ESTRADERM TTS^®

estradiol

Qualitative and Quantitative Composition

Estra-1,3,5(10)-triene-3,17ß-diol (estradiol).
Systems with 2, 4 and 8 mg active substance are available.

Pharmaceutical Form

Pharmaceutical form

Estraderm TTS^® is a thin, multilayer, transparent transdermal therapeutic system. It is a patch for application to an area of intact skin. The drug reservoir is sealed between a backing film and a release-controlling membrane which limits the rate at which estradiol is continuously released across the adhesive layer to the skin. The active substance of the patch penetrates the skin and passes directly into the bloodstream.

Dosage strength

The following three systems are available:

Release of the active substances is maintained for 4 days.

Clinical Particulars

Therapeutic Indications

Treatment of signs and symptoms of estrogen deficiency due to the menopause, whether natural or surgically induced, e.g. hot flushes, sleep disturbances, and urogenital atrophy, as well as accompanying mood changes. Prevention of accelerated postmenopausal bone loss (osteoporosis).

In patients with an intact uterus estrogen should always be supplemented by sequential administration of a progestin.

Dosage and Method of Administration

Dosage

Estraderm TTS should be applied twice weekly, i.e. the system should be changed once every 3 to 4 days. Treatment is normally initiated with Estraderm TTS 50. In the further course of treatment the dosage should be individually adapted; breast discomfort, breakthrough bleeding, fluid retention or bloating (if persisting for more than 6 weeks) are generally signs that the dose is too high and needs to be lowered. If, however, the dose selected fails to eliminate the signs and symptoms of estrogen deficiency, the higher dose should be given. For treatment of menopausal symptoms, the lowest effective dose should always be used.

For prevention of bone loss, Estraderm TTS 50 or Estraderm TTS 100 are recommended. Estraderm TTS 25 should be administered only to patients who cannot tolerate the higher dosage.

Epidemiological data suggest that estrogen therapy given for at least 5 years early in the menopause reduces subsequent hip and colles fractures by about 50%, and vertebral fractures by up to 90%.

Estraderm TTS can be administered as continuous or cyclical therapy. Continuous administration: uninterrupted application twice weekly. Cyclical administration: 3 weeks' treatment followed by an interval of 1 week without treatment.

In women with an intact uterus, estrogen therapy should be supplemented by sequential administration of a progestin according to the following schedule:

In cases where Estraderm TTS is employed for continuous estradiol therapy, it is recommended that a progestin (e.g. medroxyprogesterone acetate 10 mg, norethisterone 5 mg, norethisterone acetate 1-5 mg, or dydrogesterone 20 mg per day) be taken for 10 to 14 days (preferably 12 days) of each month. In patients receiving cyclical treatment with estradiol, the progestin should be taken on the last 12 days of each 3-week period of estradiol administration, so that the 4th week of each cycle remains without any treatment. In either case a withdrawal bleed usually occurs following the 12 days of progestin administration.

Administration

Immediately after removal of the protective release liner the patch should be applied to an area of clean, dry, and intact skin.

The site selected should be one at which little wrinkling of the skin occurs during movement of the body, e.g. buttock, hip, or abdomen, and which is not exposed to sunlight i.e. those areas normally covered by clothing.

Experience to date has shown that less irritation of the skin occurs on the buttock than at other sites of application. It is therefore recommended to apply the patch to the buttock.

The area of skin should be nongreasy and free of irritation.

Estraderm TTS must not be applied to the breast. The system should not be affixed twice in succession to the same skin site.

Contraindications

Known or suspected cancer of the breast; known or suspected cancer of the endometrium or other estrogen dependent neoplasia; undiagnosed abnormal genital bleeding; severe hepatic disease; porphyria; active deep venous thrombosis or thromboembolic disorders, or a documented history of these conditions; known hypersensitivity to the components of the therapeutic system: pregnancy and lactation.

Special Warnings and Special Precaution for Use

Warnings

Prolonged monotherapy with estrogens increases the risk of endometrial hyperplasia and carcinoma in postmenopausal women, unless supplemented by sequential administration of a progestin to protect the endometrium (see Dosage and method of administration "Dosage").

Contact sensitisation is known to occur with all topical applications. Although it is extremely rare, patients who develop contact sensitisation to any of the components of the patch should be warned that a severe hypersensitivity reaction may occur with continuing exposure to the causative agent.

Epidemiological studies have suggested that hormone replacement therapy (HRT) is associated with an increased relative risk of developing venous thromboembolism (VTE), i.e. deep venous thrombosis or pulmonary embolism. This increase in risk was found only in current HRT users and it did not persist in former users. For healthy women this amounts to a risk of one extra case of VTE each year for every 5000 patients taking HRT. This risk appeared to be higher in the first year of therapy and decreased thereafter.

Risk/benefit should therefore be carefully weighed in consultation with the patient when prescribing HRT to women with a risk factor for VTE.

Generally recognised risk factors for VTE include a personal history, a family history (the occurrence of VTE in a direct relative at a relatively early age may indicate genetic predisposition) and severe obesity (Body Mass Index > 30 kg/m²). The risk of VTE also increases with age. There is no consensus about the possible role of varicose veins in VTE.

The risk of VTE may be temporarily increased with prolonged immobilisation, major elective or posttraumatic surgery, or major trauma. In women on HRT scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Depending on the nature of the event and the duration of the immobilisation, consideration should be given to a temporary discontinuation of HRT.

If venous thromboembolism develops after initiating therapy the drug should be discontinued.

Precautions

Estraderm TTS, like any other form of sex hormone therapy, should only be prescribed after a general medical and gynaecological examination to rule out endometrial abnormalities and breast cancer. As with other hormone replacement therapy (HRT) regimens, patients receiving prolonged treatment should have regular follow-ups, including monitoring of the endometrium if this is thought necessary.

In all cases of undiagnosed persistent or irregular vaginal bleeding, adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out abnormality and the treatment should be re-evaluated.

Findings reported from available data in a meta-analysis of 51 epidemiology studies, referring predominantly to the use of estrogens without progesterone, suggest that there is a small increase in the risk of developing breast cancer in women aged 50-70 years, who have used HRT for more than five years.

The findings may be due to earlier diagnosis, the effects of HRT, or a combination of both. The risk increases with duration of treatment and is comparable to the increased risk of breast cancer observed in women, with every year of delay of the natural menopause. The increased risk disappears during the course of the first five years after stopping HRT.

The available data for the estrogen/progesterone combination products are as yet sparse and hence it is not possible as yet, to evaluate fully the effects upon breast cancer of these products. The meta-analysis showed no evidence of marked differences between the results so far obtained.

Breast cancers found in women using HRT are more likely to be localised to the breast than those found in non-users. It is important that the increased risk of being diagnosed with breast cancer, is discussed with the patient and weighed against the known benefits of HRT.

It is recommended that estrogens should not be given to women with existing breast cancer or those with a previous history of the disease.

Women with known risk factors associated with the development of breast cancer, such as a family history of the disease in first-degree relatives, or a breast condition associated with an increased risk, should be instructed in self-examination of their breasts. It is recommended that such women deemed to be at high risk, should undergo mammography prior to the start of HRT treatment, and repeated at regular intervals during treatment, as deemed appropriate by the treating physician and according to the perceived risks for each patient.

Preexisting uterine leiomyomas or fibroids may become enlarged during estrogen therapy. Women with endometriosis should be carefully monitored.

The following conditions may deteriorate on HRT: hypertension, asthma, heart failure, disorders of renal or hepatic function, migraine or epilepsy. It is essential that affected patients be kept under surveillance and HRT be stopped if there is an increase in epileptic seizures. If worsening of any of the above mentioned conditions is diagnosed or suspected during HRT, the benefits and risks of HRT should be reassessed based on the individual case.

Caution is advised in patients with a history of estrogen-related jaundice and pruritus. If cholestatic jaundice develops during treatment, the treatment should be stopped and appropriate investigations carried out.

Women with familial hypertriglyceridaemia need special surveillance. Lipid-lowering measures are recommended additionally, before HRT is started.

Although observations to date suggest that estrogens, including transdermal estradiol do not impair carbohydrate metabolism, diabetic patients should be monitored during initiation of therapy until further information is available.

Interaction with Other Medicaments and Other Forms of Interaction

Preparations which induce microsomal liver enzymes, e.g. barbiturates, hydantoins, carbamazepine, meprobamate, phenylbutazone, or rifampicin, may impair the activity of estrogens and progestins. The extent of interference with transdermally administered estradiol is not known.

Pregnancy and Lactation

Estraderm TTS should not be used during pregnancy and lactation.

Effects on Ability to Drive and Use Machines

None known.

Adverse Effects

Frequency estimate: very common = 10%, common = 1% to < 10%; uncommon = 0.1% to < 1%; rare = 0.01% to < 0.1%; very rare < 0.01%.

Central nervous system

Common: headache.

Rare: dizziness.

Cardiovascular system

Very rare: thromboembolic disorders, exacerbation of varicose veins, increase in blood pressure.

Gastrointestinal tract

Common: nausea, abdominal cramps, bloating.

Very rare: asymptomatic impaired liver function, cholestatic jaundice.

Skin and appendages

Very common: transient erythema and irritation at the site of application with or without pruritus.

Very rare: allergic contact dermatitis; reversible post-inflammatory pigmentation; generalised pruritus and exanthema.

Endocrine system

Very common: breast discomfort (sign of estrogen effect, sign of overdose).

Urogenital tract

Very common: breakthrough bleeding (usually a sign of estrogen overdose). (If the estrogen is adequately combined with a progestin, regular withdrawal bleeding occurs, as observed in the normal menstrual cycle). Like any estrogen therapy, transdermal estrogen treatment can induce endometrial hyperplasia unless estrogen intake is supplemented by adequate doses of a progestin.

Miscellaneous

Rare: oedema and/or weight changes, leg pain (not related to thromboembolic disease and usually transient lasting 3-6 weeks. If symptoms persist, the dose of estrogen should be reduced).

Very rare: anaphylactoid reactions (some of the patients had a previous history of allergy or allergic disorders).

Overdose

Owing to the mode of administration, overdose of estradiol is unlikely to occur, but can if necessary be rapidly reversed by removing the patch.

Pharmacological Properties

Pharmacodynamic Properties

Pharmacotherapeutic group: Hormone replacement therapy (ATC code G03FA01)

Estradiol

Like all steroid hormones, estrogens exert their metabolic effects intracellularly. In the cells of the target organs, estrogens interact with a specific receptor to form a complex which modulates gene transcription and subsequent protein synthesis. Such receptors have been identified in various organs, e.g. hypothalamus, pituitary, vagina, urethra, uterus, breast, and liver, and in osteoblasts.

Estradiol, which from the menarche to the menopause is produced mainly by the ovarian follicles, is the most active estrogen. After the menopause, when the ovaries have ceased to function, only small amounts of estradiol are still produced, from aromatisation of androstenedione and to a lesser extent testosterone by the aromatase enzyme, yielding oestrone and estradiol, respectively. Oestrone is further transformed to estradiol by the enzyme 17ß-hydroxysteroid dehydrogenase. Both enzymes occur in fat, liver, and muscle tissue.

In many women, the cessation of ovarian estradiol production results in vasomotor symptoms (hot flushes), sleep disturbances, and progressive atrophy of the urogenital system. These disorders can be largely eliminated by means of estrogen replacement therapy. It has also been shown that HRT or estrogens are effective in preventing the decline in skin thickness seen after the menopause. It is well established that estrogen replacement therapy prevents postmenopausal bone loss especially if initiated early in the menopause.

Transdermal therapy with Estraderm TTS delivers the physiological estrogen estradiol in unchanged form directly into the bloodstream. Estradiol concentrations are raised to levels similar to those in the early follicular phase and maintained over the application period of 3-4 days. In the plasma the concentration ratio of estradiol (E2) to oestrone (E1) undergoes a corresponding shift from between 1:5 and 1:2 to approx. 1:1, i.e. to values similar to those recorded before the menopause in women with normally functioning ovaries. Estraderm TTS thus provides physiological estrogen replacement.

Following the application of Estraderm TTS for 28 days, no effect has been observed on the concentrations or activity of the blood coagulation factors fibrinopeptide A, high-molecular-weight fibrinogen, and antithrombin III. After this period of 28 days, transdermally administered estradiol did not induce any change in the concentrations either of circulating renin substrate or of the sex-hormone-binding, thyroxine-binding, and cortisol-binding globulins. However, it has been found that after only 3 weeks' administration transdermally administered estradiol elicits a dose-dependent reduction in urinary excretion of calcium and hydroxyproline.

An increase in HDL concentrations has been observed after 24 weeks' continuous administration of Estraderm TTS 100.

The unfavourable effects of the menopause on lipid and non-lipid mediated markers of cardiovascular disease may contribute to the increased incidence of cardiovascular disease seen in postmenopausal women. An improved lipid profile may be one factor contributing to the beneficial effect of estrogen replacement therapy on the risk of coronary heart disease in postmenopausal women. Studies have indicated beneficial effects of Estraderm TTS with progestin on serum total cholesterol, low density lipoprotein (LDL), triglyceride and high density lipoprotein (HDL) levels. There have been few long-term studies of the effect of Estraderm TTS alone on these measurements and the results are thus less conclusive although generally favourable. Some studies of Estraderm TTS incorporating progestin treatment have demonstrated effects on arterial tone which may have a beneficial effect on cardiovascular risk while others have not. Recently, results from a follow-up study concluded that the addition of progestin does not appear to attenuate the cardioprotective effects of postmenopausal estrogen therapy. Deleterious effects on blood pressure, coagulation and insulin resistance have not been shown in these studies.

Unopposed estrogens increase the incidence of endometrial hyperplasia and the risk of endometrial carcinoma. Studies have reported that the addition of a progestin for 10 or more days of a cycle of estrogen administration greatly lowers the incidence of endometrial hyperplasia, and thereby irregular bleeding and endometrial carcinoma, compared to estrogen treatment alone.

Pharmacokinetic Properties

Physiological serum estradiol concentrations, which are linearly proportional to the size of the dose, are attained within 4 hours after application of Estraderm TTS 25, 50 and 100 to the skin. Steady-state serum estradiol concentrations are reached within 8 hours after application of Estraderm TTS 25, 50, and 100 and are maintained at mean levels of 23, 40, and 75 pg/mL respectively during the remainder of the application period. This corresponds to mean increases of 16, 30, and 70 pg/mL of the postmenopausal baseline value (5-10 pg/mL). The E2:E1 ratio averages 0.9:1, 1:1, and 1.35:1, respectively.

24 hours after removal of the system, the estradiol concentrations in the serum have dropped almost to the baseline value. Estradiol conjugates excreted in the urine return to pre-application levels on the second or third day after removal of the system.

During repeated application of Estraderm TTS 50 twice weekly for 3 weeks (6 applications), mean serum concentrations of estradiol rise by 30 pg/mL and mean serum concentrations of oestrone by 12 pg/mL. The average E2:E1 ratio changes from 1:5 to 0.9:1.

The amount of estradiol conjugates excreted in the urine remains elevated, at 2.0 to 2.5 mcg/g creatinine throughout the period of application. Within 2 to 3 days after removal of the system, levels return to baseline, i.e. about 0.5 mcg/g creatinine.

Estradiol

The plasma elimination half-life of estradiol is about 1 hour. Metabolic plasma clearance ranges from 650 to 900 L/(day x m²). Estradiol is mainly metabolised in the liver. Its most important metabolites are oestriol and oestrone and their glucuronides and sulfate conjugates; these are far less active than estradiol and are mainly excreted in the urine. Estrogen metabolites are also subject to enterohepatic circulation.

Preclinical Safety Data

At low physiological doses of estradiol (similar to those delivered by Estraderm TTS), neoplastic potential is negligible in experimental animals. Most of the documented effects of exogenously administered estradiol in animal studies have been consequences of the administration of supraphysiological doses and are consistent with an exaggerated pharmacological response (most notably the promotion of tumours in estrogen-responsive tissues). However, long-term unopposed treatment with physiological doses of estradiol may lead to hyperplastic changes in estrogen-dependent reproductive organs like the uterus.

A similar spectrum of tumour formation is known to occur in long-term laboratory animal studies with progestins alone or in combination with estrogen with some species differences. However, results from clinical studies and epidemiological evidence on the carcinogenic risk to humans are addressed under the section (see Special warnings and special precautions for use).

In local tolerability studies in rabbits, some skin irritation was observed.

Pharmaceutical Particulars

List of excipients

Ethanol, hydroxypropylcellulose, polyethylene terephthalate, ethylenevinylacetate copolymer, liquid paraffin, polyisobutylene, silicone-coating on the inner side of the protective liner (removed before the application of the patch).

Incompatibilities

Ultraviolet light (i.e. sunlight)

Exposure of the Estraderm TTS patch to ultraviolet light results in degradation of estradiol. Patches should not be exposed to sunlight. They should be applied immediately after removal from the sachet to skin sites covered by clothes.

Shelf life

2 years.

Special Precautions for Storage

Store below 25°C.

Estraderm TTS should be kept out of the reach of children both before and after use.

Nature and Contents of the Container

Boxes containing 8 transdermal systems which are individually packaged in a heat sealed sachet made of aluminium/Surlyn foil. (Patient information booklet is enclosed).

Medicine Classification

Prescription Medicine