1. Name Of The Medicinal Product
Progynova® 1mg
FemTab 1mg
2. Qualitative And Quantitative Composition
Each memo pack contains 28 tablets each containing estradiol valerate 1.0 mg.
3. Pharmaceutical Form
Sugar coated tablet for oral administration.
4. Clinical Particulars
4.1 Therapeutic Indications
Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in peri- and postmenopausal women.
See also section 4.4.
4.2 Posology And Method Of Administration
• Posology
Progynova (FemTab) is an oestrogen-only product.
One tablet of Progynova 1mg (FemTab 1mg) to be taken daily. It does not matter at what time of day the woman takes her tablet, but once she has selected a particular time she should keep to it every day. Treatment is continuous, which means that the next pack follows immediately without a break.
For initiation and continuation of treatment of menopausal symptoms, the lowest effective dose for the shortest duration (see also section 4.4) should be used. Treatment to control menopausal symptoms should be initiated with Progynova 1mg (FemTab 1mg). If considered necessary, Progynova 2mg (FemTab 2mg) should be used. Once treatment is established the lowest effective does necessary for relief of symptoms should be used.
In women with an intact uterus, a progestogen should be added to Progynova (FemTab) for at least 12 - 14 days each month. Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestogen in hysterectomised women.
• How to start Progynova 1mg (FemTab 1mg)
If the woman has an intact uterus and is still menstruating, a combination regimen with Progynova (FemTab) and a progestogen, commencing with the oestrogen phase, should begin on the first day of bleeding. If the menstrual periods are very infrequent or if amenorrhoea is established, she may start at any time provided, if appropriate, pregnancy has been excluded (see section 4.6 Pregnancy and lactation)..
In women transferring from a continuous combined HRT product, treatment with Progynova (FemTab) may be started on any day.
In women transferring from cyclic or continuous sequential HRT regimens the woman should complete the cycle and then change to Progynova (FemTab) without a break in therapy.
• Missed or lost tablets
If the woman forgets to take a tablet at the usual time, she may take it with in the following 12 hours. If the woman is more than 12 hours late the forgotten tablet should not be taken and the remaining tablets taken at the usual time on the right days. A missed dose may lead to breakthrough bleeding or spotting.
Children
Not recommended for children
4.3 Contraindications
- Known, past or suspected breast cancer
- Known or suspected oestrogen-dependent malignant tumours e.g. endometrial cancer
- Undiagnosed genital bleeding
- Untreated endometrial hyperplasia
- Previous idiopathic 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
- Porphyria
- Known hypersensitivity to the active substances or to any of the excipients
4.4 Special Warnings And Precautions For Use
For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.
Medical examination/follow-up:
• Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see 'Breast cancer' below). Investigations, including mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.
Conditions which require 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 Progynova (FemTab), in particular:
- Leiomyoma (uterine fibroids) or endometriosis
- A history of, or 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
- Hereditary angioedema
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
• The risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods (see section 4.8). The addition of a progestogen for at least 12 days per cycle in non-hysterectomised women greatly reduces this risk.
• Break-through bleeding and spotting may occur during the first months of treatment. If break-through 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.
• Unopposed oestrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestogens to oestrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis, if they are known to have residual endometriosis.
Breast Cancer
• A randomised placebo-controlled trial, the Women's Health Initiative study (WHI) and epidemiological studies, including the Million Women Study (MWS) have reported an increased risk of breast cancer in women taking oestrogens, oestrogen-progestogen combinations or tibolone for HRT for several years (see Section 4.8). For all HRT, an excess risk becomes apparent within a few years of use and increases with duration of intake but returns to baseline within a few (at most five) years after stopping treatment.
• In the MWS, the relative risk of breast cancer with conjugated equine oestrogens (CEE) or estradiol (E2) was greater when a progestogen was added, either sequentially or continuously, and regardless of type of progestogen. There was no evidence of a difference in risk between the different routes of administration.
• In the WHI study, the continuous combined conjugated equine oestrogen and medroxyprogesterone acetate (CEE + MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.
• HRT, especially oestrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
Venous thromboembolism
• HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. One randomised controlled trial and epidemiological studies found a two-to-threefold higher risk for users compared with non-users. For non-users, it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged between 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate = 4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later.
• Generally recognised risk factors for VTE include a personal history or family history, severe obesity (BMI > 30kg/m2) and systemic lupus erythematosus (SLE). There is no consensus about the possible role of varicose veins in VTE.
• Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. Those women already on anti-coagulant treatment require careful consideration of the benefit-risk of use of HRT.
• The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all postoperative patients, scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4 to 6 weeks earlier, if possible. Treatment should not be restarted until the woman is completely mobilised.
• 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 cardiovascular benefit with continuous combined conjugated oestrogens and medroxyprogesterone acetate (MPA). Two large clinical trials (WHI and HERS, i.e. Heart and Estrogen/progestin Replacement Study) showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products there are only limited data from randomised controlled trials examining effects in cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.
Stroke
• One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated oestrogens and MPA. For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 11 per 1000 women aged 60 – 69 years. It is estimated that for women who use conjugated oestrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate = 1) per 1000 users aged 50 – 59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60 – 69 years. It is unknown whether the increased risk also extends to other HRT products.
Ovarian Cancer
• Long-term (at least 5- 10 years) use of oestrogen-only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRT confers a different risk than oestrogen-only products.
Other conditions
• Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients in Progynova (FemTab) is increased.
• Women with pre-existing hypertriglyceridaemia should be followed closely during oestrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.
• Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).
• Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should minimise exposure to the sun or ultraviolet radiation whilst taking HRT.
• There is no conclusive evidence for improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65. It is unknown whether the findings apply to younger postmenopausal women or other HRT products.
• Progynova (FemTab) is not suitable as a contraceptive. If appropriate, contraception should be practised with non-hormonal methods.
• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
The metabolism of oestrogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbitol, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).
Ritonavir and nelfinavir, although known as strong inhibitors, 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.
Clinically, an increased metabolism of oestrogens and progestogens may lead to decreased effect and changes in the uterine bleeding profile.
4.6 Pregnancy And Lactation
• Pregnancy
Progynova (FemTab) is not indicated during pregnancy. If pregnancy occurs during medication with Progynova (FemTab) treatment should be withdrawn immediately.
The results of most epidemiological studies to date relevant to inadvertent foetal exposure to oestrogens indicate no teratogenic or foetotoxic effects.
• Lactation
Progynova (FemTab) is not indicated during lactation.
4.7 Effects On Ability To Drive And Use Machines
None known.
4.8 Undesirable Effects
The following undesirable effects have been reported in users of Progynova (FemTab) and other oral HRT preparations.
Neoplasms benign, malignant and unspecified
Breast cancer*, Endometrial cancer*
Immune system disorders
Hypersensitivity reaction, Exacerbation of hereditary angioedema.
Metabolism and nutrition disorder
Porphyria aggravated, Increased or decreased weight, Increased appetite, Carbohydrate tolerance decreased
Psychiatric disorders
Anxiety/depressive symptoms, Decreased or increased libido
Nervous system disorders
Migraine, Headache, Dizziness, Fatigue, Chorea, Stroke*
Eye disorders
Visual disturbances, Intolerance to contact lenses
Cardiac disorders
Palpitations, Myocardial infarction*
Vascular disorders
Hypertension, Thrombophlebitis, Venous Thromboembolism*
Respiratory, thoracic and mediastinal disorders
Epistaxis
Gastrointestinal disorders
Dyspepsia, Abdominal pain, Vomiting, Nausea, Bloating, Flatulence
Hepatobiliary disorders
Gall bladder disease including Cholestasis
Skin and subcutaneous tissue disorders
Rashes, various Skin disorders (including Pruritus, Eczema, Urticaria, Acne, Hirsutism, Hair loss, Erythema nodosum, Erythema multiforme, Rash hemorrhagic, Chloasma (see section 4.4)
Musculoskeletal and connective tissue disorders
Muscle cramps, Leg pain
Renal and urinary disorders
Cystitis-like symptom
Reproductive system and breast disorders
Increased size of uterine fibroids, Vaginal candidosis, Uterine cervical erosions, Changes in vaginal bleeding pattern and abnormal bleeding or flow, Breakthrough bleeding, Spotting (bleeding irregularities usually subside during continued treatment), Dysmenorrhoea, Changes in vaginal secretion, Premenstrual-like syndrome, Breast secretion, Breast tenderness, enlargement or pain.
General disorders and administration site conditions
Oedema
* Please see further information below.
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 (see section 4.4).
• Results of the largest randomised placebo-controlled trial (WHI study) and largest epidemiological study (MWS) are presented.
Million Women Study – estimated additional risk of breast cancer after 5 years of use
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US WHI studies - additional risk of breast cancer after 5 years of use
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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 (see section 4.4).
Depending on the duration of oestrogen-only use and oestrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 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
Long-term use of oestrogen-only and combined oestrogen-progestagen HRT has been associated with a slightly increased risk of ovarian cancer. In the Million Women Study 5 years of HRT resulted in 1 extra case per 2500 users.
Risk of venous thromboembolism
HRT is associated with a 1.3 - 3-fold increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of using HT (see section 4.4). Results of the WHI studies are presented:
WHI Studies - additional risk of VTE over 5 years of use
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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 (see section 4.4).
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 HRT will increase with age, see section 4.4.
WHI studies combined - Additional risk of ischaemic strokea over 5 years of use
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a No differentiation was made between ischaemic and haemorrhagic stroke.
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 (see Section 4.4)
4.9 Overdose
Nausea and vomiting may occur with an overdose. There are no specific antidotes, and treatment should be symptomatic. Withdrawal bleeding may occur in females with a uterus.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Progynova contains estradiol valerate, (the valeric-acid ester of the endogenous female oestrogen, estradiol).
The active ingredient, synthetic 17ß-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms.
5.2 Pharmacokinetic Properties
Absorption
After oral administration estradiol valerate is quickly and completely absorbed.
Distribution
Already after 0.5 - 3 hours peak plasma levels of estradiol, the active drug substance, are measured. As a rule, after 6 - 8 hours a second maximum appears, possibly indicating an entero-hepatic circulation of estradiol.
In plasma, estradiol is mainly found in its protein-bound form. About 37% are bound to SHBG and 61% to albumin. Cumulation of estradiol after daily repetitive intake of Progynova does not need to be expected.
The absolute bioavailability of estradiol amounts to 3 - 5% of the oral dose of estradiol valerate.
Metabolism
Esterases in plasma and the liver quickly decompose estradiol valerate into estradiol and valeric acid. Further decomposition of valeric acid through β-oxidation leads to C2-units and results in CO2 and water as end products. Estradiol itself undergoes several hydroxylating steps. Its metabolites as well as the unchanged substance are finally conjugated. Intermediate products of metabolism are estrone and estriol, which exhibit a weak oestrogenic activity of their own, although this activity is not so pronounced as with estradiol. The plasma concentration of conjugated estrone is about 25 to 30 fold higher than the concentration of unconjugated estrone. In a study using radioactive labelled estradiol valerate about 20% of radioactive substances in the plasma could be characterised as unconjugated steroids, 17% as glucuronised steroids and 33% as steroid sulphates. About 30% of all substances could not be extracted from the aqueous phase and, therefore, probably represent metabolites of high polarity.
Excretion
Estradiol and its metabolites are mainly excreted by the kidneys (relation of urine:faeces = 9:1). Within 5 days about 78 - 96% of the administered dose are excreted with an excretion half-life of about 27 hours.
5.3 Preclinical Safety Data
There are no preclinical safety data which could be of relevance to the prescriber and which are not already included in other relevant sections of the SPC.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Lactose monohydrate
Maize Starch
Povidone 25,000
Talc
Magnesium Stearate [E572]
Sucrose
Povidone 700,000
Macrogol 6,000
Calcium Carbonate [E170]
Titanium Dioxide [E171]
Glycerol 85% [E422]
Montan Glycol Wax
Ferric oxide pigment
Purified water
6.2 Incompatibilities
None known.
6.3 Shelf Life
5 years.
6.4 Special Precautions For Storage
None.
6.5 Nature And Contents Of Container
Container consists of aluminium foil and PVC blister strips packed in a cardboard carton.
Presentation: Carton containing memo-packs of either 1 x 28 tablets or 3 x 28 tablets.
6.6 Special Precautions For Disposal And Other Handling
None.
7. Marketing Authorisation Holder
Bayer plc
Bayer House
Strawberry Hill
Newbury
Berkshire RG14 1JA
Trading as Bayer plc, Bayer Schering Pharma
8. Marketing Authorisation Number(S)
PL 00010/0556
9. Date Of First Authorisation/Renewal Of The Authorisation
1 May 2008
10. Date Of Revision Of The Text
5th October 2011
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