Femoston 1/10 & 2/10/Femoston Conti 1/5

Femoston 1/10: White 1 mg tablets and grey 1/10 mg tablets.
14 tablets, each containing 1 mg 17β-estradiol (as hemihydrate) and 14 tablets, each containing 1 mg 17β-estradiol (as hemihydrate) and 10 mg dydrogesterone.
Femoston 2/10: Brick red 2 mg tablets and yellow 2/10 mg tablets.
14 tablets, each containing 2 mg 17β-estradiol (as hemihydrate) and 14 tablets, each containing 2 mg 17β-estradiol (as hemihydrate) and 10 mg dydrogesterone.
Excipient with known effect: Lactose monohydrate.
Femoston Conti 1/5: 28 tablets, each containing 1 mg 17β-estradiol (as hemihydrate) and 5 mg dydrogesterone.
Excipient with known effect: lactose monohydrate.
Excipients/Inactive Ingredients: Core: Lactose monohydrate, Hypromellose, Maize starch, Colloidal anhydrous silica, Magnesium stearate.
Film-coating: Femoston 1/10: 1 mg estradiol: white: Titanium dioxide (E171), Hypromellose, Macrogol 400.
1 mg estradiol and 10 mg dydrogesterone: grey: Titanium Dioxide (E171), Iron oxide black (E172), Polyvinyl alcohol, Macrogol 3350, Talc.
Femoston 2/10: 2 mg estradiol: brick red: Titanium dioxide (E171), Iron oxide red (E172), Iron oxide black (E172), Iron oxide yellow (E172), Hypromellose, Macrogol 400, Talc.
2 mg estradiol and 10 mg dydrogesterone: yellow: Titanium Dioxide (E171), Iron oxide yellow (E172), Hypromellose.
Femoston Conti 1/5: 1 mg estradiol and 5 mg dydrogesterone: salmon: Titanium dioxide (E171), Iron oxide yellow (E172), Iron oxide red (E172), Hypromellose, Macrogol 400.

Pharmacotherapeutic group: Femoston 1/10 & 2/10: Genito urinary system and sex hormones, progestogens and oestrogens, sequential preparations.
Femoston Conti 1/5: Genito urinary system and sex hormones, progestogens and oestrogens, fixed combinations.
ATC code: Femoston 1/10 & 2/10: G03FB08.
Femoston Conti 1/5: G03FA14.
Pharmacology: Pharmacodynamics: Estradiol: The active ingredient, 17β-estradiol, is chemically and biologically identical to the endogenous human estradiol. It substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms.
Femoston 2/10 & Femoston Conti 1/5: 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 estrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestogen greatly reduces the estrogen-induced risk of endometrial hyperplasia in nonhysterectomised women.
Clinical trial Information: Relief of oestrogen-deficiency symptoms and bleeding patterns; Relief of climacteric complaints was achieved during the first weeks of treatment.
Femoston 1/10 & Femoston 2/10: Withdrawal bleeding usually started at mean day 28 of the cycle.
Femoston 1/10: Regular withdrawal bleeding occurred in 76% of the women with a mean duration of 5 days. Break through bleeding and/or spotting appeared in 23% of the women during the first three months of therapy and in 15% of the women during months 10-12 of treatment. Amenorrhoea (no bleeding or spotting) occurred in 21% of the cycles during the first year of treatment.
Femoston 2/10: Regular withdrawal bleeding occurred in 89% of the women with a mean duration of 5 days. Break through bleeding and/or spotting appeared in 22% of the women during the first three months of therapy and in 19% of the women during months 10-12 of treatment. Amenorrhoea (no bleeding or spotting) occurred in 12% of the cycles during the first year of treatment.
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). For Femoston 2/10 the percentage of women who maintained or gained BMD in lumbar zone during treatment was 94.5%.
Femoston 2/10 also had an effect on hip BMD.
The increase after two years of treatment with Femoston 2/10 was 2.6% ± 5.0% (mean ± SD) at femoral neck, 4.6% ± 5.0% (mean ± SD) at trochanter and 4.1% ± 7.4% (mean ± SD) at Wards triangle.
The percentage of women who maintained or gained BMD in the 3 hip areas after treatment with Femoston 2/10 was 71-88%.
Femoston Conti 1/5: Amenorrhea was seen in 88% of the women during months 10-12 of treatment. Irregular bleeding and/or spotting appeared in 15% of the women during the first 3 months of treatment and in 12% during months 10-12 of treatment.
Prevention of osteoporosis: Oestrogen deficiency at menopause is associated with increase in bone turnover a 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 one year of treatment the bone mineral density in the lumbar vertebrae increased about 4.0% + 3.4% (mean ± SD). In 90% of the subjects the bone mineral density increased or stayed the same during treatment. Femoston conti 1/5 also had an effect on hip BMD. The increase after one year of treatment with Femoston conti 1/5 was 1.5% ± 4.5% (mean ± SD) at femoral neck, 3.7% ± 6.0% (mean ± SD) at trochanter and 2.1% ± 7.2% (mean ± SD) at Wards triangle. The percentage of women who maintained or gained BMD in the 3 hip areas after treatment with Femoston conti 1/5 was 71%, 66 and 81% respectively.
Pharmacokinetics: Estradiol: Absorption: Absorption of estradiol is dependent on the particle size, micronized estradiol is readily absorbed from the gastrointestinal tract.
The following tables provide mean steady-state pharmacokinetic parameters of estradiol (E2), estrone (E1) and estrone sulphate (E1S) for each dose of micronized estradiol. Data is presented as mean (SD).
Femoston 1/10 & Femoston Conti 1/5: (See Table 1.)

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Femoston 2/10: (See Table 2.)

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Distribution: Oestrogens are found either unbound or bound. About 98-99% of the estradiol dose binds to plasma proteins, from which about 30-52% on albumin and about 46-69% on the sex hormone-binding globulin (SHBG).
Metabolism: Following oral administration, estradiol is extensively metabolised. The major unconjugated and conjugated metabolites are estrone and estrone sulphate. These metabolites can contribute to the oestrogen activity, either directly or after conversion to estradiol. Estrone sulphate may undergo enterohepatic circulation.
Elimination: In urine, the major compounds are the glucuronides of estrone and estradiol. The elimination half-life is between 10-16 h. Oestrogens are secreted in the milk of nursing mothers.
Dose and time dependencies: Following daily oral administration of Femoston, estradiol concentrations reached a steady-state after about five days. Generally, steady-state concentrations appeared to be reached within 8 to 11 days of dosing.
Dydrogesterone: Absorption: Following oral administration, dydrogesterone is rapidly absorbed with a T_max between 0.5 and 1.5 hours.
The following table provides mean steady-state pharmacokinetic parameters of dydrogesterone (D) and dihydrodydrogesterone (DHD) after multiple dose administration of dydrogesterone. Data is presented as mean (SD).
Femoston 1/10 & 2/10: (See Table 3.)

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Femoston Conti 1/5: (See Table 4.)

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After a single dose, food delays the peak plasma concentration of dydrogesterone with approximately 1 hour, resulting in approximately 20% lower dydrogesterone peak plasma concentrations without affecting the extent of exposure to dydrogesterone and DHD.
Distribution: After oral administration of dydrogesterone the apparent volume of distribution is large, being approximately 22000 L. Dydrogesterone and DHD are more than 90% bound to plasma proteins.
Metabolism: Following oral administration, dydrogesterone is rapidly metabolized to DHD. The levels of the main active metabolite 20α-dihydrodydrogesterone (DHD) peak at similar times as dydrogesterone. The plasma levels of DHD are substantially higher as compared to the parent drug. The AUC and C_max ratios of DHD to dydrogesterone are approximately 25 and 20, respectively. The mean terminal half-lives of dydrogesterone and DHD is about 15 hours. 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 17α-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. The apparent total body clearance of dydrogesterone from plasma is high at approximately 20 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 20 mg. 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 conditions are generally reached after 3 days of treatment.
Toxicology: 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).

Femoston 1/10: Hormone replacement therapy for women with disorders due to natural or surgically induced menopause with an intact uterus.
Elderly population: The experience in treating women older than 65 years is limited.
Femoston 2/10: Hormone replacement therapy for women with disorders due to natural or surgically induced menopause.
Femoston Conti 1/5: Hormone replacement therapy (HRT) for the relief of symptoms due to estrogen deficiency in women with a uterus.
Prevention of postmenopausal osteoporosis in women with a uterus.

Method of administration: For oral use.
Femoston can be taken irrespective of food intake.
Paediatric population: There is no relevant indication for the use of Femoston in the paediatric population.
Femoston 1/10: One tablet, containing 1 mg estradiol, daily during 14 consecutive days per cycle of 28^th days on one tablet, containing 1 mg estradiol and 10 mg dydrogesterone, daily during the remaining 14 days has to be taken immediately after a 28 day cycle, the next treatment cycle is to be started. Patients should take one tablet a day orally, according to the sequence indicated on the package. Medication is to be continued without interruption.
If the patient is still menstruating, it is recommended to begin treatment on the first day after onset of menstruation.
If the patient is menstruating infrequently it is advisable to begin treatment after 10-14 days monotherapy of progestogen ("chemical curettage").
In patients who had their last period more than approximately 12 months ago treatment can be started at any time.
Femoston 2/10 and Femoston conti 1/5: Should be taken continuously without a break between packs.
For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see also Precautions) should be used.
Depending on the clinical response, the dosage can be subsequently be adjusted.
Patients changing from another continuous sequential or cyclical preparation should complete the 28-day cycle and then change to Femoston 2/10 or Femoston conti 1/5.
Patients changing from a continuous combined preparation may start therapy at any 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 taking the forgotten tablet. The likelihood of breakthrough bleeding or spotting may be increased.
Femoston 2/10: The oestrogen is dosed continuously. The progestogen is added for the last 14 days of every 28 day cycle, in a sequential manner.
Treatment commences with one brick red tablet daily for the first 14 days followed by one yellow tablet daily for the next 14 days, as directed on the 28 day calendar pack.
In general, sequential combined treatment should start with Femoston 1/10.
Femoston conti 1/5: The oestrogen and the progestogen are to be taken every day without interruption. One tablet is to be taken daily for a 28 day cycle.
Continuous combined treatment may be started with Femoston 1/5 depending on the time since menopause and the severity of the symptoms.

Both estradiol 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 symptomatic treatment will be necessary. Aforementioned information is also applicable for overdosing in children.

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 or current venous thromboembolism (deep venous thrombosis, pulmonary embolism).
Known thrombophilic disorders (e.g. protein C, protein S or antithrombin deficiency, see Precautions).
Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction).
Acute liver disease, or a history of liver disease, as long as the liver function tests have failed to return to normal.
Porphyria.
Known hypersensitivity to the active substances or to any of the excipients.

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 re-instituting 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' as follows). 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 as follows); Risk factors for estrogen 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 as follows); Epilepsy; Asthma; Otosclerosis.
Reasons for immediate withdrawal of therapy: Therapy should be discontinued in case a contraindication 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 Adverse Reactions). 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 estrogen-progestogen HRT that becomes apparent after about 3 (1-4) years (see Adverse Reactions).
Oestrogen-only therapy: The WHI trial found no increase in the risk of breast cancer in hysterectomised women using oestrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is substantially lower than that found in users of oestrogen-progestogen combinations (see Adverse Reactions).
Results from a large meta-analysis showed that after stopping treatment the excessive risk will decrease with time and time needed to return to baseline depends on 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 estrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
Ovarian cancer: Ovarian cancer is much rarer than breast cancer.
Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking oestrogen-only or combined oestrogen-progestogen HRT, which becomes apparent within 5 years of use and diminishes over time after Stopping. Some other studies, including the WHI trial suggest that use of combined HRTs may be associated with a similar, or slightly smaller, risk (see Adverse Reactions).
Venous thromboembolism: HRT is associated with 1.3-3 fold risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT than later (see Adverse Reactions).
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 Contraindications).
Generally recognised risk factors for VTE include: use of oestrogens, older age, major surgery, prolonged immobilization, 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 immobilization 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 benefits-risk of use of HRT.
If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic-symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).
Coronary artery disease (CAD): There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined oestrogen-progestogen or oestrogen-only HRT.
Combined oestrogen-progestogen therapy: The relative risk of CAD during use of combined oestrogen-progestogen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to oestrogen-progestogen use is very low in healthy women close to menopause, but will rise with more advanced age.
Oestrogen-only: Randomised controlled data found no increased risk of CAD in hysterectomised women using oestrogen-only therapy.
Ischaemic Stroke: Combined oestrogen-progestogen and oestrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see Adverse Reactions).
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.
Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.
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 radioimmunoassay) or T3 levels (by radioimmunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).
HRT use does not improve cognitive function. There is some evidence of increased risk of probable dementia in women who start using continuous combined or oestrogen-only HRT after the age of 65.
Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
This oestrogen-progestogen combination treatment is not contraceptive.
ALT elevations: During clinical trials with patients treated for hepatitis C virus (HCV) infections with the combination regimen ombitasvir/paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medicinal products such as CHCs. Additionally, also in patients treated with glecaprevir/pibrentasvir, ALT elevations were observed in women using ethinylestradiol-containing medicinal products such as CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co-administration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir and also the regimen glecaprevir/pibrentasvir. (See Interactions).
Effects on ability to drive and use machines: Femoston has no or negligible influence on the ability to drive and use machines.

Pregnancy: Femoston is not indicated during pregnancy. If pregnancy occurs during medication with Femoston, the medication must be withdrawn immediately.
The results of most epidemiological studies to date relevant to inadvertent fetal exposure to combinations of oestrogens with progestogens indicate no teratogenic or fetotoxic effect.
There are no adequate data from the use of estradiol/dydrogesterone in pregnant women.
Lactation: Femoston is not indicated during lactation.

The most commonly reported adverse drug reactions of patients treated with estradiol/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 as follows during clinical trials (n=5108): (See Table 5).

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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 y lower than that seen in users of oestrogen-progestogen combinations.
The level of risk is dependent on the duration of use (see Precautions).
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: (See Tables 6, 7 and 8).

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Endometrial cancer risk: 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 Precautions).
Depending on the duration of oestrogen-only use and oestrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 women between the ages of 50 and 65.
Adding a progestogen to oestrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study the use of five years of combined (sequential or continuous) HRT did not increase the risk of endometrial cancer (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 Precautions). 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 1.3-3-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 HRT (see Precautions). Results of the WHI studies are presented: (See Table 9.)

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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 Precautions).
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 Precautions). (See Table 10.)

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Other adverse reactions have been reported in association with oestrogen/progestogen treatment (including estradiol/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, 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.

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 P450 enzymes, 2B6, 3A4, 3A5, 3A7 such as anticonvulsants (e.g. phenobarbital, carbamazepine, phenytoin) 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.
Pharmacodynamic Interactions: During clinical trials with the HCV combination drug regime ombitasvir/paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medicinal products such as CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co-administration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir and also the regimen with glecaprevir/pibrentasvir (see Precautions).
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.

Incompatibilities: Not applicable.
Special precautions for disposal: No special requirements.

Do not store above 30°C.
Store in the original package.
Shelf life: 3 years.

Oestrogens, Progesterones & Related Synthetic Drugs

G03FB08 - dydrogesterone and estrogen ; Belongs to the class of progestogens and estrogens in sequential preparations.

C