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 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.
The oestrogen is dosed continuously. The progestogen is added for the last 14 days of every 28 day
cycle, in a sequential manner.
The treatment commenceswith one brick red tablet daily for the first 14 days followed by one
yellow tablet for the next 14 days, as indicated on the calendar pack for 28 days.
Femoston 2/10 should be taken continuously without a break between the packs.
For the treatment of oestrogen 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.
Women switching from cyclical or continuous sequential hormone replacement therapy should
complete first the 28 day cycle of this treatment and then start with Femoston 2/10.
In women switching from continuous combined hormone replacement therapy, the treatment can
be started on any convenient time.
If a dose has been forgotten, it should be taken as soon as possible. If more than 12 hours have
elapsed, treatment should be continued with the next tablet without taken the forgotten tablet. The
likelihood of breakthrough bleeding or spotting may be increased.
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 oestrogen-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 one of the excipients listed in section 6.1.

For the treatment of symptoms of oestrogen 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 prematuremenopause 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, contra-indications 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 asmammography, 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 conditionsmay 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 oestrogen-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 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 can
prevent the excess risk associated with oestrogen-only HRT.
• Breakthrough 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 oestrogenprogestogen
HRT, which becomes apparent within 5 years of use and diminishes over time after
stopping. Some other studies, including theWHI 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 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 oestrogens, 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. Patientsmust 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
oestrogen-progestogen or oestrogen-only HRT.
Combined oestrogen-progestogen therapy:
The relative risk of coronary artery disease during combined oestrogen-progestogen 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 oestrogenprogestogen
use is very low in healthy women who are close to the menopause. This number will
however increase as they get older.
Oestrogen monotherapy
In randomised controlled studies no increased risk of coronary artery disease was found in
hysterectomised women using oestrogen monotherapy.
Ischemic Stroke
Combined oestrogen-progestogen therapy and oestrogen 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
• Oestrogens may cause fluid retention and therefore, patients with a reduced cardiac or renal
function should be carefully observed.
• Women with a pre-existing hypertriglyceridaemia should be closely followed during
oestrogen replacement or hormone replacement therapy, since in rare cases in women with
this abnormality, the plasma triglycerides increased considerably during oestrogen therapy,
and have led to pancreatitis.
Oestrogens 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 (angiotensin-renin 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
oestrogen preparations after the age of 65 years.
• Patients with rare hereditary conditions, such as galactose intolerance, total lactase
deficiency or glucose-galactose malabsorption should not take this medicinal product.
• This oestrogen-progestogen combination treatment is not a contraceptive.

 

No studies have been carried out relating to interactions.
The efficacy of oestrogens and progestogensmay be disrupted:
- The metabolism of oestrogens (and progestogens) 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 oestrogens (and progestogens).
- Clinically an increased metabolismof oestrogens and progestogensmay 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 oestrogens and progestogens 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

Themost commonly reported 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 have been 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             Infections and parasitic infestations	Back pain	Vaginal candidiasis	Cystitis-like syndrome	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           Neoplasms, benign, malignant and unspecified		Increase in weight	Decrease in weight           Increase in sizeof myoma

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)

Age at start HRT (years)	Incidence per 1000 neverusers of HRT over a 5 year period (50-54 vears)*	Risk ratio	Additional cases per 1000 HRT users after 5 years
Oestrogen only HRT
50	13.3	1.2	2.7
Combined oestrogen-progestogen
50	13.3	1.6	8.0
*Taken from baseline incidence rates in England in 2015 in women with BMI 27 (kg/m2). Note: Since the background incidence of breast cancer differs by EU country, the number of 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)

Age at start HRT (years)	Incidence per 1000 neverusers of HRT over a 5 year period (50-54 vears)*	Risk ratio	Additional cases per 1000 HRT users after 5 years
Oestrogen only HRT
50	26.6	1.3	7.1
Combined oestrogen-progestogen
50	26.6	1.8	20.8

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

Age range (yrs)	Incidence per 1000 women in placebo arm over 5 years	Risk ratio & 95%CI	Additional cases per 1000 HRT users over 5 years (95%CI)
CEE oestrogen-only
50 - 79	21	0.8 (0.7 – 1.0)	-4 (-6 – 0)*
CEE+MPA oestrogen & progestogen‡
50 - 79	17	1.2 (1.0 – 1.5)	+4 (0 – 9)

 

*WHI study in women with no uterus, which did not show an increase in risk of breast cancer.
‡When the analysis was restricted to women who had not used HRT prior to the study there was no
increased risk apparent during the first 5 years of treatment: after 5 years the risk was higher than in
non-users.
Risk of endometrial cancer
Postmenopausal women with a uterus:
The risk of endometrial cancer is around 5 in every 1,000 women with an uterus not using HRT.
In women with a uterus the use of oestrogen monotherapy is not recommended, because this
increases the risk of endometrial cancer (see section 4.4).
Depending on the duration of use of oestrogen monotherapy and the oestrogen 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 progestogen to the oestrogen 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 2,000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2,000
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 theWHI 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
oestrogen-progestogen HRT (see section 4.4).
Risk of an ischemic stroke
The use of oestrogen monotherapy and combined oestrogen-progestogen 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 oestrogen-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.
Report 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 all suspected adverse reactions.

 

 

 

 

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 overdosing. It is unlikely that any specific or symptomatic treatment will be
necessary.
Paediatric patients:
The aforementioned information also applies for overdosing in children.

Pharmacotherapeutic category: urogenital system and sex hormones, progestogens and oestrogens,
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 oestrogen production in
postmenopausal women and alleviates menopausal symptoms. Oestrogens prevent loss of bone
mass following menopause or ovarectomy.

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

 

Dydrogesterone is an orally active progestogen that has an activity comparable with parenterally
administered progesterone.
As oestrogens promote the growth of the endometrium, if no progestogen is used, they will lead to
an increased risk of endometrial hyperplasia and carcinoma. The addition of a progestogen largely
reduces the oestrogen-induced risk in women with an uterus.
Information from clinical studies
• Alleviation of oestrogen-deficiency symptoms and the bleeding pattern:
• Alleviation ofmenopausal 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 3months treatment; for 19% of thewomen 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
Oestrogen deficiency after the menopause is associated with an increase in bone turnover and
decline in bonemass. The effect of oestrogens 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.
TheWHI study and meta-analyses of other studies showed that use of HRT (oestrogen preparations
or combined preparations) by predominantly healthy women leads to a reduction in the risk of hip,
vertebral and other osteoporotic fractures. HRTmay 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:
Oestrogensmay 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
oestrogen 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.
Oestrogens 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)

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 quicklymetabolized 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 fromrespectively 5 to 7 and 14 to 17 hours. A common feature of allmetabolites 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 oestrogenic 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).
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.

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.

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.