Hormone replacement therapy (HRT) for estrogen deficiency symptoms in menopausal women at
least 6 months since last menses.
Prevention of osteoporosis in postmenopausal women at high risk of future fractures. Femoston
should only be used in patients who are intolerant of other products, approved for the prevention
of osteoporosis or for whom these products are contra-indicated (see also section 4.4).
Experience with treatment of women older than 65 years is limited.

Femoston 2/10 is taken orally daily according to a continuous sequential regimen, as described
below.
For each cycle of 28 days for the first 14 days one brick red tablet with estradiol is taken once a
day and for the following 14 days one yellow tablet with estradiol and dydrogesterone is taken
once a day, as indicated on the calendar pack for 28 days.
After a cycle of 28 days on the 29th day a new cycle of 28 days begins. The treatment cycles
therefore follow one another without a break.
For the treatment of estrogen deficiency in postmenopausal women as an initial and maintenance
dose the lowest effective dose should be used and the duration of treatment period should be kept
as short as possible (see also section 4.4).

In general sequential combined treatment should be started with Femoston 1/10.
Depending on the clinical response the dose can be adjusted accordingly.
In women who are not taking hormone replacement therapy or in women switching from
continuous combined hormone replacement therapy, the treatment can be started on any
convenient day. In women switching from cyclical or continuous sequential hormone replacement
therapy, treatment should start on the day immediately after completion of the previous cycle.
If a tablet is missed it is recommended to take the next tablet without taking the forgotten tablet.
Forgetting a tablet may increase the chance of breakthrough bleeding or spotting.
Femoston 2/10 can be taken both with and without food.
Paediatric patients
There are no relevant indications for the use of Femoston 2/10 in paediatric patients.

- Presence or suspicion of breast cancer; history of breast cancer; - Presence or suspicion of estrogen-sensitive tumours (for example endometrial cancer); - Vaginal bleeding of which the cause has not been determined; - Untreated endometrial hyperplasia; - History of active venous thromboembolism (deep vein thrombosis, pulmonary embolism); - Presence of a thrombophilic condition (e.g. protein C, protein S or antithrombin deficiency, see section 4.4); - Active or recent arterial thromboembolic disease (angina pectoris, myocardial infarction); - Acute liver disease or history of liver disease as long as the liver function values have not returned to normal; - Porphyry. - Known hypersensitivity to the active ingredients or to one of the excipients listed in section 6.1;

For the treatment of symptoms of estrogen deficiency in postmenopausal women, treatment with
hormone replacement therapy (HRT) should only be initiated if these symptoms adversely affect
the quality of life. A careful appraisal of the advantages and disadvantages of HRT should be
carried out regularly, at least annually, and the treatment should only be continued if the
advantages outweigh the disadvantages.
Evidence relating to the risks associated with HRT in the treatment of premature menopause is
limited. But because of the low absolute risk in young women the balance of advantages and
disadvantages for these women are more positive than for older women.

Medical examination / follow up
Before starting HRT or if its use is to be reinstated the use after an interruption, a full medical
history (including family history) should be taken. Physical examination (including
gynaecological and breast examination) should be carried out guided by the history, contraindications
and warnings. During the treatment period regular 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 immediately (see the section “Breast
cancer” below).

Regular examination of the breasts, including imaging techniques such as mammography, should
be carried out in accordance with the current guidelines for healthy women, taking into account
here the medical need of the individual woman.

Conditions which need supervision
If one of the following conditions is present, was present in the past and/or has 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 the treatment
with Femoston 2/10, in particular in case of:
- Leiomyoma (uterine fibroma) or endometriosis
- Risk factors for thromboembolic disorders (see below)
- Risk factors for estrogen-sensitive tumours (breast cancer in first degree family member)
- Hypertension
- Liver disease (liver adenoma)
- Diabetes mellitus with or without vascular symptoms
- Cholelithiasis
- Migraine or (severe) headache
- Systemic Lupus Erythematodes
- A history of endometrial hyperplasia (see below)
- Epilepsy
- Asthma
- Otosclerosis
- Meningioma

Reasons for immediate discontinuance of treatment
Hormone replacement therapy should be discontinued immediately where a contra-indication is
discovered and in the following situations:
- Jaundice or deterioration in the liver function.
- Significant increase in blood pressure.
- New onset of migraine-type headache.
- Pregnancy.

Endometrial hyperplasia and carcinoma
• In women whose uterus has not been removed the risk of endometrial hyperplasia and
endometrial cancer is increased if over a prolonged period estrogen-only HRT is taken. The
reported increased risk of endometrial cancer in users of estrogen preparations varies from 2 to
12 times as great compared with non-users, depending on the treatment period and the estrogen
dose (see section 4.8). After stopping the treatment the risk remains high for at least 10 years.
• The cyclical combination of an estrogen preparation with a progestagen for at least 12 days per
month/per 28-day cycle or continuous combined estrogen-progestagen treatment in women
with a uterus protects against the increased risk associated with estrogen preparations.
• Breakthrough bleeding and spotting may occur during the first months of the treatment. If
breakthrough bleeding or spotting appears after some time on therapy or continues after
treatment has been discontinued, further investigation is indicated. This may mean that an
endometrial biopsy must be taken to exclude malignancy.

Breast cancer
All the available data indicate an increased risk of breast cancer if women are using combined
estrogen and progestagen as HRT and possibly also if they are using estrogen-only as HRT. This
risk depends on the duration of use.

Combined estrogen-progestagen treatment:
• Both a randomised placebo-controlled study, the Women’s Health Initiative Study (WHI), and
epidemiological studies have consistently demonstrated an increased risk of breast cancer in
women using combined estrogen-progestagen HRT. The increased risk is apparent after around
3 years (see section 4.8).
Estrogen monotherapy:
• In the WHI study no increased risk of breast cancer was found in hysterectomised women
using estrogen-only HRT. Observational studies have predominantly reported a small
increase in the risk of the diagnosis of breast cancer that is substantially lower than found in
users of combined estrogens and progestagens (see section 4.8).
The increased risk becomes apparent within a few years of use and increases as the duration of
use increases, but falls again to the initial value within a few (at the most 5) years after stopping
the treatment.
Treatment with HRT, especially combined estrogen-progestagen treatment, increases the density
of the mammography images, which may adversely effect on 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 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 to 3 times higher risk of developing venous thromboembolism
(VTE), i.e. deep vein thrombosis or pulmonary embolism. This is greater during the first year
of HRT treatment than afterwards (see section 4.8).
• Patients with a known thrombophilic status have an increased risk of VTE and HRT may
increase the risk further. HRT is therefore contra-indicated in these patients (see section 4.3).
• General risk factors for the occurrence of VTE are: the use of estrogens, greater age, major
surgical intervention, prolonged immobilisation, obesity (Body Mass Index > 30 kg/m2),
pregnancy/ postpartum period, systemic lupus erythematodes (SLE) and carcinoma.
There is no consensus about the possible role of varicosis in VTE. As in all postoperative
patients, precautions should be taken after surgery to prevent VTE. Where prolonged
immobilisation is anticipated after elective surgery, consideration should be given to stopping
the HRT 4 to 6 weeks before the operation and only restarting it when the woman is
completely mobilised again.

• Women without a history of VTE, but with a first degree family member with a history of
thrombosis at a young age, should be offered screening after careful information relating to the
limitations of such screening (only a proportion of thrombophilic conditions are identified in
screening). If a congenital thrombophilic condition is identified, which is accompanied in a
family with thrombosis or if the condition is serious (e.g. antithrombin, protein S or protein C
deficiencies or a combination of conditions) HRT is contra-indicated.
• In women already treated chronically with anticoagulation therapy, careful consideration
should be given to the advantages and disadvantages of the treatment.

• If VTE develops after initiating therapy, the administration of medication should be
discontinued immediately. Patients must be informed that they should contact their doctor
immediately if potential thromboembolic symptoms occur (e.g.: painful swelling of a leg,
sudden pain in the chest, shortness of breath).

Coronary artery disease (CAD)
There is no evidence from randomised controlled studies of a protective effect against myocardial
infarction in women with or without existing coronary artery disease who receive combined
estrogen-progestagen or estrogen-only HRT.
Combined estrogen-progestagen therapy:
The relative risk of coronary artery disease during combined estrogen-progestagen HRT is
slightly increased. Since the absolute risk of coronary artery disease in the initial situation is
greatly age-dependent, the number of extra cases of coronary artery disease as a result of estrogenprogestagen
use is very low in healthy women who are close to the menopause. This number will
however increase as they get older.
Estrogen monotherapy
In randomised controlled studies no increased risk of coronary artery disease was found in
hysterectomised women using estrogen monotherapy.

Ischemic Stroke
Combined estrogen-progestagen therapy and estrogen monotherapy are associated with an up to
1.5 times higher risk of an ischemic stroke. The relative risk does not change with age or with
the time after the menopause. However, because the absolute risk of a CVA in the initial
situation is strongly dependent on age, the overall risk of a CVA in women using HRT will
increase with age (see section 4.8).

Other conditions
• Estrogens may cause fluid retention. For this reason patients with a reduced cardiac or renal
function must therefore be carefully observed.
• Women with a pre-existing hypertriglyceridaemia should be closely followed during
estrogen replacement or hormone replacement therapy, since in rare cases in women with
this abnormality, the plasma triglycerides increased considerably during estrogen therapy,
and have led to pancreatitis.
Estrogens cause an increase in the thyroid binding globulin (TBG), which leads to increased
circulating thyroid hormone, measured as the protein bound iodine (PBI), T4 levels (column or RIA)
or T3 levels (RIA). The T3-resin uptake is decreased as a result of the increased TBG levels. The free
T3 and T4 concentrations remain unchanged. Other binding proteins may also be elevated in the
serum, such as corticoid binding globulin (CBG) and the sex-hormone binding globulin (SHBG),
leading to increased blood levels of corticosteroids and sex hormones. Free and/or biologically active
hormone concentrations remain unchanged. Other plasma proteins may be increased (angiotensinrenin
substrate, alpha-1-antitrypsin, ceruloplasmin).

• HRT does not improve cognitive functions. There is no evidence of increased risk of
possible dementia in women who start using treatment of combined preparations or estrogen
preparations after the age of 65 years.
• Patients with rare hereditary conditions, such as galactose intolerance, Lapp-lactase
deficiency or glucose-galactose malabsorption should not take this medicinal product.
• This combined estrogen-progestagen is not a contraceptive product.

 

No studies have been carried out relating to interactions.

The efficacy of estrogens and progestagens may be disrupted:
- The metabolism of estrogens (and progestagens) may be increased by concomitant use of
substances known to induce enzymes which are involved in the metabolism of medicinal
products. This applies particularly for P450 enzymes. These substances include antiepileptics
(phenobarbital, phenytoin, carbamazepine) and antibacterials /antivirals (for
example rifampicin, rifabutin, nevirapine, efavirenz).
- Ritonavir and nelfinavir, although known as strong inhibitors, do in fact have an inducing
effect when used concomitantly with steroid hormones.
- Herbal preparations containing St. John’s wort (Hypericum perforatum) may also increase
the metabolism of estrogens (and progestagens).
- Clinically an increased metabolism of estrogens and progestagens may lead to a reduced
efficacy and changes in the bleeding pattern.

Pregnancy
Femoston 2/10 is not indicated during pregnancy. If pregnancy occurs during the treatment with
Femoston 2/10, the treatment should be stopped immediately.
There are no adequate data available on the use of estradiol/dydrogesterone during pregnancy. The
results of most epidemiological studies to date that are relevant for the assessment of effects of
inadvertent foetal exposure to combined estrogens and progestagens indicate no teratogenic risk or
toxic effect for the foetus.
Lactation
Femoston 2/10 is not indicated in women who are breastfeeding.
Fertility
Femoston 2/10 is not indicated in women of child-bearing age.

Femoston 2/10 has no or a negligible effect on the ability to drive or to operate machinery.

The most commonly indicated undesirable effects in patients that were treated in clinical trials
with estradiol/dydrogesterone, are headache, abdominal pain, breast pain/tenderness and back
pain.
The following undesirable effects were observed during clinical trials (n=4929) with the
frequencies indicated below. *Undesirable effects from spontaneous reports that were not
observed in clinical trials have been added to the frequency “rare”.

Organ system	Very common ≥1/10	Common ≥1/100 to <1/10	Uncommon ≥1/1,000 to <1/100	Rare  ≥1/10,000 to 1/1,000
Blood and lymphatic system disorders				Haemolytic anaemia*
Immune system disorders			Hypersensitivity
Psychiatric disorders		Depression; Nervousness	Change in libido
Central nervous system disorders	Headache	Migraine; Dizziness		Meningioma*
Eye disorders				Steepening of the cornea*; Intolerance to contact lenses*
Cardiac disorders				Myocardial infarction
Vascular disorders			Venous thromboembolism*; Hypertension; Peripheral vascular disease; Varicosis;	Stroke *
Gastrointestinal disorders	Abdominal pain	Nausea; Vomiting; Flatulence	Dyspepsia
Hepatobiliary disorders			Abnormal liver function (sometimes combined with jaundice, asthenia or malaise and abdominal pain); Gall bladder disorders\
Skin and subcutaneous tissue disorders		Allergic skin reactions (e.g. rash, urticaria, pruritus)		Angioedema, Erythema nodosum*; Vascular purpura; Chloasma or melasma which may persist when the treatment is discontinued;*
Musculoskeletal and connective tissue disorders	Back pain			Leg cramps*
Reproductive system and breast disorders	Breast pain/ tenderness;	Menstruation disorders (including postmenopausal spotting; metrorrhagia; menorrhagia, oligo/ amenorrhoea, irregular menstruation, dysmenorrhoea); Pelvic pain Cervical secretion;	Breast enlargement; Premenstrual syndrome (PMS)
General disorders and administration site reactions		Asthenic disorders (asthenia, fatigue, malaise); Peripheral oedema
Investigations		Increase in weight	Decrease in weight

Risk of breast cancer
• An up to 2 times higher risk of the diagnosis of breast cancer is reported in women who have
used combined estrogen-progestagen HRT for more than 5 years.
• For users of estrogen monotherapy the increased risk is substantially lower than for users of
combined estrogen-progestagen therapy.
• The level of the risk depends on the duration of use (see section 4.4)
• The results of the biggest randomised placebo-controlled study (WHI) and the biggest
epidemiological study (MWS) are set out below.

Million Women Study (MWS) – estimated extra risk of breast cancer after 5 years use

Age group (years)	Extra cases per 1,000 non-HRT users over a period of 5 years*	Risk ratio#	Extra cases per 1,000 HRT users over a period of 5 years (95%CI)
Estrogen mono HRT
50-65	9-12	1.2	1-2 (0-3)
Combined estrogen-progestagen therapy as HRT
50-65	9-12	1.7	6 (5-7)
#Overall risk ratio. The risk ratio is not constant, but will rise with a longer duration of use N.B.: Since the background incidence of breast cancer differs for each EU country, the number of extra cases of breast cancer will also be proportionately different. *Deduced from the baseline incidence in developed countries

 

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

Age group (years)	Incidence per 1,000 women in the placebo group over a period of 5 years	Risk ratio & 95% Confidence interval (CI)	Extra cases per 1,000 HRT users over a period of 5 years (95%CI)
EEC estrogen mono HRT
50-79	21	0.8 (0.7 – 1.0)	-4 (-6 – 0)*
EEC+ MPA combined estrogen-progestagen HRT ‡
50-79	17	1.2 (1.0 – 1.5)	+4 (0 – 9)

‡if the analysis was limited to women who did not use HRT before the start of the study no increased risk was
observed during the first 5 years of treatment: after 5 years the risk was higher than for non-users.
*WHI study in women with no uterus, in which no increased risk of breast cancer was observed.

Risk of endometrial cancer
Postmenopausal women with a uterus:
The risk of endometrial cancer is around 5 in every 1,000 women with a uterus not using HRT.
In women with a uterus the use of estrogen monotherapy is not recommended, because this
increases the risk of endometrial cancer (see section 4.4).
Depending on the duration of use of estrogen monotherapy and the estrogen dose used, the
increase in the risk of endometrial cancer in epidemiologic studies varied between 5 and 55 extra
cases diagnosed per 1,000 women aged between 50-65 years.
The addition of a progestagen to the estrogen monotherapy for at least 12 days per cycle may
prevent this increased risk. In the Million Women Study the risk of endometrial cancer did not
increase for 5 years of combined (sequential or continuous) HRT (RR 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 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 to 3 times higher relative risk of developing venous
thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The chance of this is
greater during the first year of HRT treatment (see section 4.4). The results of the WHI are set out
below:

WHI Studies – extra risk of VTE during 5 years use

age group (years)	Incidence per 1,000 women in the placebo group over a period of 5 years	Risk ratio and 95% CI	Extra cases per 1,000 HRT users over a period of 5 years (95% CI)
Oral estrogen mono HRT*
50-59	7	1.2 (0.6-2.4)	1 (-3 – 10)
Oral combined estrogen-progestagen HRT
50-59	4	2.3 (1.2 – 4.3)	5 (1 - 13)

* Study in women with no uterus.

Risk of coronary artery disease
The risk of coronary artery disease is slightly increased in users aged over 60 years for combined
estrogen-progestagen HRT (see section 4.4).
Risk of an ischemic stroke
The use of estrogen monotherapy and combined estrogen-progestagen HRT is associated with
up to a 1.5 times higher relative risk of an ischemic stroke. The risk of a haemorrhagic stroke is
not increased during use of HRT.

This relative risk does not depend on the age or the duration of use, but because the risk in the
initial situation is strongly dependent on age, the risk of a stroke in users of HRT generally
increases with the increase in age (see section 4.4).

Combined WHI studies – extra risk of an ischemic stroke* during 5 years use

Age group (years)	Incidence per 1,000 women in the placebo group over a period of 5 years	Risk ratio and 95% CI	Extra cases per 1,000 HRT users over a period of 5 years (95% CI)
50-59	8	1.3 (1.1-1.6)	3 (1-5)

*No distinction is made between ischemic and haemorrhagic stroke

Other reported undesirable effects associated with treatment with estrogen/progestagen:
Neoplasms, benign, malignant and unspecified:
Benign and malignant estrogen-dependent neoplasms, for example endometrial cancer and
ovarian cancer. Increase in size of meningioma.

Immune system disorders:
Systemic Lupus Erythematodes (SLE).

Nutritional and metabolic disorders:
Hypertriglyceridaemia.

Central nervous system disorders:
Possible dementia, chorea, aggravation of epilepsy.

Vascular disorders:
Arterial thromboembolism.

Gastrointestinal disorders:
Pancreatitis (in women with pre-existing hypertriglyceridaemia).

Skin and sub-cutaneous disorders:
Erythema multiforme.

Renal and urinary tracts disorders:
Urine incontinence.

Reproductive system and breast disorders
Fibrocystic breast disorder, uterine cervical erosion.

Congenital, familial and genetic disorders.
Aggravation of porphyria.

Investigations:
Increased level of total thyroid hormone.

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side
effects not listed in this leaflet. By reporting side effects you can help provide more
information on the safety of this medicine.

To report any side effect(s):
-National Pharmacovigilance Center (NPC)
o Fax: +966-1-205-7662
o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
o Toll free phone: 8002490000
o E-mail: npc.drug@sfda.gov.sa

 

 

 

Both estradiol and dydrogesterone are substances with a low toxicity. Symptoms such as nausea,
vomiting, breast tenderness, dizziness, abdominal pain drowsiness/fatigue and withdrawal
bleeding may occur in case of overdose. Specific or symptomatic treatment is probably not
necessary.
The information described above also applies after overdose in children.

Pharmacotherapeutic category: urogenital system and sex hormones, progestagens and estrogens,
sequential products
ATC code: G03FB08.
Estradiol
The active ingredient, synthetic 17β-estradiol is chemically and biologically identical to the
natural human female sex hormone estradiol. It substitutes for the loss of own estrogen production
in postmenopausal women and alleviates menopausal symptoms. Estrogens prevent loss of bone
mass following menopause or ovarectomy.
Dydrogesterone
Dydrogesterone is an orally active progestagen that has an activity comparable with parenterally
administered progesterone.
As estrogens promote the growth of the endometrium, if no progestagen is used, they will lead to
an increased risk of endometrial hyperplasia and carcinoma. The addition of a progestagen largely
reduces the estrogen-induced risk in women with a uterus.

Information from clinical studies
• Alleviation of estrogen-deficiency symptoms and the bleeding pattern:
• Alleviation of menopausal symptoms was achieved in the initial weeks of treatment.
89% of women suffered from regular withdrawal bleeding that lasted on average 5 days. The
withdrawal bleeding usually started on day 28 of the cycle. 22% of the women suffered from
breakthrough bleeding or spotting during the first 3 months treatment; for 19% of the women this
was during the 10th to 12th month of treatment. Amenorrhoea (no bleeding or spotting) occurred in
12% of cycles during the first year of treatment.

Osteoporosis prevention
Estrogen deficiency after the menopause is associated with an increase in bone turnover and
decline in bone mass. The effect of estrogens on bone density is dose-related. Protection seems to
be effective as long as the treatment continues. After discontinuation of the HRT the rate of bone
mass loss is the same as that in untreated women.
The WHI study and meta-analyses of other studies showed that use of HRT (estrogen preparations
or combined preparations) by predominantly healthy women leads to a reduction in the risk of hip,
vertebral and other osteoporotic fractures. HRT may possibly also lead to prevention of fractures
in women with a low bone density and/or in whom osteoporosis is established, but the available
data relating to this patient group is limited.
After two years treatment with Femoston 2/10, the bone density of the lumbar spine increased by
6.7%  3.9% (mean  SD). The percentage of women in whom during the treatment the bone
density of the lumbar spine was maintained or increased was 94.5%.
Femoston 2/10 also had an effect on the bone density of the hip. After two years treatment with
Femoston 2/10 the bone density at the femoral neck increased by 2.6%  5.0% (mean SD), at the
trochanter by 3.5%  5.0% (mean SD) and at the Ward’s triangle 4.1%  7.4% (mean SD). The
percentage of women in whom after treatment with Femoston 2/10 the bone density in the 3 hip
areas was maintained or increased, was 71-88%.

 

Estradiol
Absorption:
Absorption of estradiol depends on the particle size: micronized estradiol is readily absorbed from
the gastrointestinal tract.
The following table gives the average steady state pharmacokinetic parameters of estradiol
(E2), estrone (E1) and estrone sulphate (E1S) for each dose of micronized estradiol. Data are
presented as averages (SD).

Estradiol 2 mg
Parameters	E2	E1	Parameters	E1S
Cmax (pg/ml)	103.7 (48.2)	622.2 (263.6)	Cmax (ng/ml)	25.9 (16.4)
Cmin (pg/ml)	48 (30)	270 (131)	Cmin (ng/ml)	5.7 (5.9)
Cav (pg/ml)	68 (31)	429 (191)	Cav (ng/ml)	13.1(9.4)
AUC0- 24 (pg.h/ml)	1619 (733)	10209 (4561)	AUC0- 24 (ng.h/ml)	307.3 (224.1)

Distribution:
Estrogens may occur bound or unbound. Approx. 98-99% of the estradiol dose binds to plasma
proteins, with approx. 30-52% to albumin and approx. 46-69 % to sex-hormone binding globulin
(SHBG).
Biotransformation:
Following oral administration estradiol is metabolised on a large scale. The main unconjugated
and conjugated metabolites are estrone and estrone sulphate. These metabolites may contribute to
estrogen activity, either directly, or after conversion into estradiol. Estrone sulphate may undergo
enterohepatic circulation.

Elimination:
Glucuronides are the main components of estrone and estradiol in the urine. The elimination halflife
is between 10 and 16 hours.
Estrogens are secreted in the breast milk.
Dose and time dependencies:
Following daily oral administration of Femoston estradiol concentrations reach a steady state after
around 5 days.
Generally steady state concentrations appear to be reached within 8 to 11 days of dosing.

Dydrogesterone
Absorption:
Following oral administration dydrogesterone is quickly absorbed with a Tmax between 0.5 and 2.5
hours. The absolute biological availability of dydrogesterone (20 mg oral dose versus 7.8 mg
intravenous infusion) is 28%.
The following table gives the average pharmacokinetic parameters of dydrogesterone (D) and
dihydrodydrogesterone (DHD) data are presented as averages (SD).

Dydrogesterone 10 mg
Parameters	D	DHD
Cmax (ng/ml)	2.54 (1.80)	62.50 (33.10)
Cmin (ng/ml)	0.13 (0.07)	3.70 (1.67)
Cav (ng/ml)	0.42 (0.25)	13.04 (4.77)
AUC0-τ (ng·h/ml)	9.14 (6.43)	311.17 (114.35)

Distribution:
Following intravenous administration of dydrogesterone the steady-state distribution volume is
around 1400 l. More than 90% of dydrogesterone and DHD is bound to plasma proteins.
Biotransformation:
Following oral administration dydrogesterone is quickly metabolized to DHD. The levels of the
main active metabolite 20α-dihydrodydrogesterone (DHD) show a peak around 1.5 hours after
administration. The plasma levels of DHD are substantially higher than those of the related
medicinal product. The AUC and Cmax ratios of DHD and dydrogesterone are of the order of
magnitude of respectively 40 and 25. The mean terminal half-life of dydrogesterone and DHD
varies from respectively 5 to 7 and 14 to 17 hours. A common feature of all metabolites described
is the retention of the 4,6-diene-3-one configuration of the original molecule and the absence of
17α-hydroxylation. This explains the absence of estrogenic and androgenic effects of
dydrogesterone.

Elimination:
Following oral administration of labelled dydrogesterone on average 63% of the dose is excreted
in the urine. The total plasma clearing is 6.4 l/minute. Excretion is complete within 72 hours.
DHD is predominantly present in the urine as the conjugated glucuronic acid.
Dose and time dependencies:
The pharmacokinetics of single and multiples doses are linear in the oral dosage range of 2.5 to
10 mg. Comparison of the kinetics of single and multiple doses shows that the
pharmacokinetics of dydrogesterone and DHD do not change as a result of repeated doses.
Steady state was reached after 3 days treatment.

There are no relevant preclinical data for the prescriber that are in addition to the data already
stated in other sections of the Summary of Product Characteristics (SmPC).

Composition of the tablet core
Lactose monohydrate
Hypromellose
Maize starch
Colloidal (anhydrous) silica
Magnesium stearate

Composition of the film coating

Formulation	Tablet colour	Composition
2 mg estradiol	brick red	Titanium dioxide (E171) Red iron oxide (E172) Black iron oxide (E172) Yellow iron oxide (E172) Hypromellose Macrogol 400 Talc
mg estradiol and 10 mg dydrogesterone	yellow	Titanium Dioxide (E171) Yellow iron oxide (E172) Hypromellose Macrogol 400 Talc

 

 

Not applicable.

3 years.

Do not store above 30°C

PVC-Aluminium blister packs in a printed cardboard carton.
Blister pack: 28 film-coated tablets
84 film-coated tablets
280 (10 x 28) film-coated tablets
Not all the pack forms listed are marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.