology

Nuvelle Continuous is a continuous combined HRT product.

One tablet is taken daily. Each pack covers 28 days of treatment. It does not matter at what time of day the woman takes her tablet, but once she has selected a particular time, she should keep to it every day. Treatment is continuous, which means that the next pack follows immediately without a break.

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.

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

•    How to start Nuvelle Continuous

Women without prior hormone replacement therapy and those changing from another continuous combined hormone replacement therapy may start Nuvelle Continuous at any time.

Women changing from a continuous sequential or cyclical hormone replacement therapy should complete the cycle and then change to Nuvelle Continuous without a break in therapy.

•    Missed or lost tablets

If the woman forgets to take a tablet at the usual time she may take it within the following 12 hours. If the woman is more than 12 hours late the forgotten tablet should not be taken and the remaining tablets taken at the usual time on the right days. A missed dose may lead to breakthrough bleeding or spotting.

Children

Not recommended for children

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 listed in section 6.1

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 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 Nuvelle Continuous, 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

-    Hereditary angioedema

Reasons for immediate withdrawal of therapy:

Therapy should be discontinued if or when a contraindication 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 progestogen cyclically for at least 12 days per month/28 day 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-progestagen 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 substantially lower than that found in users of oestrogen-progestagen 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. 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- to 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 use than later (see Section 4.8).

•Generally recognised risk factors for VTE include use of oestrogens, older age, major surgery, prolonged immobilisation obesity (BMI> 30kg/m²), pregnancy/post-partum 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.

•    Patients with 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, 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.

•    Those women already on 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-progestogen or oestrogen-only HRT.

Combined oestrogen-progestagen therapy

The relative risk of CAD during use of combined oestrogen-progestogen 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-progestogen use is very low in healthy women close to menopause, but will rise with more advanced age.

Oestrogen-only

Randomised controlled data found no increased risk of CAD in hysterectomised women using oestrogen-only therapy.

Ischaemic 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)

Other conditions

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

•    Women with pre-existing hypertriglyceridaemia should be followed closely during 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).

•    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.

•    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.

•    Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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).

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 progestogens.

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

4.6 Fertility, pregnancy and lactation

•    Pregnancy

Nuvelle Continuous is not indicated during pregnancy. If pregnancy occurs during medication with Nuvelle Continuous 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 OC 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

Nuvelle Continuous is not indicated during breast-feeding.

4.7 Effects on ability to drive and use machines

None known

4.8 Undesirable effects

The following undesirable effects have been reported in users of Nuvelle Continuous and other oral HRT preparations.

Neoplasms benign, malignant and unspecified

Breast cancer*, Endometrial cancer*

Immune system disorders

Hypersensitivity reaction, Exacerbation of hereditary angioedema Metabolism and nutrition disorders

Porphyria aggravated, Increased or decreased weight, Increased appetite, Carbohydrate tolerance decreased

Psychiatric disorders

Anxiety/ depressive symptoms, Decreased or increased libido Nervous system disorders

Migraine, Headache, Dizziness, Fatigue, Chorea, Stroke*

Eye disorders

Visual disturbances, Intolerance to contact lenses

Cardiac disorders

Palpitations, Myocardial infarction*

Vascular disorders

Hypertension, Thrombophlebitis, Venous Thromboembolism*

Respiratory, thoracic and mediastinal disorders Epistaxis

Gastrointestinal disorders

Dyspepsia, Abdominal pain, Vomiting, Nausea, Bloating, Flatulence.

Hepatobiliary disorders

Gall bladder disease including Cholestasis

Skin and subcutaneous tissue disorders

Rashes, various Skin disorders, Chloasma (including Pruritus, Eczema, Urticaria, Acne, Hirsutism, Hair loss, Erythema nodosum, Erythema multiforme, Rash haemorrhagic), Chloasma (see section 4.4)

Musculoskeletal and connective tissue disorders Muscle cramps, Leg pain

Renal and urinary disorders Cystitis-like symptom

Reproductive system and breast disorders

Increased size of uterine fibroids, Vaginal candidosis, Uterine cervical erosions, Changes in vaginal bleeding pattern and abnormal bleeding or flow, Breakthrough bleeding, Spotting (bleeding irregularities usually subside during continued treatment), Dysmenorrhoea, Changes in vaginal secretion, Premenstrual-like syndrome, Breast secretion, Breast tenderness, enlargement or pain,

General disorders and administration site conditions Oedema

*Please see further information below.

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 of use

Age range (years)	Additional cases per 1000 never-users of HRT over a 5 year period a	Risk ratio & 95% CI b	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-progestagen
50 - 65	9 - 12	1.7	6 (5 - 7)

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 of use

Age	Incidence per 1000 women	Risk ratio & 95%	Additional cases per
range	in placebo arm over 5	CI	1000 HRT
(years)	years		users

Oral oestrogen-only a
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)
a 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-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 stroke^a over 5 years of 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)
a No differentiation was made between isc		laemic and haemorrhagic stroke.

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

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

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

Nausea and vomiting may occur with an overdose.

There are no specific antidotes and treatment should be symptomatic. Withdrawal bleeding may occur in females.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Progestogens and estrogens, sequential preparations, sex hormones and modulators of the genital system, ATC: G03FB05

•    Estradiol/estradiol valerate:

Nuvelle Continuous contains the active ingredient, synthetic 17^-estradiol which 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.

•    Progestogen:

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

•    Prevention of osteoporosis:

-    Oestrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass.

-    The effect of oestrogens on the bone mineral density is dose-dependent. Protection appears to be effective for 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.

5.2 Pharmacokinetic properties

17B-estradiol is readily and completely absorbed from the gastrointestinal tract. Following ingestion of one tablet, maximum drug serum levels of estradiol and norethisterone were 85.2pg/ml and 13.5ng/ml after 9 hours and 1 hour, respectively. Estradiol is converted by the liver and other tissues to estrone, estriol and other metabolites. Estradiol is excreted into the bile and is then reabsorbed from the intestine. During this enterohepatic circulation degradation of the estradiol occurs. 90-95% of estradiol is excreted in the urine as biologically inactive glucuronides and sulphate conjugates.

Norethisterone acetate is rapidly absorbed from the gastrointestinal tract and transformed to norethisterone. It is then metabolised and excreted as glucuronides and sulphate conjugates which are eliminated with the urine and faeces. Approximately half the dose is recovered in the urine in the first 24 hours.

5.3 Preclinical safety data

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

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Nuvelle Continuous contains the following excipients: lactose monohydrate, maize starch, pre-gelatinised maize starch, povidone 25 000, talc, magnesium stearate (E572), methylhydroxypropyl cellulose, macrogol 6000, titanium dioxide (E171), ferric oxide pigment, red (E172).

6.2    Incompatibilities

None

6.3    Shelf life

3 years

6.4    Special precautions for storage

None

6.5    Nature and contents of container

Container consists of 20pm hard tempered aluminium foil and 250pm transparent PVC film blister strips packed in a cardboard carton.

Presentation: Carton containing memo-packs of either 1 x 28 tablets or 3 x 28 tablets.

6.6    Special precautions for disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

Bayer PLC Bayer House Strawberry Hill Newbury Berkshire RG14 1JA United Kindgom

8    MARKETING AUTHORISATION NUMBER(S)

PL 00010/0552

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

25/02/2008

10    DATE OF REVISION OF THE TEXT

14/03/2016