Gadofem

Hormone replacement therapy for oestrogen deficiency symptoms in postmenopausal women more than 1 year post menopause.

Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis.

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The experience treating women older than 65 years is limited.

Women who do not take hormone replacement therapy (HRT) or women who change from another continuous combined product may start treatment at any time. Women changing from a cyclic, sequential combined HRT regimen, treatment should begin the day following completion of the prior regimen.

Posology

One tablet is taken daily. Each blister is for 28 days of treatment.

Method of administration

The tablets are to be swallowed whole with some liquid irrespective of food intake. Treatment is continuous, which means that the next pack follows immediately without a break. The tablets should preferably be taken at the same time every day. If a tablet is forgotten it should be taken as soon as possible. If more than 24 hours have elapsed no extra tablet needs to be taken. If several tablets are forgotten, vaginal bleeding may occur.

For treatment of post menopausal symptoms, the lowest effective dose should be used.

) should be used.

Additional information on special populations

Paediatric population

Gadofem is not indicated for use in children and adolescents.

Geriatric patients

There are no data suggesting a need for dosage adjustment in elderly patients.

Patients with hepatic impairment

Pharmacokinetic properties). Gadofem is contraindicated in women with severe hepatic disease.

Patients with renal impairment

In women with mild or moderate renal impairment, a slight increase of drospirenone exposure was observed but is not expected to be of clinical relevance. Gadofem is contraindicated in women with severe renal disease.

- Undiagnosed genital bleeding

- Known, past or suspected cancer of the breast

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

- Untreated endometrial hyperplasia

- Previous or current venous thromboembolism (deep venous thrombosis, pulmonary embolism)

- Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction)

- Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal

- Known thrombophilic disorders (e.g. protein

- Severe renal insufficiency or acute renal failure

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- Porphyria

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

Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women.

Medical examination/follow-up

Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse. 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 Gadofem, in particular:

- Leiomyoma (uterine fibroids) or endometriosis,

- Risk factors for, thromboembolic disorders (see below)

- Risk factors for oestrogen dependent tumours, e.g. 1st degree heredity for breast cancer

- Hypertension

- Liver disorders (e.g. liver adenoma)

- Diabetes mellitus with or without vascular involvement

- Cholelithiasis

- Migraine or (severe) headache

- Systemic lupus erythematosus

- A history of endometrial hyperplasia (see below)

- Epilepsy

- Asthma

- Otosclerosis

Reasons for immediate withdrawal of therapy

Therapy should be discontinued in case a contra-indication is discovered and in the following situations:

- Jaundice or deterioration in liver function

- Significant increase in blood pressure

- New onset of migraine-type headache

- Pregnancy

Endometrial hyperplasia and carcinoma

In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among oestrogen-only users varies from 2- to 12-fold greater compared with non-users, depending on the duration of treatment and oestrogen dose. After stopping treatment risk may remain elevated for at least 10 years.

The addition of a progestogen cyclically for at least 12 days per month/28 day cycle or continuous combined oestrogen-progestogen therapy in non-hysterectomised women prevents the excess risk associated with oestrogen-only HRT.

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 suggests an increased risk of breast cancer in women taking combined oestrogen-progestogen and possibly also oestrogen-only HRT, that is dependent on the duration of taking HRT.

The randomised placebo-controlled trial, the Women's Health Initiative study (WHI), and 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 years. The excess risk becomes apparent within a few years of use but returns to baseline within a few (at most five) years after stopping treatment.

HRT, especially oestrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Ovarian cancer

Ovarian cancer is much rarer than breast cancer.

Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking oestrogen-only or combined oestrogen-progestagen 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.

Venous thromboembolism

HRT is associated with a 1.3- to 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.

Generally recognised risk factors for VTE include use of oestrogens, older age, major surgery, a personal history or family history 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.

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.

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

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

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

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.

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.

Other conditions

Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed.

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

Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-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.

The progestin component in Gadofem is an aldosterone antagonist exhibiting weak potassium sparing properties.).

Women with elevated blood pressure may experience a decrease in blood pressure under treatment with Gadofem due to the aldosterone antagonist activity of drospirenone. Gadofem should not be used to treat hypertension. Women with hypertension should be treated according to hypertension guidelines.

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking HRT.

Each tablet of this medicinal product contains 46 mg lactose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption who are on a lactose-free diet should take this amount into consideration.

Gadofem has no influence on the ability to drive and use machines.

The table below reports adverse reactions by MedDRA system organ classes (MedDRA SOCs). The frequencies are based on clinical trial data. The adverse reactions were recorded in 7 Phase III clinical studies (n=2424 women) and considered as at least possibly causally related to Gadofem (E2 1 mg / DRSP doses 0.5, 1, 2, or 3 mg).

The most commonly reported adverse reactions were breast pain (> 10%) and during the first few months of treatment, bleeding and spotting (> 10%). Bleeding irregularities usually subside during continued treatment. The frequency of bleeding decreases with the duration of treatment.

The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

Additional information on special populations

The following, undesirable effects classified as at least possibly related to Gadofem treatment by the investigator, were recorded in 2 clinical studies in hypertensive women.

Metabolism and nutrition disorders

Hyperkalemia

Cardiac disorders

Cardiac failure, atrial flutter, QT interval prolonged, cardiomegaly

Investigations

Blood aldosterone increased.

The following undesirable effects have been reported in association with HRT products: Erythema nodosum, eythema multiforme, chloasma and hemorrhagic dermatitis.

Breast cancer risk

An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestagen therapy for more than 5 years. Any increased risk in users of oestrogen-only therapy is substantially lower than that seen in users of oestrogen-progestagen combinations. The level of risk is dependent on the duration of use. Results of the largest randomised placebo-controlled trial (WHI study) and largest epidemiological study (MWS) are presented.

Endometrial cancer risk

Postmenopausal women with a uterus

The endometrial cancer risk is about 5 in every 1000 women with an uterus not using HRT. In women with a uterus, use of oestrogen-only HRT is not recommended because it increases the risk of endometrial cancer. 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 progestagen to oestrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study the use of five years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer (RR of 1.0 (0.8-1.2)).

Ovarian cancer

Use of oestrogen-only or combined oestrogen-progestagen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed.

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 HT. Results of the WHI studies are presented:

Risk of coronary artery disease

The risk of coronary artery disease is slightly increased in users of combined oestrogen-progestagen HRT over the age of 60.

Risk of ischaemic stroke

The use of oestrogen-only and oestrogen-progestagen 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

Other adverse reactions have been reported in association with oestrogen/progestogen treatment

- Gall bladder disease.

- Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura.

- Probable dementia over the age of 65.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

In clinical studies in male volunteers doses up to 100 mg of drospirenone were well tolerated. Based on general experience with combined oral contraceptives, symptoms that may possibly occur are nausea and vomiting and - in young girls and some women - vaginal bleeding. There are no specific antidotes, and, therefore, treatment should be symptomatic

Pharmacotherapeutic group: progestogens and estrogens, combinations. ATC code: G03FA17

Oestradiol

Gadofem contains synthetic 17ß-oestradiol, which is chemically and biologically identical to endogenous human oestradiol. It substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms. Oestrogens prevent bone loss following menopause or ovariectomy.

Drospirenone

Drospirenone is a synthetic progestogen.

As oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestogen reduces, but does not eliminate the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

Drospirenone displays aldosterone antagonist activity. Therefore, increases in sodium and water excretion and decreases in potassium excretion may be observed.

In animal studies, drospirenone has no oestrogenic, glucocorticoid or antiglucocorticoid activity.

Clinical trial information

- Relief of oestrogen-deficiency symptoms and bleeding patterns

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

Amenorrhea was seen in 73% of the women during months 10-12 of treatment. Breakthrough bleeding and /or spotting appeared in 59% of the women during the first three months of treatment and in 27% during months 10-12 of treatment.

- Prevention of osteoporosis

Oestrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass.

The effect of oestrogen on the bone mineral density is dose-dependent. Protection appears to be effective 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 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 2 years of treatment with Gadofem, the increase in hip bone mineral density (BMD) was 3.96 +/- 3.15% (mean +/- SD) in osteopenic patients and 2.78 +/- 1.89% (mean +/- SD) in non-osteopenic patients. The percentage of women who maintained or gained BMD in hip zone during treatment was 94.4% in osteopenic patients and 96.4% in non-osteopenic patients.

Gadofem also had an effect on lumbar spine BMD. The increase after 2 years was 5.61 +/- 3.34% (mean +/- SD) in osteopenic women and 4.92+/- 3.02% (mean +/- SD) in non-osteopenic women. The percentage of osteopenic women who maintained or gained BMD in lumbar zone during treatment was 100% , whereas this percentage was 96.4% in non-osteopenic women.

- Antimineralocorticoid activity

DRSP has aldosterone antagonistic properties that can result in a decrease in blood pressure in hypertensive women. In a double-blind placebo-controlled trial hypertensive postmenopausal women treated with Gadofem (n=123) for 8 weeks experienced a significant decrease in systolic/diastolic blood pressure values (office cuff versus baseline -12/-9 mm Hg, corrected for placebo effect -3/-4 mm Hg; 24h ambulatory blood pressure measurement versus baseline -5/—3 mm Hg, corrected for placebo effect -3/-2 mm Hg).

Gadofem should not be used to treat hypertension. Women with hypertension should be treated according to hypertension guidelines.

Drospirenone

- Absorption

After oral administration drospirenone is rapidly and completely absorbed. With a single administration, peak serum levels of approx. 21.9 ng/ml are reached about 1 hour after ingestion. After repeated administration, a maximum steady-state concentration of 35.9 ng/ml is reached after about 10 days. The absolute bioavailability is between 76 and 85%. Concomitant ingestion of food had no influence on the bioavailability.

- Distribution

After oral administration, serum drospirenone levels decrease in two phases which are characterised by a mean terminal half-life of about 35-39 hours. Drospirenone is bound to serum albumin and does not bind to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG). Only 3-5% of the total serum drug concentrations are present as free steroid. The mean apparent volume of distribution of drospirenone is 3.7-4.2 l/kg.

- Biotransformation

Drospirenone is extensively metabolized after oral administration. The major metabolites in plasma are the acid form of drospirenone, generated by opening of the lactone ring, and the 4,5-dihydro-drospirenone-3-sulphate, formed by reduction and subsequent sulfatation. Both major metabolites are pharmacologically inactive. Drospirenone is also subject to oxidative metabolism catalysed by CYP3A4.

- Elimination

The metabolic clearance rate of drospirenone in serum is 1.2-1.5 ml/min/kg showing an intersubject variability of about 25%. Drospirenone is excreted only in trace amounts in unchanged form. The metabolites of drospirenone are excreted with the faeces and urine at an excretion ratio of about 1.2 to 1.4. The half-life of metabolite excretion with the urine and faeces is about 40 hours.

- Steady-state conditions and linearity

Following daily oral administration of Gadofem, drospirenone concentrations reached a steady-state after about 10 days. Serum drospirenone levels accumulated by a factor of about 2 to 3 as a consequence of the ratio of terminal half-life and dosing interval. At steady-state, mean serum levels of drospirenone fluctuate in the range of 14-36 ng/ml after administration of Gadofem. Pharmacokinetics of drospirenone are dose-proportional within the dose range of 1 to 4 mg.

Oestradiol

- Absorption

Following oral administration, oestradiol is rapidly and completely absorbed. During the absorption and the first liver passage, oestradiol undergoes extensive metabolism, thus reducing the absolute bioavailability of oestrogen after oral administration to about 5% of the dose. Maximum concentrations of about 22 pg/ml were reached 6-8 hours after single oral administration of Gadofem. The intake of food had no influence on the bioavailability of oestradiol as compared to drug intake on an empty stomach.

- Distribution

Following oral administration of Gadofem only gradually changing serum levels of oestradiol are observed within an administration interval of 24 hours. Because of the large circulating pool of oestrogen sulphates and glucuronides on the one hand and the enterohepatic recirculation on the other hand, the terminal half-life of oestradiol represents a composite parameter that is dependent on all of these processes and is in the range of about 13-20 hours after oral administration.

Oestradiol is bound non-specifically to serum albumin and specifically to SHBG. Only about 1-2% of the circulating oestradiol is present as free steroid, 40-45% is bound to SHBG. The apparent volume of distribution of oestradiol after single intravenous administration is about 1 l/kg.

- Biotransformation

Oestradiol is rapidly metabolized, and besides oestrone and oestrone sulphate, a large number of other metabolites and conjugates are formed. Oestrone and oestriol are known as pharmacologically active metabolites of oestradiol; only oestrone occurs in relevant concentrations in plasma. Oestrone reaches about 6-fold higher serum levels than oestradiol. The serum levels of the oestrone conjugates are about 26-times higher than the corresponding concentrations of free oestrone.

- Elimination

The metabolic clearance has been found to be about 30 ml/min/kg. The metabolites of oestradiol are excreted via urine and bile with a half-life of about 1 day.

- Steady-state conditions and linearity

Following daily oral administration of Gadofem, oestradiol concentrations reached a steady-state after about five days. Serum oestradiol levels accumulate approx. 2-fold. Orally administered oestradiol induces the formation of SHBG which influences the distribution with respect to the serum proteins, causing an increase of the SHBG-bound fraction and a decrease in the albumin-bound and unbound fraction indicating non-linearity of the pharmacokinetics of oestradiol after ingestion of Gadofem. With a dosing interval of 24 hours, mean steady-state serum levels of oestradiol fluctuate in the range of 20-43 pg/ml following administration of Gadofem. Pharmacokinetics of oestradiol are dose-proportional at doses of 1 and 2 mg.

Special populations

- Hepatic impairment

The pharmacokinetics of a single oral dose of 3 mg DRSP in combination with 1 mg oestradiol (E2) was evaluated in 10 female patients with moderate hepatic impairment (Child Pugh B) and 10 healthy female subjects matched for age, weight, and smoking history. Mean serum DRSP concentration-time profiles were comparable in both groups of women during the absorption/ distribution phases with similar Cmax and tmax values, suggesting that the rate of absorption was not affected by the hepatic impairment. The mean terminal half-life was about 1.8-times greater and an about 50% decrease in apparent oral clearance (CL/f) was seen in volunteers with moderate hepatic impairment as compared to those with normal liver function.

- Renal Impairment

The effect of renal insufficiency on the pharmacokinetics of DRSP (3 mg daily for 14 days) were investigated in female subjects with normal renal function and mild and moderate renal impairment. At steady-state of DRSP treatment, serum DRSP levels in the group with mild renal impairment (creatinine clearance CLcr, 50-80 ml/min) were comparable to those in the group with normal renal function (CLcr, > 80 ml/min). The serum DRSP levels were on average 37% higher in the group with moderate renal impairment (CLcr, 30-50 ml/min) compared to those in the group with normal renal function. Linear regression analysis of the DRSP AUC(0-24 hours) values in relation to the creatinine clearance revealed a 3.5% increase with a 10 ml/min reduction of creatinine clearance. This slight increase is not expected to be of clinical relevance.

Animal studies with oestradiol and drospirenone have shown expected oestrogenic and gestagenic effects. There are no preclinical data of relevance to the prescriber that are additional to those already included in other sections of the SPC.

Not applicable.

No special requirements.