Elleste Duet 2 mg

One orange tablet contains 2 mg estradiol (as estradiol hemihydrate).

One grey tablet contains 2 mg estradiol (as estradiol hemihydrate) and 1 mg norethisterone acetate.

For excipients, see 6.1.

Film coated tablets.

Hormone Replacement Therapy (HRT) for estrogen deficiency symptoms in post- and peri- 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 of treating women older than 65 years is limited.

This product is a continuous sequential HRT. One orange tablet to be taken daily for the first 16 days, followed by one grey tablet for the next 12 days. A new cycle should then begin without any break. Therapy may start at any time in patients with established amenorrhoea or who are experiencing long intervals between spontaneous menses. In patients who are menstruating it is advised that therapy starts on the first day of bleeding. Patients changing from another cyclical or continuous sequential preparation should complete the cycle and may then change to Elleste Duet 2 mg without a break in therapy. Patients changing from a continuous combined preparation may start therapy at any time if amenorrhoea is established, or otherwise start on the first day of bleeding.

Elderly

There are no special dosage requirements in elderly patients.

Children

Not to be used in children.

Elleste Duet tablets are available in two strengths: Elleste Duet 1 mg (containing 1 mg estradiol and 1 mg norethisterone acetate) and Elleste Duet 2 mg (containing 2 mg estradiol and 1 mg norethisterone acetate). For initiation and continuation of treatment of post- and peri-menopausal symptoms, the lowest effective dose for the shortest duration (see also Section 4.4) should be used.

Missed Tablet: If a tablet is missed it should be taken within 12 hours of when normally taken; otherwise the tablet should be discarded, and the usual tablet should be taken the following day. If a tablet is missed there is an increased likelihood of breakthrough bleeding or spotting.

Known, past or suspected breast cancer;

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

Undiagnosed genital bleeding;

Untreated endometrial hyperplasia;

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

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.

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.

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 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 wth Elleste Duet 2 mg, in particular:

- Leiomyoma (uterine fibroids) or endometriosis

- A history of, or risk factors for, thromboembolic disorders (see below)

- Risk factors for estrogen 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

The risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods (see section 4.8). The addition of a progestogen for at least 12 days per cycle in non-hysterectomised women greatly reduces this risk.

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

A randomised placebo-controlled trial, the Women's Health Initiative Study (WHI), and epidemiological studies, including the Million Women Study (MWS), have reported an increased risk of breast cancer in women taking estrogens, estrogen-progestogen combinations or tibolone for HRT for several years (see Section 4.8). For all HRT, an excess risk becomes apparent within a few years of use and increases with duration of intake but returns to baseline within a few (at most five) years after stopping treatment.

In the MWS, the relative risk of breast cancer with conjugated equine estrogens (CEE) or estradiol (E2) was greater when a progestogen was added, either sequentially or continuously, and regardless of type of progestogen. There was no evidence of a difference in risk between the different routes of administration.

In the WHI study, the continuous combined conjugated equine estrogen and medroxyprogesterone acetate (CEE + MPA)_product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.

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

Venous Thromboembolism

HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. One randomised controlled trial and epidemiological studies found a two to threefold higher risk for users compared with non-users. For non-users, it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate = 4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later.

Generally recognised risk factors for VTE include a personal history or family history, severe obesity (BM>30 kg/m²) and systemic lupus erythematosus (SLE). There is no consensus about the possible role of varicose veins in VTE.

Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. Those 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 thromboembolic symptom (e.g., painful swelling of a leg, sudden pain in the chest, dyspnea).

Coronary Artery Disease

There is no evidence from randomised controlled trials of cardiovasular benefit with continuous combined conjugated estrogens and medroxyprogesterone acetate (MPA). Two large clinical trials (WHI and HERS i.e. Heart and Estrogen/progestin Replacement Study) showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products there are only limited data from randomised controlled trials examining effects in cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.

Stroke

One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated estrogens and MPA. For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 11 per 1000 women aged 60-69 years. It is estimated that for women who use conjugated estrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate = 1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.

Ovarian Cancer

Long-term (at least 5 to 10 years) use of estrogen-only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRT confers a different risk than estrogen-only products.

Other conditions

Estrogens may cause fluid retention and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients in Elleste Duet 2 mg is increased.

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

Estrogens increase thyroid binding globulin (TBG) levels, 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-1-antitrypsin, ceruloplasmin).

There is no conclusive evidence for improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65. It is unknown whether the findings apply to younger post-menopausal women or other HRT products.

There is an increased risk of gall bladder disease in women receiving post-menopausal estrogens.

In rare cases benign, and in even rarer cases malignant liver tumours leading in isolated cases to life-threatening intra-abdominal haemorrhage have been observed after the use of hormonal substances such as those contained in Elleste Duet 2mg. If severe upper abdominal complaints, enlarged liver or signs of intra-abdominal haemorrhage occur, a liver tumour should be considered in the differential diagnosis.

Elleste Duet 2mg Tablets contain sunset yellow colouring (E110) which can cause allergic-type reactions, including asthma. This allergy is more common in people who are allergic to aspirin.

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

The metabolism of estrogens 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 estrogens and progestogens.

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

The requirement for oral anti-diabetics or insulin can change as a result of the effect on glucose tolerance. Some laboratory tests can be influenced by estrogens such as tests for thyroid function (see section 4.4) or glucose tolerance.

Pregnancy:

Elleste Duet 2 mg is not indicated during pregnancy. If pregnancy occurs during medication with Elleste Duet 2 mg 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 inadvertant foetal exposure to combinations of estrogens + progestogens indicate no teratogenic or foetotoxic effect.

Lactation:

Elleste Duet 2 mg is not indicated during lactation.

No adverse effects on the ability to drive or operate machines have been reported.

Undesirable effects observed with estrogens and progestogens are detailed in the following table. The effects are grouped according to system organ class.

*Venous thromboembolism i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone replacement therapy users than among non-users. For further information, see section 4.3 Contraindications and 4.4 Special Warnings and precautions for use.

Breast Cancer

According to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women's Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users.

For estrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which>80% of HRT use was estrogen-only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95%CI 1.21 – 1.49) and 1.30 (95%CI 1.21 – 1.40), respectively.

For estrogen plus progestogen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with estrogens alone.

The MWS reported that, compared to never users, the use of various types of estrogen-progestogen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of estrogens alone (RR = 1.30, 95%CI: 1.21 – 1.40) or use of tibolone (RR=1.45; 95%CI 1.25-1.68).

The WHI trial reported a risk estimate of 1.24 (95%CI 1.01 – 1.54) after 5.6 years of use of estrogen-progestogen combined HRT (CEE + MPA) in all users compared with placebo.

The absolute risks calculated from the MWS and the WHI trial are presented below:

The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:

Ø For women not using HRT, about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years.

Ø For 1000 current or recent users of HRT, the number of additional cases during the corresponding period will be

Ø For users of estrogen-only replacement therapy

• between 0 and 3 (best estimate = 1.5) for 5 years' use

• between 3 and 7 (best estimate = 5) for 10 years' use.

Ø For users of estrogen plus progestogen combined HRT,

• between 5 and 7 (best estimate = 6) for 5 years' use

• between 18 and 20 (best estimate = 19) for 10 years' use.

The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to estrogen-progestogen combined HRT (CEE + MPA) per 10,000 women years.

According to calculations from the trial data, it is estimated that:

Ø For 1000 women in the placebo group,

• about 16 cases of invasive breast cancer would be diagnosed in 5 years.

Ø For 1000 women who used estrogen + progestogen combined HRT (CEE + MPA), the number of additional cases would be

• between 0 and 9 (best estimate = 4) for 5 years' use.

The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) (see section 4.4).

Endometrial cancer

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed estrogens. According to data from epidemiological studies, the best estimate of the risk is that for women not using HRT, about 5 in every 1000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. Depending on the duration of treatment and estrogen dose, the reported increase in endometrial cancer risk among unopposed estrogen users varies from 2-to 12-fold greater compared with non-users. Adding a progestogen to estrogen-only therapy greatly reduces this increased risk.

Very rare cases of estrogen-dependent neoplasms benign and malignant (e.g. endometrial cancer), myocardial infarction, stroke, chloasma, erythema multiforme, erythema nodosum, vascular purpura, haemorrhagic eruption and probable dementia (see section 4.4) have been reported in women using HRT.

Overdosage may be manifested by nausea and vomiting. If overdosage is discovered within two or three hours and is so large that treatment seems desirable, gastric lavage can be considered. There are no specific antidotes for overdosage and further treatment should be symptomatic.

Pharmacotherapeutic group: Progestogens and estrogens, sequential preparations,

norethisterone and estrogen.

ATC Code: G03FB05

Estradiol

The active ingredient, synthetic 17β-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of estrogen production in menopausal women, and alleviates menopausal symptoms.

Estrogens prevent bone loss following menopause or ovariectomy. Estrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. The effect of estrogens 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.

Norethisterone acetate

As estrogens promote the growth of the endometrium, unopposed estrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestogen reduces but does not eliminate the estrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

Pharmacokinetic parameters for Elleste Duet 2 mg (2 mg estradiol + 1 mg norethisterone tablets) are provided in the table below. The data were obtained from an open label, two way crossover pharmacokinetic study in which treatment was administered for 7 days to achieve steady state (n=24). Pharmacokinetic data were collected over 24 hours.

Estradiol

Readily and fully absorbed from the GI tract when given orally, peak levels are generally observed 3-6 hours after ingestion, but by 24 hours concentrations have returned to baseline.

Estradiol is converted to estrone and estriol primarily in the liver. These are excreted into the bile and undergo enterohepatic recirculation and further degradation before being excreted in the urine (90-95%) as biologically inactive glucuronide and sulphate conjugates or in the faeces (5-10%), mostly unconjugated.

Norethisterone acetate

Norethisterone acetate is absorbed from GI tract and its effects last for at least 24 hours. Maximum blood concentrations are generally reached 1-4 hours after administration. Norethisterone acetate undergoes first pass effect, being transformed to norethisterone which is then metabolised and excreted mainly in the urine as glucuronide and sulphate conjugates.

Both estradiol and norethisterone acetate have been shown to induce adverse effects in preclinical reproductive toxicity studies. Chiefly, estradiol showed embryotoxic effects and induced anomalies in urogenital tract development, e.g. feminisation of male foetuses in high doses. Norethisterone acetate showed embryotoxic effects and induced anomalies in urogenital tract development. In mice, additional anomalies in non-urogenital foetal development, including hydrocephalus and clubfoot, have been detected.

Tablet core:

Lactose monohydrate, maize starch, povidone 25, talc (purified) and magnesium stearate.

Film-coating material:

Estradiol only (orange) tablets

Hydroxypropylmethyl cellulose (E464), titanium dioxide (E171), macrogol 400 and sunset yellow (E110).

Estradiol and Norethisterone Acetate (grey) tablets

Hydroxypropylmethyl cellulose (E464), titanium dioxide (E171), macrogol 400, black iron oxide (E172)

Not applicable

3 years

Do not store above 25°C. Store in the original package.

Aluminium foil and UPVC blister packed in a cardboard carton.

Pack sizes: 28 tablets and 84 (3 x 28) tablets.

There are no special instructions for handling.

Meda Pharmaceuticals Ltd

249 West George Street

Glasgow

G2 4RB

Trading as:

Meda Pharmaceuticals Ltd

Skyway House

Parsonage Road

Takeley

Bishop's Stortford

CM22 6PU

UK

PL 15142/0064

23^rd February 2005 / 27^th August 2007

1st August 2009