1. Name Of The Medicinal Product
ESTRADIOL IMPLANT 25mg
2. Qualitative And Quantitative Composition
Each implant contains 25mg estradiol.
3. Pharmaceutical Form
Implant
4. Clinical Particulars
4.1 Therapeutic Indications
Hormone replacement therapy for estrogen deficiency symptoms in postmenopausal women.
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.
4.2 Posology And Method Of Administration
Dosage and Administration
Dose
Adults: 25 - 100 mg
Estradiol implants are available in strengths of 25, 50 and 100mg. For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see also section 4.4) should be used. In most patients, implantation of a 25mg dose provides relief of symptoms and prevents osteoporosis. Some patients may require 50 mg or even higher doses initially.
If possible, subsequent doses should be reduced stepwise (for example, 100mg to 50mg to 25mg), eventually using 25mg as a maintenance dose. Frequency of replacement depends on the duration of activity of the implants administered and the severity of the symptoms. Patients require a further implant when symptoms return, usually every 4 to 8 months.
Use of a progestagen
Women with an intact uterus:
Because of the sustained absorption of estradiol, the endometrium of post-menopausal or ovariectomised women is liable to progressive hypertrophy. Therefore, in women with an intact uterus, additional administration of a progestagen is recommended, for 12-14 days in each cycle, to prevent endometrial hyperplasia.
When the patient no longer requires or seeks re-implantation with estradiol pellets, it is recommended that, in those women with an intact uterus, cyclical administration of an oral progestagen should be continued until there is a cessation of withdrawal bleeding, in order to prevent the possibility of continued endometrial stimulation.
Hysterectomised women:
Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestagen in hysterectomised women.
Administration
Estradiol implants should be inserted subcutaneously, (either by means of a trocar and cannula or in the wound at the time of laparotomy), into an area where there is relatively little movement or blood supply, such as the lower abdominal wall or the buttock. Insertion is made under local anaesthesia and the wound is closed either with an adhesive dressing or a fine suture.
Full aseptic 'no touch' technique should be adopted.
Removal of the implant
Since the implant consists entirely of estradiol without any auxilliary ingredients, it is biodegradable and no removal procedure is required. In the rare event that removal of the implant should be necessary, the implant may be located by palpation or, if not successful, by Magnetic Resonance Imaging. This technique can identify the implant by its size and structure. The implant can then be precisely located by insertion of a localiser wire with the tip ending at the implant. After locating the implant, it can be removed following a small incision under local anaesthetic.
Starting/switching treatment
An Estradiol implant may be inserted immediately in women experiencing a surgical menopause.
In women not taking HRT or who are changing from a continuous-combined HRT product, an Estradiol implant may be inserted at any time. In women who are switching from a sequential HRT regimen, the implant should be inserted right after the withdrawal bleeding has ended.
4.3 Contraindications
• Known, past or suspected breast cancer.
• Known or suspected estrogen-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
• Known hypersensitivity to the active substance.
• Porphyria.
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 (section 4.3) and warnings for use (section 4.4). 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 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 Estradiol implants, in particular:
• Leiomyoma (uterine fibroids) or endometriosis.
• A history of, or risk factors for, thromboembolic disorders (see below).
• 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 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
• The risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods (see section 4.8). The addition of a progestagen for at least 12 days of the cycle in non-hysterectomised women greatly reduces this risk.
• The endometrial safety of Estradiol implants with the addition of progestagen in women with an intact uterus has not been studied in clinical trials.
• 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 estrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestagens to estrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis if they are known to have residual endometriosis (but see above).
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 estrogens, estrogen-progestagen 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 use 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 estrogens (CEE) or estradiol (E2) was greater when a progestagen was added, either sequentially or continuously, and regardless of type of progestagen. There was no evidence of a difference in risk between the different routes of administration.
In the WHI Study, the continuous combined conjugated equine estrogen 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 estrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
Ovarian cancer
Long-term (at least 5 to 10 years) use of estrogen-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 estrogen-only products.
Venous thromboembolism
• HRT is associated with a higher risk of developing venous thromboembolism (VTE) i.e. deep vein thrombosis or pulmonary embolism. One randomised controlled trial and epidemiological studies found a 2-3 fold 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 use than later.
• Generally recognised risk factors for VTE include a personal or family history, severe obesity (Body Mass Index >30 kg/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 anticoagulant 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 (eg, painful swelling of a leg, sudden pain in the chest, dyspnea).
Coronary artery disease (CAD)
There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated estrogens 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 estrogens 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 estrogens 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.
Other conditions
• Estrogens 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 the circulating active ingredient in Estradiol implants is increased.
• Women with pre-existing hypertriglyceridemia should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition.
• Estrogens 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).
• 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 post-menopausal women or other HRT products.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
The metabolism of estrogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamezapine) 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 estrogens.
Since Estradiol implants are administered parentally, the first-pass effect in the liver is avoided and, thus, parentally administered estrogens might be less affected than oral hormones by enzyme inducers.
Clinically, an increased metabolism of estrogens and progestagens may lead to decreased effect and changes in the uterine bleeding profile.
4.6 Pregnancy And Lactation
Estradiol implants are not indicated during pregnancy. If pregnancy occurs during medication with Estradiol implants treatment should be withdrawn immediately. The results of most epidemiological studies to date relevant to inadvertent foetal exposure to estrogens indicate no teratogenic or foetotoxic effects.
Estradiol implants are not indicated during lactation.
4.7 Effects On Ability To Drive And Use Machines
As far as known Estradiol implants have no effect on alertness or concentration.
4.8 Undesirable Effects
The following adverse reactions have been associated with estrogen therapy in general.
Genito-urinary tract:
Intermenstrual bleeding, increase in the size of the uterine fibromyomata, endometrial proliferation, excessive production of cervical mucus, aggravation of endometriosis, pre-menstrual like syndrome.
Endometrial cancer
In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed estrogens. According to data from epidemiological studies, the best estimate of the risk is that for women not using HRT, about 5 in every 1000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. Depending on the duration of treatment and estrogen dose, the reported increase in endometrial cancer risk among unopposed estrogen users varies from 2- to 12-fold greater compared with non-users. Adding a progestagen to estrogen-only therapy greatly reduces this increased risk.
Breast:
Tenderness, pain, enlargement, secretion.
Breast cancer
According to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women's Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users.
For estrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which >80% of HRT use was estrogen-only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95%CI 1.21 – 1.49) and 1.30 (95%CI 1.21 – 1.40), respectively.
For estrogen plus progestagen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with estrogens alone.
The MWS reported that, compared to never users, the use of various types of estrogen-progestagen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of estrogens alone (RR = 1.30, 95%CI: 1.21 – 1.40) or use of tibolone (RR=1.45; 95%CI 1.25-1.68).
The WHI trial reported a risk estimate of 1.24 (95%CI 1.01 – 1.54) after 5.6 years of use of estrogen-progestagen combined HRT (CEE + MPA) in all users compared with placebo.
The absolute risks calculated from the MWS and the WHI trial are presented below:
The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:
Ø For women not using HRT, about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years.
Ø For 1000 current or recent users of HRT, the number of additional cases during the corresponding period will be
Ø For users of estrogen-only replacement therapy
• between 0 and 3 (best estimate = 1.5) for 5 years' use
• between 3 and 7 (best estimate = 5) for 10 years' use.
Ø For users of estrogen plus progestagen combined HRT,
• between 5 and 7 (best estimate = 6) for 5 years' use
• between 18 and 20 (best estimate = 19) for 10 years' use.
The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to estrogen-progestagen combined HRT (CEE + MPA) per 10,000 women years.
According to calculations from the trial data, it is estimated that:
Ø For 1000 women in the placebo group,
• about 16 cases of invasive breast cancer would be diagnosed in 5 years.
Ø For 1000 women who used estrogen + progestagen combined HRT (CEE + MPA), the number of additional cases would be
• between 0 and 9 (best estimate = 4) for 5 years' use.
The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) (see section 4.4).
Gastro-intestinal tract:
Nausea, vomiting, cholelithiasis, cholestatic jaundice, gall bladder disease. Changes in liver function.
Cardiovascular system:
Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone replacement therapy users than among non-users. For further information, see section 4.3 Contraindications and 4.4 Special warnings and precautions for use.
Myocardial infarction and stroke, thrombosis, rise of blood pressure.
Skin and subcutaneous disorders:
Chloasma, erythema nodosum, erythema multiforme, vascular purpura, rash.
Eyes:
Discomfort of the cornea if contact lenses are used.
CNS:
Headache, migraine, mood changes. Probable dementia (see section 4.4).
Metabolic:
Sodium and water retention, reduced glucose tolerance, and change in body weight.
High dosages and/or prolonged use of estrogens may cause psychotic disturbances.
Prolonged exposure to estrogens may increase risk of development of cardiac and renal disease, estrogen-dependant neoplasms benign and malignant, e.g. melanoma, otosclerosis, multiple sclerosis and systemic lupus erythematosus.
4.9 Overdose
Acute overdose with Estradiol implants is not known to occur.
With chronic use supraphysiological levels of estradiol can be found, however these do not generally result in adverse symptoms, signs or metabolic effects. None the less it would seem prudent in the circumstances to withhold further implantation or other administration of exogenous estrogens until estradiol levels have fallen to within the pre-menopausal physiological range.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Estradiol/Estradiol valerate: The active ingredient, synthetic 17-estradiol is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of estrogen production in menopausal women, and alleviates menopausal symptoms. Estrogens prevent bone loss following menopause or ovariectomy.
Clinical Trial Information
• Relief of estrogen-deficiency symtoms and bleeding patterns
Relief of menopausal symptoms was achieved usually during the first week of treatment.
• Prevention of osteoporosis
- Estrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. The effect of estrogens on 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 progestagen – 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.
- Studies have reported significant increases in bone mineral density at spine and hip after treatment with Estradiol implants (25-100 mg every 6 months) for 1 to 15.5 years.
5.2 Pharmacokinetic Properties
After insertion of an Estradiol implant 25mg, into the subcutaneous fat the estradiol plasma level reaches its maximum of about 400 pmol/l in a few weeks and shows a slow and gradual decline to about 150 pmol/l at 6 months. As with other estrogens, there are large interindividual differences in estradiol levels, but intraindividual variability appears to be small. Unlike oral estrogen therapy, subcutaneous administration bypasses the gastrointestinal tract, where estradiol is converted to estrone and avoids the first-pass effect of the liver. Therefore more unconjugated estradiol is observed and the liver is less burdened.
The transport, metabolism, and excretion of estradiol released from the implants are comparable to those of endogenous estradiol. Thus, about 38 per cent of circulatory estradiol will be bound to SHBG, 60 per cent is bound to albumin, and only 2-3 per cent is free. The main metabolic end products are estriol and 2-hydroxyestrone, which are synthesised after conversion of estradiol to estrone. Most of the estradiol is excreted by the kidneys, mainly after conjugation with glucuronic and sulphuric acid. There is a significant enterohepatic circulation of estradiol and its metabolites. Most of the conjugated biliary estrogens undergo hydrolysis in the intestines after which they are reabsorbed. Therefore, only a small part of the administered estradiol will ultimately be lost in the faeces.
After long-term treatment, accumulation may occur (with doses of 50 mg or more, especially when reimplantation is performed after periods of less than 6 months), but in most cases there is only a moderate increase and levels remain well within the normal premenopausal range. However, in rare cases (mainly with implantation intervals of only 3 or 4 months) plasma levels may rise above 1750 pmol/l. There are some indications that supraphysiological levels occur most frequently in women with a history of depression or surgical castration.
5.3 Preclinical Safety Data
There are no preclinical data of relevance to the prescriber which are additional to that included in other sections of the SPC.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Estradiol implants contain no auxiliary ingredients.
6.2 Incompatibilities
None known.
6.3 Shelf Life
5 years.
6.4 Special Precautions For Storage
Do not store above 25°C. Store in the original package.
6.5 Nature And Contents Of Container
Each sterile implant is supplied singly, in a sealed glass tube.
6.6 Special Precautions For Disposal And Other Handling
Full aseptic 'no-touch' technique should be used.
Administrative Data
7. Marketing Authorisation Holder
Organon Laboratories Limited, Cambridge Science Park, Milton Road, Cambridge, CB4 0FL, U.K.
8. Marketing Authorisation Number(S)
0065/5074R
9. Date Of First Authorisation/Renewal Of The Authorisation
31/8/87 Renewed 06/07/1995
10. Date Of Revision Of The Text
May 2005
Ref: US06ESTRADIOL25v1.1
