Estrofem®: composition and pharmaceutical form
One film-coated tablet contains 2 mg of estradiol as estradiol hemihydrate; one mite tablet contains 1 mg. The tablets contain lactose monohydrate, so the medicine should not be used in rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome.
The medicine contains oestrogen only and is intended for hormone replacement therapy. It is taken by mouth once a day, without a break in use.
How Estrofem® works
The active substance is synthetic 17β-estradiol, chemically and biologically identical to human endogenous estradiol. It makes up the shortfall of oestrogens in women during the menopause and thereby relieves menopausal symptoms; they resolve within the first few weeks of treatment.
From the fact that the medicine contains only oestrogen follows its main feature in use. In women with an intact uterus, prolonged oestrogen-only therapy raises the risk of endometrial hyperplasia and cancer, so they also need a progestagen. In women whose uterus has been removed that problem does not arise — which is precisely why the medicine is intended above all for them.
Indications
Hormone replacement therapy for the treatment of symptoms caused by oestrogen deficiency in postmenopausal women.
The medicine is indicated mainly in women whose uterus has been removed, that is, in those who do not need combined oestrogen-progestagen therapy. Experience in women over 65 is limited.
- hormone replacement therapy is started when menopausal symptoms adversely affect quality of life;
- treatment of menopausal symptoms begins with the lowest effective hormone dose and continues for as short a time as possible;
- the benefit-risk balance is assessed at least once a year, and therapy continues exactly as long as the benefit of treatment outweighs the risk that comes with it.
Method of use and dosage
Increasing or decreasing the daily dose is considered if after 3 months of treatment there is no satisfactory relief of symptoms caused by oestrogen deficiency, or if the medicine is not well tolerated. The day treatment starts depends on whether the uterus is intact and on which regimen the patient was on before.
| Situation | How to start |
| Women whose uterus has been removed | treatment may be started on any day |
| Women with an intact uterus, not menstruating, previously on sequential replacement therapy | treatment may be started on day 5 of bleeding and only in combination with a progestagen for at least 12–14 days |
| Women previously on continuous combined replacement therapy | treatment together with progesterone may be started on any day |
| Choice of progestagen | the type and dose must ensure suppression of oestrogen-induced endometrial proliferation |
| Missed tablet | take it as soon as possible within the next 12 hours; if more than 12 hours have passed, the missed tablet is discarded |
A missed dose in women with an intact uterus may increase the likelihood of bleeding or spotting. If endometriosis was not previously diagnosed, using a progestagen in women whose uterus has been removed is not recommended.
Contraindications
Hypersensitivity to the active substance or to any excipient. Known, past or suspected breast cancer. Known, past or suspected oestrogen-dependent malignant tumours, for example endometrial cancer. Undiagnosed genital bleeding. Untreated endometrial hyperplasia. Porphyria.
A separate block of contraindications concerns blood clotting and the vessels: past or present venous thromboembolic disease — deep vein thrombosis, pulmonary embolism; known disorders with a tendency to thrombosis, such as protein C, protein S or antithrombin deficiency; active or recent arterial thromboembolic disorders such as coronary heart disease and myocardial infarction. Acute liver disease or liver disease in the history also belongs here — until liver function test results return to normal values.
Special warnings and precautions
Before starting or changing therapy a full medical history is taken, including the family history, and a physical examination is carried out, including gynaecological examination and examination of the breasts, in order to exclude contraindications. During treatment periodic medical check-ups are carried out, with their frequency and type tailored to the individual; the woman is told to report any changes in her breasts to the doctor or nurse, and mammography and other investigations are performed according to the generally accepted screening schedule.
- close monitoring is needed in patients who have now, have had in the past, or saw worsen during pregnancy or previous hormone treatment: uterine fibroids or endometriosis, risk factors for thromboembolic disorders and for oestrogen-dependent tumours including breast cancer in first-degree relatives, arterial hypertension, liver disease, diabetes with or without vascular changes, gallstones, migraine or severe headaches, systemic lupus erythematosus, endometrial hyperplasia in the history, epilepsy, bronchial asthma, otosclerosis;
- the medicine is withdrawn immediately if any contraindication appears, and also in the case of jaundice or impaired liver function, a significant rise in blood pressure, migraine-type headaches and pregnancy;
- in women with an intact uterus, bleeding or spotting is possible during the first months of treatment; if it appears after some time or persists after treatment ends, the cause is investigated, including endometrial biopsy to exclude a tumour;
- unopposed oestrogen stimulation can lead to a premalignant state or a tumour in persisting endometriotic foci, so in women after hysterectomy in whom endometriosis or persisting foci were previously found, adding a progestagen is worth considering;
- where surgery with prolonged immobilisation is planned, temporary withdrawal of therapy 4–6 weeks before the operation is recommended, with resumption after the patient is fully mobile again; if venous thromboembolism develops during treatment, the medicine is withdrawn.
Oestrogens may increase fluid retention, so patients with circulatory or renal failure need particular monitoring, and where hypertriglyceridaemia was previously identified, supervision is intensified: rare cases of a marked rise in plasma triglycerides leading to pancreatitis have been described. Oestrogens raise the concentration of binding proteins — thyroid-binding globulin, corticosteroid-binding globulin and sex hormone-binding globulin — so that measures of total thyroid hormone, corticosteroids and sex hormones rise, while the concentrations of the free, biologically active hormones stay unchanged. Hormone replacement therapy does not improve cognitive function, and for women starting it after the age of 65 there are data on a probable risk of dementia.
Interaction with other medicines
The metabolism of oestrogens may be increased by the concurrent administration of substances that induce drug-metabolising enzymes, in particular the cytochrome P450 enzymes. Clinically, increased oestrogen metabolism leads to a weakening of their effect and to changes in the bleeding pattern.
- such inducers include the antiepileptics phenobarbital, phenytoin and carbamazepine;
- and also anti-infective medicines: rifampicin, rifabutin, nevirapine, efavirenz;
- ritonavir and nelfinavir, though potent inhibitors, show inducing properties when given together with sex hormones;
- herbal preparations containing St John's wort may likewise induce the metabolism of oestrogens.
Estrofem®'s interaction list is short, and every item on it works in the same direction: they weaken the effect of therapy. That is why, when any of those medicines is prescribed, it is worth discussing with the doctor in advance whether the regimen will need changing.
Pregnancy and breastfeeding
Use of the medicine in pregnant women or where pregnancy is suspected is contraindicated. What is more, pregnancy is among the situations in which the medicine is withdrawn immediately.
That restriction follows from the indication itself: hormone replacement therapy is meant for postmenopausal women, that is, for those whose own oestrogen production has already ceased. If pregnancy occurs or is suspected, treatment is stopped and a doctor consulted.
Adverse reactions
In the clinical trials conducted, adverse reactions occurred in fewer than 10% of patients. The most frequent were breast tenderness or pain, abdominal pain, oedema and headache.
- common: depression, headache, abdominal pain, nausea, cramps in the leg muscles, breast tenderness, enlargement or pain, peripheral oedema, weight gain;
- uncommon: visual disturbances, venous embolism, dyspepsia, vomiting, bloating and flatulence, gallstones, rash or urticaria;
- very rare or of unknown frequency, from spontaneous reports after marketing: generalised hypersensitivity reactions up to anaphylactic reaction and shock, worsening of migraine, stroke, dizziness, diarrhoea, hair loss, irregular genital bleeding, raised blood pressure;
- also reported in connection with oestrogen treatment: myocardial infarction, congestive heart failure, venous thromboembolic disease, gallbladder disease, chloasma, erythema multiforme and nodosum, vascular purpura, itching, vaginal candidiasis, oestrogen-dependent benign and malignant tumours, endometrial hyperplasia, enlargement of uterine fibroids, insomnia, epilepsy, changes in libido, worsening of asthma and probably dementia.
The numbers deserve separate attention. The risk of endometrial cancer in women with an intact uterus not on therapy is about 5 cases per 1000; with oestrogen-only therapy it rises 2- to 12-fold depending on duration and dose, which gives between 5 and 55 additional cases per 1000 women aged 50 to 65, and it may remain elevated for 10 years after treatment ends — adding a progestagen for at least 12 days of the cycle prevents that excess risk. Replacement therapy is associated with a 1.3- to 3-fold rise in the risk of venous thromboembolism, the event being more likely in the first year of use, and with a one-and-a-half-fold increase in the relative risk of ischaemic stroke, while the risk of haemorrhagic stroke does not rise. For ovarian cancer a meta-analysis of 52 studies gave a relative risk of 1.43: in women aged 50 to 54, five years of use gives about one additional diagnosis per 2000 against a background of two cases per 2000. The Women's Health Initiative study showed no increase in breast cancer risk in women with the uterus removed on oestrogen-only therapy; in observational studies a small rise became visible after about 3 years and returned to baseline within a few years, usually up to 5, after treatment stopped.
Overdose
In overdose, nausea and vomiting may occur. There is no specific antidote and symptomatic treatment is used.
Such a short section is explained by the nature of the medicine: exceeding the dose once is usually not dangerous, and the risks of replacement therapy are tied not to a single overdose but to the length of use and to whether, with an intact uterus, a progestagen has been added to the oestrogen.
How to get a prescription for Estrofem® online
The medicine is prescription-only, and the doctor's first question will be whether the uterus is intact. The answer decides whether it can be prescribed at all: the medicine is intended mainly for women whose uterus has been removed, and with an intact uterus oestrogen-only therapy requires adding a progestagen for at least 12 days of the cycle.
The doctor will then take a full history, including the family history: breast cancer in close relatives, thromboses and embolisms in the patient and in the family, clotting disorders, liver disease, hypertension, diabetes, gallstones, migraine, lupus, epilepsy, asthma, otosclerosis, fibroids and endometriosis. Findings from the gynaecological examination, the breast examination and mammography will be needed, along with details of the medicines being taken — antiepileptics, anti-infectives and supplements containing St John's wort, which weaken the action of oestrogens. The doctor will assess these circumstances during the online consultation and, if there are no contraindications, will issue an electronic prescription.
