FEMOSTON 2/10 MG FILM-COATED TABLETS - summary of medicine characteristics

Femoston 2/10mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 2mg oestradiol (as hemihydrate) or a combination of 2mg oestradiol (as hemihydrate) and 10mg dydrogesterone.

Excipient with known effect: lactose monohydrate

For the full list of excipients see 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablets

Oestradiol only tablets: Round, biconvex, brick-red film-coated tablets with inscription ‚379‘.

Oestradiol/dy­drogesterone combination tablets: Round, biconvex, yellow film-coated tablets with inscription ‚379‘.

4.1 Therapeutic indications

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

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 in treating women older than 65 years is limited.

4.2 Posology and method of administration

Femoston 1/10 and Femoston 2/10, are continuous sequential hormone replacement therapies.

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 Femoston 1/10. 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 Femoston 2/10

Starting Femoston

In women who are not taking hormone replacement therapy and who are amenorrhoeic, 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.

Administration

For the first 14 days during a 28-cycle, one tablet containing oestradiol is taken daily; during the following 14 days one tablet containing oestradiol and dydrogesterone is taken.

After a cycle of 28 days, on the 29th day, a new 28-day cycle begins. This means that the treatment should be taken continuously without a break between packs. Femoston can be taken with or without food.

The days of the week are printed on the back of the blister strips. Firstly, the tablets from the part marked with arrow 1 should be taken, then all the tablets from the part marked with arrow 2 should be taken.

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. The likelihood of breakthrough bleeding or spotting may be increased.

Paediatric population:

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

4.3 Contraindications

– Known, past or suspected breast cancer;

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

– Known or suspected progestogen-dependent neoplasms (e.g. meningioma)

– Undiagnosed genital bleeding;

– Untreated endometrial hyperplasia;

– Previous idiopathic 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;

Porphyria;

Known hypersensitivity to the active substances or to any of the excipients.

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 Femoston, in particular:

– Leiomyoma (uterine fibroids) or endometriosis

– 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.

Break-through bleeding and spotting may occur during the first months of treatment. If breakthrough 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 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 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 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 metaanalysis 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 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.

– 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 ages, major surgery, prolonged immobilisation, severe 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 to 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 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 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).

HRT use does not improve cognitive function. There is some evidence of increased risk of possible 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 non-hormonal contraceptive methods.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

The efficacy of oestrogens and progestogens might be impaired:

The metabolism of oestrogens and progestogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically the P450 enzymes 2B6, 3A4, 3A5, 3A7, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamezapin) 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 an increased plasma level of the affected substances up to toxic concentrations. 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:

Femoston is not indicated during pregnancy. If pregnancy occurs during medication with Femoston, treatment should be withdrawn immediately.

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.

There are no adequate data from the use of oestradiol/dy­drogesterone in pregnant women.

Lactation:

Femoston is not indicated during lactation.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

The most commonly reported adverse drug reactions of patients treated with oestradiol/dy­drogesterone in clinical trials are headache, abdominal pain, breast pain/tenderness and back pain.

The following undesirable effects have been observed with the frequencies indicated below during clinical trials (n=4929):

Breast Cancer risk

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 of 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)

additional cases of breast cancer will also change proportionately.

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

Endometrial cancer

Postmenopausal women with a uterus

The endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT.

In women with a uterus, use of oestrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4). Depending on the duration of oestrogen-only use and oestrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 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 (R.R of 1.0 (0.8–1.2)).

Ovarian cancer

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 1.31–1.56). For women aged 50 to 54 years after 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.

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

1Study in women with no uterus

Risk of coronary artery disease

The risk of coronary artery disease is slightly increased in users of combined oestrogen-progestogen HRT over the age of 60 (see section 4.4).

Risk of ischaemic stroke

The use of oestrogen-only and oestrogen + progestogen 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*2 over 5 years’ use

No differentiation was made between ischaemic and haemorrhagic stroke

Other adverse reactions have been reported in association with oestrogen/pro­gestogen treatment (including oestradiol/dy­drogesterone):

Neoplasms benign, malignant and unspecified:

Oestrogen dependent neoplasms both benign and malignant, e.g. endometrial cancer, ovarian cancer. Increase in size of progestogen dependent neoplasms, e.g. meningioma.

Blood and lymphatic system disorders:

Haemolytic anaemia

Immune system disorders:

Systemic lupus erythematosus

Metabolism and nutrition disorders:

Hypertriglyce­ridemia

Nervous system disorders:

Probable dementia over the age of 65 (see section 4.4), chorea, exacerbation of epilepsy

Eye disorders:

Steepening of corneal curvature, contact lenses intolerance

Vascular disorders:

Arterial thromboembolism

Gastrointestinal disorders:

Pancreatitis (in women with pre-existing hypertriglyce­ridemia)

Skin and subcutaneous tissue disorders:

Erythema multiforme, erythema nodosum, chloasma or melasma, which may persist when drug is discontinued.

Musculoskeletal and connective tissue disorders:

Leg cramps

Renal and urinary disorders:

Urinary incontinence

Reproductive system and breast disorders:

Fibrocystic breast disease, uterine cervical erosion

Congenital,  familial and genetic disorders:

Aggravated porphyria

Investigations:

Total thyroid hormones increased

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Both oestradiol and dydrogesterone are substances with low toxicity. Symptoms such as nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue, and withdrawal bleeding could occur in cases of overdosing. It is unlikely that any specific or symptomatic treatment will be necessary.

Aforementioned information is applicable for overdosing by children also.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

The ATC code is G03FB08. (Oestrogens: urogenital system and sex hormones)

Sequential hormone replacement therapy (combined oestradiol and dydrogesterone).

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. Oestrogens prevent bone loss following menopause or ovariectomy.

Dydrogesterone

Dydrogesterone is an orally-active progestogen having an activity comparable to parenterally administered progesterone. 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.

Clinical trial information

Relief of oestrogen-deficiency symptoms and bleeding patterns.

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

– Regular withdrawal bleeding with Femoston 1/10 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 (no bleeding or spotting) occurred in 21–25% of the women for months 10 to 12 of treatment.

– With Femoston 2/10, 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 Femoston 1/10, amenorrhoea occurred in 7–11% of the women for months 10 to 12 of treatment.

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.

– After two years of treatment with Femoston 2/10, the increase in lumbar spine bone mineral density (BMD) was 6.7% ± 3.9% (mean ± SD). The percentage of women who maintained or gained BMD in lumbar zone during treatment was 94.5%. For Femoston 1/10 the increase in lumbar spine BMD was 5.2% ± 3.8% (mean ± SD), and the percentage of women with no change or an increase in lumbar spine BMD was 93%.

– Femoston also had an effect on hip BMD. The increase after two years of treatment with 1mg oestradiol was 2.7% ± 4.2% (mean ± SD) at femoral neck, 3.5% ± 5.0% (mean ± SD) at trochanter and 2.7%± 6.7% (mean ± SD) at Wards triangle. After two years of treatment with 2mg oestradiol these figures were respectively, 2.6% ± 5.0%; 4.6% ± 5.0% and 4.1% ± 7.4%. The percentage of women who maintained or gained BMD in the 3 hip areas after treatment with 1mg oestradiol was 67–78% and 71–88% after treatment with 2mg oestradiol.

5.2 Pharmacokinetic propertiesOestradiol

Absorption

Absorption of oestradiol is dependent on the particle size: micronized oestradiol is readily absorbed from the gastrointesti­nal tract.

The following table provides the mean steady state pharmacokinetic parameters of oestradiol (E2), estrone (E1) and estrone sulphate (E1S) for each dose of micronized oestradiol. Data is presented as mean (SD).

Distribution

Oestrogens can be found either unbound or bound. About 98–99% of the oestradiol dose binds to plasma proteins, from which about 30–52% to albumin and about 4669% to the sex hormone-binding globulin (SHBG).

Metabolism

Following oral administration, oestradiol 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 oestradiol. Estrone sulphate may undergo enterohepatic circulation.

Elimination

In urine, the major compounds are the glucuronides of estrone and oestradiol. The elimination half-life is between 10–16 h.

Oestrogens are secreted in the milk of nursing mothers.

Dose and time dependencies

Following daily oral administration of Femoston, oestradiol concentrations reached a steady-state after about five days.

Generally, steady state concentrations appeared to be reached for within 8 to 11 days of dosing.

Absorption

Following oral administration, dydrogesterone is rapidly absorbed with a Tmax between 0.5 and 2.5 hours. The absolute bioavailability of dydrogesterone (oral 20mg dose versus 7.8mg intravenous infusion) is 28%.

The following table provide the mean steady state pharmacokinetic parameters of dydrogesterone (D) and dihydrodydroges­terone (DHD). Data is presented as mean (SD).___________­________________________­________________________­________________

Distribution

After intravenous administration of dydrogesterone the steady-state volume of distribution is approximately 1400 L. Dydrogesterone and DHD are more than 90% bound to plasma proteins.

Metabolism

Following oral administration, dydrogesterone is rapidly metabolised to DHD. The levels of the main active metabolite 20 a-dihydrodydroges­terone (DHD) peak about 1.5 hours post dose. The plasma levels of DHD are substantially higher as compared to the parent drug. The AUC and Cmax ratios of DHD to dydrogesterone are in the order of 40 and 25, respectively. Mean terminal half-lives of dydrogesterone and DHD vary between 5 to 7 and 14 to 17 hours, respectively. A common feature of all metabolites characterised is the retention of the 4,6 diene-3-one configuration of the parent compound and the absence of 17a- hydroxylation. This explains the lack of oestrogenic and androgenic effects of dydrogesterone.

Elimination

After oral administration of labelled dydrogesterone, on average 63% of the dose is excreted into the urine. Total plasma clearance is 6.4 L/min. Within 72 hours excretion is complete. DHD is present in the urine predominantly as the glucuronic acid conjugate.

Dose and time dependencies

The single and multiple dose pharmacokinetics are linear in the oral dose range 2.5 to 10mg. Comparison of the single and multiple dose kinetics shows that the pharmacokinetics of dydrogesterone and DHD are not changed as a result of repeated dosing. Steady state was reached after 3 days of treatment.

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 (SmPC).

Environmental risk assessment (ERA):

This medicinal product may pose a risk to the aquatic environment. Medicines no longer required should not be disposed of via wastewater or household waste. Any unused product or waste material should be disposed of in accordance with local requirements or returned to the pharmacy.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Oestradiol only tablets (brick-red):

Tablet core:

Lactose

Hypromellose

Maize starch

Colloidal anhydrous silica

Magnesium stearate

Film coat:

Hypromellose

Talc

Macrogol 400

Titanium dioxide E171

Iron oxide red E172

Iron oxide black E172

Iron oxides yellow E172

Oestradiol/Dy­drogesterone tablets (yellow):

Tablet core:

Lactose

Hypromellose

Maize starch

Colloidal anhydrous silica

Magnesium stearate

Film coat:

Hypromellose

Talc

Macrogol 400

Titanium dioxide (E171)

Iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PVC film with a covering aluminium foil.

Blister packs: 28 film-coated tablets

84 film-coated tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

This medicinal product may pose a risk to the aquatic environment. Medicines no longer required should not be disposed of via wastewater or household waste. Any unused product or waste material should be disposed of in accordance with local requirements or returned to the pharmacy.

7 MARKETING AUTHORISATION HOLDER

Mylan Products Ltd.

20 Station Close

Potters Bar

Herts

EN6 1TL

United Kingdom