SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Bedol

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

17-P oestradiol 2 mg

3    PHARMACEUTICAL FORM

Film Coated Tablet

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in peri- and post-menopausal women.

4.2    Posology and method of administration

Administration: Oral

Bedol is an oestrogen-only product. The calendar pack consists of 28 tablets each containing 2 mg of 17-B oestradiol. One tablet is taken on each day of the 28 day treatment cycle.

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.

Starting Bedol

Treatment of hysterectomised women and postmenopausal women may be started on any convenient day. If the patient is menstruating, treatment is started up to day 5 of bleeding. Patients changing from a cyclic or continuous sequential preparation should complete the cycle and then start Bedol 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.

Progestogen administration (where indicated)

Women with intact uteri should normally use a standard dose of a progestogen in either a cyclic or continuous sequential or continuous combined regimen. Where a progestogen is necessary, it should be added for at least 12 - 14 days every 28 day cycle to reduce the risk to the endometrium (see Section 4.4). It should be started on the recommended day of the cycle, considering the day of the first Bedol tablet to be day 1. If a progestogen has been prescribed as continuous combined therapy it should be started at the same time as Bedol. A menstrual type vaginal bleed occurs at the end of the treatment cycle when progestogens are given as sequential regimens.

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

Missed doses

If a dose is forgotten the patient should be advised to take it as soon as they remember. However, if a whole day has passed, patients should be advised not to take the missed tablet but to continue to take one tablet daily. A missed dose may increase the likelihood of break-through bleeding and spotting.

Children or males: Bedol is not intended for children or males.

Use in the elderly: There are no special dosage requirements.

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

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

Active 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.

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 (section 4.3) and warnings (section 4.4) 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 with Bedol, in particular:

-    Leiomyoma (uterine fibroids) or endometriosis;

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

-    Risk factors for oestrogen dependent tumours, eg 1^st degree heredity for breast cancer;

-    Hypertension;

-    Liver disorders (eg liver adenoma);

-    Diabetes mellitus with or without vascular involvement;

-    Cholelithiasis;

-    Migraine or severe headache;

-    Systemic lupus erythematosus;

-    A history of endometrial hyperplasia (see below);

-    Epilepsy;

-    Asthma;

-    Otosclerosis.

Reasons for immediate withdrawal of therapy

Therapy should be discontinued when 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 oestrogens 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.

Unopposed oestrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestogens to oestrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis, if they are known to have residual endometriosis.

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 oestrogens, oestrogen-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 oestrogens (CEE) or oestradiol (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 oestrogen 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 oestrogen-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 between 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 (Body Mass Index > 30 kg/m²) and systemic lupus erythematosis (SLE). There is no consensus about the 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 post-operative 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 four to six weeks earlier, if possible. Treatment should not be started 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, dyspnoea).

Coronary artery disease (CAD)

There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated oestrogens 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 oestrogens and MPA (medroxyprogesterone acetate). 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 oestrogens 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 5-10 years) use of oestrogen-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 oestrogen-only products.

Other conditions

Oestrogens 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 ingredient (17P-oestradiol) in Bedol is increased.

Women with pre-existing hypertriglyceridemia should be followed closely during oestrogen replacement or hormone replacement therapy since rare cases of large increases in 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 radio-immunoassay) or T3 levels (by radioimmunoassay). 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-hormonebinding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biologically 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.

Bedol is not an oral contraceptive neither will it restore fertility. Women of child bearing potential should be advised to adhere to non-hormonal contraceptive methods.

4.5 Interaction with other medicinal products and other forms of interaction

The metabolism of oestrogens 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.

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

4.6 Pregnancy and lactation

Bedol is not indicated during pregnancy. If pregnancy occurs during medication with Bedol treatment should be withdrawn immediately. The results of most epidemiological studies to date, relevant to inadvertent foetal exposure to oestrogens, indicate no teratogenic or foetotoxic effects.

Bedol is not indicated during lactation.

4.7 Effects on ability to drive and use machines

No effects on the ability to drive and use machines are reported.

4.8 Undesirable effects

NB: Patients with intact uteri taking progestogens for endometrial safety may report symptoms associated with this class of drugs. These include vaginal bleeding and premenstrual-like symptoms. (See also Section 4.4 for further information on endometrial hyperplasia)

Genito-urinary system — increase in size of uterine fibroids, vaginal candidiasis, change in cervical erosion and in degree of cervical secretion, cystitis like syndrome.

Breasts — tenderness, enlargement, secretion, breast cancer (see below)

Gastrointestinal — nausea, vomiting, abdominal cramps, bloating, cholestatic jaundice.

Skin — chloasma or melasma which may persist when drug is discontinued, erythema multiforme, erythema nodusum, haemorrhagic eruption.

Eyes — steepening of corneal curvature, intolerance to contact lenses.

CNS — headaches, migraine, dizziness, chorea.

Miscellaneous — increase or decrease in weight, reduced carbohydrate tolerance, aggravation of porphyria, oedema, change in libido, leg cramps.

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 oestrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which >80% of HRT use was oestrogen-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 oestrogen plus progestogen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with oestrogens alone.

The MWS reported that, compared to never users, the use of various types of oestrogen-progestogen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 - 2.12) than use of oestrogens alone (RR = 1.30, 95%CI: 1.21 - 1.40) or use of tibolone (RR=1.45; 95%CI 1.251.68).

The WHI trial reported a risk estimate of 1.24 (95%CI 1.01 - 1.54) after 5.6 years of use of oestrogen-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:

• 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.

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

o For users of oestrogen-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. o For users of oestrogen 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 oestrogen-progestogen combined HRT (CEE + MPA) per 10,000 women years.

According to calculations from the trial data, it is estimated that: o For 1000 women in the placebo group,

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

o For 1000 women who used oestrogen + 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 oestrogens. 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 oestrogen dose, the reported increase in endometrial cancer risk among unopposed oestrogen users varies from 2-to 12-fold greater compared with non-users. Adding a progestogen to oestrogen-only therapy greatly reduces this increased risk.

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

-    Oestrogen dependent neoplasms benign and malignant, eg endometrial cancer

-    Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among HRT users than among nonusers. For further information see sections “4.3 Contraindications” and “4.4 Warnings and precautions for use”.

-    Myocardial infarction and stroke

-    Gall bladder disease

-    Probable dementia ( see section 4.4)

4.9 Overdose

Nausea and vomiting may occur after overdosage. Treatment should be symptomatic; there is no specific antidote.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

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

5.2 Pharmacokinetic properties

17-P oestradiol is absorbed rapidly after oral administration. The rate and completeness of absorption of 17-P oestradiol in Bedol were found to be bioequivalent to Zumenon as assessed by the maximum concentrations of achieved (Bedol C_max= 187 pmol/L), time to maximum concentration (T_max) and area under the concentration time curve (AUC).

5.3 Preclinical safety data

Studies in animals have indicated that administration of very high doses of oestrogens will induce neoplastic tumours in some animal species.

The results of the studies of 17-P oestradiol have not suggested any unwanted effects at the therapeutic doses used in the human.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose    EP    86.0 mg

Crospovidone USNF 4.0 mg Povidone    EP    5.0 mg

Talc    EP    2.5 mg

Magnesium stearate    EP    0.5 mg

Opadry White Y-1-7000    HSE 2.0 mg

10