ZUMENON 1 MG FILM-COATED TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Zumenon® 1mg Film-coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 1 mg estradiol (as hemihydrate)

Excipient with known effect: each tablet contains 119.1 mg lactose monohydrate.

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Film-coated tablets

Round, biconvex, white tablets with inscription ‘379’ on one side

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in postmenopausal women at least 6 months since last menses.

Older people

The experience treating women older than 65 years is limited.

4.2 Posology and method of administration

Posology

One tablet to be taken orally

Zumenon is an oestrogen only continuous HRT for women with or without a uterus.

In women with a uterus, a progestogen should be added to Zumenon for 12–14 days each month to reduce the risk to the endometrium. Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestogen in hysterectomised wo­men.

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.

In general, treatment should start with Zumenon 1mg. Depending on the clinical response, the dosage can afterwards be adjusted to individual need. If the complaints linked to oestrogen deficiency are not ameliorated the dosage can be increased by using Zumenon 2mg.

Starting Zumenon

In women who are not taking hormone replacement therapy and who are amenorrhoeic, are hysterectomised, or women who switch from a continuous combined hormone replacement therapy, treatment may be started on any convenient day. In women transferring from a cyclic or continuous sequential HRT regimen, treatment should begin the day following completion of the prior regimen. If the patient has regular menstruation periods, treatment is started on day one of bleeding.

Administration

The dosage is one tablet per day. Zumenon should be taken continuously without a break between packs. Zumenon can be taken with or without food.

If a dose has been forgotten, it should be taken as soon as possible. When more than 12 hours have elapsed, it is recommended to continue with the next dose without taking the forgotten tablet. In the case of a missed or delayed dose the likelihood of breakthrough bleeding or spotting may be increased.

Paediatric population:

There is no relevant indication for the use of Zumenon in the paediatric population.

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 vein 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 substance or to any of the excipients;

Porphyria

4.4 Special warnings and precautions for use

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

Evidence regarding the risks associated with HRT in the treatment of premature menopause is

limited. Due to the low level of absolute risk in younger women, however, the balance of benefits

and risks for these women may be more favourable than in older women.

Medical examination/follow up

Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic checkups 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 Zumenon, in particular:

– Leiomyoma (uterine fibroids) or endometriosis

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

– Risk factors for oestrogen dependent tumours, e.g. 1st 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 in cases where a contra-indication is discovered and in the following situations:

– Jaundice or deterioration in liver function

– Significant increase in blood pressure

– New onset of migraine-type headache

– Pregnancy

Endometrial hyperplasia and carcinoma

In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among oestrogen-only users varies from 2-to 12-fold greater compared with non-users, depending on the duration of treatment and oestrogen dose (see section 4.8).

After stopping treatment risk may remain elevated for at least 10 years.

The addition of a 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.

For oral doses of estradiol >2 mg the endometrial safety of added progestogens has not been demonstrated.

Break-through bleeding and spotting may occur during the first few 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

The overall evidence shows an increased risk of breast cancer in women taking combined oestrogen-progestogen or oestrogen-only HRT, that is dependent on the duration of taking HRT.

Combined oestrogen-progestogen therapy

The randomised placebo-controlled trial the (Women’s Health Initiative study (WHI), and a meta-analysis of prospective 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 (1–4) 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-progestogen combinations (see section 4.8).

Results from a large meta-analysis showed that after stopping treatment, the excess risk will decrease with time and the time needed to return to baseline depends on the duration of the prior HRT use. When HRT was taken for more than 5 years, the risk may persist for 10 years or more.

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. Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking oestrogen-only or combined oestrogen-progestogen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping. Some other studies including the WHI trial, suggest that the use of combined HRTs may be associated with a similar, or slightly smaller risk (see section 4.8).

Venous thromboembolism

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

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

Generally recognised risk factors for VTE include, use of oestrogens, older age, major surgery, prolonged immobilisation, obesity (BMI > 30 kg/m2), pregnancy/pos­tpartum period, systemic lupus erythematosus (SLE), and cancer. There is no consensus about the possible role of varicose veins in VTE.

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

In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is ‘severe’ (e.g, antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT is contraindicated.

Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

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

Coronary artery disease (CAD)

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

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

Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by 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-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).

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, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Women who may be at risk of pregnancy should be advised to adhere to nonhormonal contraceptive methods.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

The efficacy of oestrogens might be impaired:

– The metabolism of oestrogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, 2B6, 3A4, 3A5, 3A7, such as anticonvulsants (eg. phenobarbital, phenytoin, carbamezepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

– Ritonavir and nelfinavir, although known as strong inhibitors of CYP450 3A4, A5, A7, 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 via the CYP450 3A4 pathway.

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

Oestrogens might interfere with the metabolism of other drugs:

Oestrogens per se may inhibit CYP450 drug-metabolising enzymes via competitive inhibition. This is in particular to be considered for substrates with a narrow

therapeutic index, such as                                                   

tacrolimus and cyclosporine A (CYP450 3A4, 3A3)

fentanyl (CYP450 3A4)

theophylline (CYP450 1A2).

Clinically this may lead to a plasma increase of the affected substances up to toxic levels. Thus, careful drug monitoring for an extended period of time might be indicated and a dosage decrease of tacrolimus, fentanyl, cyclosporin A, and theophylline may be necessary.

4.6 Fertility, pregnancy and lactation

Pregnancy

Zumenon is not indicated during pregnancy. If pregnancy occurs during medication with Zumenon, 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.

Lactation:

Zumenon is not indicated during lactation.

4.7 Effects on ability to drive and use machines

Zumenon does not affect the ability to drive and use machines.

4.8 Undesirable effects

Serious undesirable effects associated with the use of hormone replacement therapy are also mentioned in section 4.4 ‘Special warnings and precautions for use’.

The table below reports undesirable effects, that have been reported in users of hormone replacement therapy (HRT) by MedDRA system organ classes (MedDRA SOCs).

Other adverse reactions have been reported in association with estradiol treatment (frequency unknown):

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)

Breast cancera

Oestrogen dependent neoplasms benign and malignant, e.g. endometrial cancerb, ovarian c

cancerc

Increase in size of leiomyoma

Nervous system disorders

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

Chorea

Exacerbation of epilepsy

Vascular disorders

Strokef

Arterial thromboembolism, i.e. anginae and myocardial infarctione. For further information see sections 4.3 and 4.4.

Venous thromboembolismd, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism. For further information see sections 4.3 and 4.4.

Gastrointestinal disorders

Pancreatitis (in women with pre-existing hypertriglyce­ridaemia)

Gastroesophageal reflux disease

Hepatobiliary disorders

Hepatic function abnormal, sometimes with jaundice

Skin and subcutaneous tissue disorders

Angioedema, chloasma, erythema multiforme, vascular purpura.

Renal and urinary disorders

Urinary incontinence

Reproductive system and breast disorders

Fibrocystic breast disease

An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestogen therapy for more than 5 years.

The increased risk in users of oestrogen-only therapy is lower than that seen in users of oestrogen-progestogen combinations.

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

Absolute risk estimations based on results of the largest randomised placebo-controlled trial (WHI-study) and the largest meta-analysis or prospective epidemiological studies are presented.

Largest meta-analysis of prospective epidemiological studies –

Estimated additional risk of breast cancer after 5 years’ use in women with BMI 27 (kg/m2)

Estimated additional risk of breast cancer after 10 years’ use in women with BMI 27 (kg/m2)

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

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 progestogen 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)).

Use of oestrogen-only or combined oestrogen-progestogen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed (see section 4.4). A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.311.56). For women aged 50 to 54 years taking 5 years of HRT this results in about 1 extra case per 2000 users. In women aged 50 to 54 who are not taking HRT about 2 women in 2000 will be diagnosed with ovarian cancer over a 5-year period.

d. Risk of venous thromboembolism

HRT is associated with a 1.3–3-fold increased relative risk of developing venous thromboembolism

(VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of using HT (see section 4.4). Results of the WHI studies are presented:

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

The risk of coronary artery disease is slightly increased in users of combined oestrogenproges­togen

HRT over the age of 60 (see section 4.4).

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Natural and semisynthetic oestrogens, plain. ATC code: G03CA03.

Oestradiol

The active ingredient, synthetic 17p-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.

Combined therapy with progestogens is also recommended in hysterectomised women with a history of endometriosis as cancer development in extra-uterine endometriotic implants in women on oestrogen-only therapy has been reported (see section 4.4 Special warnings and precautions).

Clinical trial information

Relief of oestrogen-deficiency symptoms and bleeding patterns

– Relief of menopausal symptoms was achieved during the first few weeks of treatment.

– Hot flushes have been shown to be significantly reduced with 1 mg and 2 mg 17 beta estradiol at 4 weeks.

– Regular withdrawal bleeding in women treated with Zumenon 1mg daily for 28 days and Dydrogesterone 10mg daily for the last 12–14 days of a 28 day cycle, occurred in approximately 75–80% of women with a mean duration of 5 days. Withdrawal bleeding usually started on the day of the last pill of the progestogen phase. Break-through bleeding and/or spotting occurred in approximately 10% of the women; amenorrhoea occurred in 21–25% of the women for months 10 to 12 of treatment.

– In women treated with Zumenon 2mg daily for 28 days and Dydrogesterone 10mg daily for the last 12–14 days of a 28 day cycle, approximately 90% of women had regular withdrawal bleeding. The start day and duration of bleeding, and the number of women with intermittent bleeding was the same as with Zumenon 1mg, amenorrhoea (no bleeding or spotting) occurred in 711% of the women for months 10 to 12 of treatment.

5.2 Pharmacokinetic properties

Estradiol, estra-1,3,5(10)-triene-3,17B-diol is identical to human ovarian estradiol.

Absorption

Absorption of estradiol is dependent on the particle size: micronized estradiol is rapidly absorbed from the gastrointestinal tract with arithmetic mean Tmax values at steady-state of 3.9 hours.

The following table provides the arithmetic mean steady state pharmacokinetic parameters of estradiol (E2), estrone (E1) and estrone sulphate (E1S) for 1 mg dose of micronized estradiol. Data is presented as arithmetic mean (standard deviation).

Distribution

Oestrogens can be found either unbound or bound. About 98– 99% of the estradiol dose binds to plasma proteins, from which about 30–52% to albumin and about 46–69% to the sex hormonebindin­gglobulin (SHBG).

Biotransformation

Following oral administration, estradiol is extensively metabolised. The major unconjugated and conjugated metabolites are estrone and estrone sulphate. These metabolites can contribute to the oestrogen activity, either directly or after conversion to estradiol. Estrone sulphate may undergo enterohepatic circulation.

Elimination

In urine, the major compounds are the glucuronides of estrone and estradiol. The elimination half-life of estradiol and its main metabolites is between 1016 h.

Oestrogens are secreted in the milk of nursing mothers.

Linearity/non-linearity

The mean estradiol exposure at steady-state after oral daily dosing of 2 mg micronized estradiol is approximately 2-fold greater than that after daily dosing of 1 mg micronized estradiol. Based on the elimination half-life of the micronized estradiol, it can be estimated that estradiol concentrations reach steady-state approximately within one week following oral daily administration.

5.3 Preclinical safety data

There are no preclinical safety data of relevance to the prescriber in the target population that are additional to those already included in other sections of the Summary of Product Characteristics.

6 PHARMACEUTICAL PARTICULARS

7   MARKETING AUTHORISATION HOLDER

8 MARKETING AUTHORISATION NUMBER(S)

PL 46302/0052

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

01/08/1996 / 16/08/2001