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FEMTRAN is a transdermal delivery system containing estradiol as the active ingredient. Estradiol is estra-1,3,5(10)-triene-3, 17beta-diol, the major oestrogenic hormone produced by the human ovary. The CAS Registry number for estradiol is 50-28-2.
The FEMTRAN transdermal delivery system is a transparent oval patch containing estradiol in an adhesive matrix. Three strengths of FEMTRAN are available: 25, 50 and 100.
| 25 | 50 | 100 | |
|---|---|---|---|
| Estradiol content: | 2mg | 3.8mg | 7.6mg |
| Size (release area): | 6.5cm² | 12.5cm² | 25cm² |
| Nominal daily in-vivo release of estradiol | 25mcg | 50mcg | 100mcg |
When applied to intact skin, transdermal delivery from FEMTRAN patches is maintained over 7 days. Transdermal delivery
of estradiol overcomes the problems of its short half-life, seen when estradiol is given orally, due to extensive first
pass metabolism.
The FEMTRAN transdermal delivery system is comprised of two layers.
A protective liner is attached to the adhesive surface. This must be removed prior to applying the patch to the skin.
The excipients of the FEMTRAN transdermal delivery system include acrylate copolymer adhesive, fatty acid esters and polyethylene backing. FEMTRAN patches do not contain alcohol.
FEMTRAN provides systemic oestrogen replacement therapy by releasing estradiol. Estradiol is the major oestrogenic hormone secreted by the human ovary from the menarche to the menopause and is the most potent of the endogenous oestrogens.
Oestrogens are important in the development and maintenance of the female reproductive system and secondary sexual characteristics. They also contribute to the shaping of the skeleton, maintenance of tone and elasticity of urogenital structures and changes in the epiphyses of the long bones that allow for the pubertal growth spurt and its termination. Oestrogens play an important role in various metabolic processes, including the modulation of bone resorption.
Oestrogens exert their metabolic effects by binding to specific receptors in target cells. Oestrogen receptors have been identified in all known oestrogen target organs including the uterus, hypothalamus, pituitary, vagina, urethra, breast, liver and osteoblasts.
There are several forms of naturally occurring oestrogen. Estradiol is the principal intracellular human oestrogen and is substantially more potent than the others, estrone or estriol. The ovarian follicle secretes 70 to 500 micrograms of estradiol daily, varying with the phase of the menstrual cycle. This is converted primarily to estrone, and to small amounts of estriol in the liver. The estradiol/estrone ratio during fertile life is greater than 1. However, in postmenopausal women, estrone is the most abundant circulating oestrogen. After menopause, when the ovaries have ceased to function, estrone is produced from the aromatisation of androstenedione and only small amounts of estradiol are produced from metabolic conversion of testosterone and estrone.
The oestrogen deficiency around and after the menopause produces symptoms such as severe hot flushes, night sweats, insomnia, dyspareunia and progressive atrophy of the urogenital system in many women. These disorders can be largely eliminated by means of oestrogen replacement therapy. There is also an increased risk of bone fractures and osteoporosis, particularly of the vertebral column, hip, and wrist due to the increased loss of bone substance caused by low levels of oestrogen, and cardiovascular disease. Short-term treatment with oestrogen replacement therapy perimenopausally has been shown to prevent loss of bone density. There is currently no evidence of the minimum duration of oestrogen replacement therapy which will be effective for younger postmenopausal women in reducing fracture when they reach 75 years of age (the age of greatest fracture risk).
Known risk factors for postmenopausal osteoporosis include early menopause or surgical oophorectomy, prolonged secondary amenorrhoea, prolonged systemic steroid use and a family history of osteoporosis. Women especially at risk are those who are Caucasian, small boned, smokers and live a sedentary lifestyle. The mainstays for decreasing the risk of postmenopausal osteoporosis are weight-bearing exercise, adequate calcium and Vitamin D intake, and when indicated, pharmacologic therapy. When Femtran is used for the short term relief of menopausal symptoms, it will provide a concomitant effect in reducing bone mineral density loss.
Transdermal administration of oestrogen offers many advantages over conventional oral delivery. It avoids the hepatic first-pass effects resulting in a constant serum level which reflects the pre-menopausal physiological serum profile and ratio of estradiol to estrone. In plasma, the concentration ratio of estradiol (E2) to estrone (E1) undergoes a shift from between 1:5 and 1:2 to approximately 1:1, i.e. to values which are recorded before the menopause in women with normally functioning ovaries. Gastrointestinal side effects are avoided also. The skin metabolises estradiol to a small extent only, thus transdermal administration provides therapeutic serum levels of estradiol using smaller total doses than oral therapy. Constant delivery of the therapeutic dose is maintained with FEMTRAN patches over the 7 day application period. However, therapy is easily discontinued by removal of the patch.
Following the application of transdermal estradiol 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 any of the sex hormone-binding, thyroxine-binding or cortisol-binding globulins. It has been found, however, that after only three weeks' administration, transdermally administered estradiol elicits a dose-dependent reduction in urinary excretion of calcium and hydroxyproline.
Independent of the route of administration, oestrogen at doses which are necessary for improvement of menopausal complaints exerts a dose dependent stimulating effect on mitosis and proliferation of the endometrium. Oestrogen monotherapy increases the frequency of endometrial hyperplasia and thus the risk of endometrial cancer. In order to avoid endometrial hyperplasia the sequential administration of a progestogen for 10-12 days is recommended in non-hysterectomised postmenopausal women (see Precautions: WHI study and Million Women study).
Transdermal estradiol administration aims at achieving smooth, stable, plateau-like estradiol serum levels similar to those during the early/mid follicular phase of the reproductive life span. Estradiol serum levels in the range between 30 - 100pg/mL are necessary for an efficacious transdermal oestrogen replacement therapy. Nominal average in vivo absorption rates for FEMTRAN 25, FEMTRAN 50 and FEMTRAN 100 are 25mcg/day, 50mcg/day and 100mcg/day respectively. In pharmacokinetic studies mean steady state estradiol levels of 35pg/mL were obtained after application of the FEMTRAN 50 patch and 70pg/mL after application of the FEMTRAN 100 patch. No accumulation of either estradiol or estrone occurred after multiple one-week applications, with serum levels returning to baseline within 6 hours of patch removal.
Linear dose proportionality has been demonstrated for the FEMTRAN transdermal delivery system. In a 1-week application study in 54 post-menopausal women FEMTRAN 100 produced estradiol serum level profiles and pharmacokinetic parameters that were twice as high as FEMTRAN 50. Statistical analyses confirmed the 2:1 dose proportionality. Similarly, a 2-week crossover study with a one week washout period between treatments in 24 postmenopausal women demonstrated dose proportionality between FEMTRAN 50 and FEMTRAN 25, with a Cave of 38pg/mL and 22pg/mL for FEMTRAN 50 and FEMTRAN 25 respectively.
Two transdermal absorption studies were conducted comparing serum estradiol level profiles and pharmacokinetic parameters following once-a-week application of FEMTRAN patches and twice-a-week applications of another brand of patches. Both patch strengths were examined: In the first study FEMTRAN 50 was compared with the similar strength twice-a-week patch and in the second study FEMTRAN 100 was compared with the similar strength twice-a-week patch. With both patch strengths, FEMTRAN once-a-week treatments maintained smoother and more stable estradiol serum level profiles than did the twice-a-week patches. Cmax, AUC and MSS were all significantly higher for the twice-a-week patch application, but towards the end of the one-week application interval, both FEMTRAN patches maintained similar (144 hours) or higher (168 hours) mean trough serum levels than did the twice-a-week patches. The mean peak to end of application interval trough level fluctuations were smaller with FEMTRAN than with the twice-a-week patches.
The biotransformation and excretion of transdermally administered estradiol is the same as that of the endogenous hormone. The plasma elimination half-life of estradiol is approximately one hour. Estradiol is eliminated from the body with a total serum clearance of approximately 15-30mL/min/kg by biotransformation mainly in the liver but also extrahepatically. Its most important metabolites are estriol and estrone and their conjugates (glucuronides, sulphates); these are far less pharmacologically active than estradiol. The bulk of the conjugates are excreted in the urine. Oestrogen metabolites are also subject to enterohepatic circulation.
For short term treatment of complaints associated with the menopause and post-menopause, including signs and symptoms of oestrogen deficiency whether naturally or surgically induced.
Oestrogen replacement therapy in patients with an intact uterus should always be supplemented by the sequential administration of a progestogen. Combination HRT should not be used in hysterectomised women because it is not needed in these women and may increase the risk of breast cancer.
Hormone replacement therapy should only be continued for as long as the benefit in alleviating postmenopausal symptoms outweighs the risks for the individual woman. The need for continuing treatment should be reviewed periodically (eg at 6-monthly intervals).
Treatment is usually initiated with the FEMTRAN 50 patch applied to the skin once weekly. Treatment should begin with the lowest effective dose and be adjusted as necessary until symptoms are controlled.
The prolonged use of oestrogens alone in the climacteric can induce hyperplasia of the endometrium and, in this connection, increase the risk of endometrial cancer. This risk can best be minimised by the additional administration of a progestogen (normally for 10-12 days per month). This generally leads to secretory conversion and shedding of the uterine lining and, as a result, to menstruation-like bleeding after the end of the period of progestogen treatment. (see Warnings and Precautions).
In women who are not currently taking oral oestrogens, treatment with FEMTRAN can be initiated at once. In women who are currently taking oral oestrogen, treatment can be initiated one week after withdrawal of oral therapy, or sooner if symptoms reappear before the end of the week.
Following removal of the protective liner the adhesive side of the FEMTRAN patch should be placed on a clean, dry area of the skin of the lower trunk or buttocks. FEMTRAN must not be applied to the breasts. The sites of application should be rotated, with an interval of at least one week between applications to a particular site. The patches should not be applied twice in succession to the same site. The area selected should not be oily, damaged, or irritated. The waistline should be avoided since tight clothing may rub the patch off. FEMTRAN should be applied to skin sites that will be covered by clothes. The patch should be applied immediately after opening the pouch and removing the protective liner. The patch should be pressed firmly in place with the palm of the hand for about 10 seconds, making sure there is good contact, especially around the edges.
The patch should be changed once weekly. Only one patch should be worn at any time during the 7-day dosing interval. If the patch is applied correctly, the patient can bath or shower as usual. In the event that a patch falls off, a new patch should be applied for the remainder of the 7-day dosing interval.
Known allergy to estradiol or any of the components of the transdermal delivery system; severe uncontrolled hypertension; pregnancy; lactation; suspected or existing tumour of the uterus, breast or ovaries; endometriosis; severe disturbances of liver function; previous or existing liver tumours; active deep vein thrombosis, active arterial thromboembolic disease (e.g. angina, myocardial infarction, stroke), or a documented history of these conditions; severe diabetes with vascular changes; sickle cell anaemia; disturbances of lipometabolism; a history of herpes of pregnancy; otosclerosis with deterioration during pregnancy; jaundice or persistent itching during a previous pregnancy; undiagnosed abnormal vaginal bleeding; non-hysterectomised women unless on concomitant progestogen therapy.
HRT should not be initiated or continued to prevent or treat cardiovascular disease.
The benefits and risks of HRT must always be carefully weighed, including consideration of the emergence of risks as therapy continues. HRT should only be used for the short term relief of menopausal symptoms. Oestrogens with or without progestogens should be prescribed at the lowest effective doses and for the shortest duration consistent with the treatment goals and risks for the individual woman. The risks of HRT should be assumed to be similar for all doses of oestrogens and oestrogen/progestogen combinations.
Occurrence for the first time of migrainous headaches or more frequent occurrence of unusually severe headaches, sudden perceptual disorders (eg. disturbances of vision or hearing), first signs of thrombophlebitis or thromboembolic symptoms (for example, unusual pains in or swelling of the legs, stabbing pains on breathing or coughing for no apparent reason), a feeling of pain and tightness in the chest, pending operations (six weeks beforehand), immobilisation (for instance, following accidents), onset of jaundice, onset of hepatitis, itching of the whole body, increase in epileptic seizures, significant rise in blood pressure, pregnancy.
Oestrogens with or without progestogens should not be used for the long-term maintenance of general health, including the primary prevention of cardiovascular disease. The Women's Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli and deep vein thrombosis in postmenopausal women during 5 years of treatment with conjugated equine oestrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg) relative to placebo. Other doses of conjugated oestrogens and medroxyprogesterone acetate and other combinations of oestrogens and progestogens were not studied in the WHI and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, oestrogens and progestogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. See section below: 'WHI Study'.
The prolonged use of oestrogens alone in the climacteric can induce hyperplasia of the endometrium and, in this connection, increase the risk of endometrial cancer. This risk can best be minimised by the additional administration of a progestogen (normally for 10-12 days per month). This generally leads to secretory conversion and shedding of the uterine lining and, as a result, to menstruation-like bleeding after the end of the period of progestogen treatment (see Dosage and Administration).
Before starting therapy with FEMTRAN a thorough general medical and gynaecological examination (including the breasts and a Pap-smear) should be carried out and pregnancy excluded. As a precaution, control examinations should be conducted at intervals of about 12 months during treatment.
Where applicable, contraception should be practised with non-hormonal methods (with the exception of the rhythm and temperature methods).
If irregular bleeding occurs repeatedly during the use of FEMTRAN, or if the bleeding in the treatment-free weeks is unusually profuse, thorough differential-diagnostic clarification is essential.
If there are, repeatedly, persistent skin irritations (eg. persistent erythema or pruritus at the application site) even if the application site has been regularly changed as instructed in the directions, one should consider cessation of transdermal treatment.
Contact sensitisation is known to occur with all topical applications. Although contact sensitisation to any components of the patch is extremely rare, patients who develop it should be warned that a severe hypersensitivity reaction may occur with subsequent exposure to the causative agent.
Should there be a suspicion of a prolactinoma, this should be ruled out before starting treatment.
Close medical supervision is necessary in patients with diabetes, hypertension, varicose veins, asthma, otosclerosis, systemic lupus erythematosus, multiple sclerosis, epilepsy, porphyria, tetany, chorea minor, heart failure, disturbances of kidney or liver function, migraine. Patients with fibrocystic disease of the breasts and patients with first degree relatives who have had breast cancer also require close supervision and should be instructed in breast self-examination. The same applies to patients with benign tumours of the uterine smooth muscles, since the size of such tumours can increase under oestrogen therapy.
The Women's Health Initiative (WHI) study reported increased risks of myocardial infarction and stroke, as well as pulmonary emboli and deep vein thrombosis in postmenopausal women during five years of treatment with oral conjugated equine oestrogens (0.625mg) combined with medroxyprogesterone acetate (2.5mg) relative to placebo.
Epidemiological studies have suggested that HRT may be associated with an increased relative risk of developing venous thromboembolism (VTE), i.e. deep venous thrombosis or pulmonary embolism.
In a subset of WHI, women in the oral oestrogen plus progestogen group had a two-fold greater rate of VTE, including deep vein thrombosis and pulmonary embolism, compared to women receiving placebo. The rates of VTE were 34 and 16 per 10,000 person-years in the treatment and placebo groups respectively. The increase in VTE risk was observed during the first year and persisted.
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 disposition), and severe obesity. 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 post-traumatic surgery, or major trauma. Depending on the nature of the event and the duration of immobilisation, consideration should be given to a temporary discontinuation of HRT. Treatment should be stopped at once if there are symptoms of a thrombotic event or suspicion thereof.
The use of oestrogens alone as well as combined/sequential oestrogen and progestogen use is associated with an increased risk of breast cancer. This emerges towards the end of the first year of treatment.
The WHI study reported a 26% increase in invasive breast cancer (38 vs 30 per 10,000 person-years) during five years of treatment with oral oestrogen/progestogen combination compared with placebo.
A meta-analysis from 51 epidemiological studies reported that there is a modest increase in the risk of having breast cancer diagnosed in women who have used hormone replacement therapy (HRT) for more than five years. The findings may be due to an earlier diagnosis, the biological effects of HRT, or a combination of both. The relative risk increases with duration of treatment (by 2.3% per year of use). This is comparable to the increased risk of breast cancer observed in women with every year of delay of natural menopause (2.8% per year of delay). The increased risk gradually disappears during the course of the first five years after cessation of HRT. Breast cancers found in women using HRT are more likely to be localised to the breast than those found in non-users (see WHI study below).
Mammographic density may be increased after the use of combined HRT. This may have implications for the sensitivity and specificity of breast cancer screening.
Prolonged exposure to unopposed oestrogens increases the risk of development of endometrial hyperplasia or carcinoma. Studies have suggested that the addition of a progestogen to the regimen reduces the risk of endometrial hyperplasia and/or cancer. Oestrogen or oestrogenic compounds must not be used alone as hormone replacement therapy in women who have not had a hysterectomy. Close clinical surveillance of all women taking oestrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of "natural" oestrogens results in a different endometrial risk profile than synthetic oestrogens of equivalent oestrogen dose.
An increased risk of ovarian cancer in menopausal women taking oestrogen only replacement therapy was observed in a large US study enrolling over 40,000 women on HRT. These women were followed up for a mean duration of 13.4 years (range 1 month to 19.8 years). The increased risk of ovarian cancer in those taking oestrogen replacement therapy was 80%, RR 1.8 (95% CI, 1.1-3.0) at 10 to 19 years. This risk increased with duration of use: RR for 20 years or more years of use was 3.2 (95% CI, 1.7-5.7). This equates to approximately 3 and 8 additional cases per 10,000 women-years at these time points; (the incidence of ovarian cancer in non-users was 4.4 per 10,000 women years). This observation was most obvious in those women on long-term oestrogen replacement therapy who had a prior history of hysterectomy (defined as simple hysterectomy or hysterectomy with unilateral oophorectomy). In this subpopulation, the RR was 2.0 (95% CI, 0.96-4.3) for between 10 and 19 years of use and 3.4 (95% CI, 1.6-7.5) for 20 years or more.
The influence of HRT on ovarian cancer is not clear. Scientific results are contradictory. The epidemiological study by Lacey et al. (as summarised above) found a slightly increased risk of ovarian cancer for women on long-term ERT, while a meta-analysis of 15 studies by Coughlin et al. did not find an increased risk for women on ERT.
In rare cases benign and in even rarer cases malignant liver tumours leading in isolated cases to life-threatening intra-abdominal haemorrhage have been observed after the use of hormonal substances such as the one contained in FEMTRAN. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, a liver tumour should be included in the differential-diagnostic considerations.
A two fold increase in the risk of gall bladder disease in women receiving oral estrogens (including oral contraceptives) has been reported.
The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during four years of treatment with oral conjugated oestrogens plus medroxyprogesterone acetate relative to placebo. It is not known whether these findings apply to younger postmenopausal women.
In a prospective randomised US clinical trial involving 8506 postmenopausal women who received oral hormone replacement therapy (HRT) using a continuous combined regimen of conjugated equine oestrogens (conjugated oestrogens) 0.625mg/day plus medroxyprogesterone acetate 2.5mg/day and 8102 women who received placebo for an average of 5.2 years, adverse effects on the cardiovascular system and the incidence of breast cancer were observed. The Women's Health Initiative (WHI) study was designed to investigate the efficacy and safety of long-term HRT in preventing coronary heart disease (CHD) in healthy postmenopausal women with an intact uterus. A global index summarising the balance of risks and benefits included an analysis of the primary outcome CHD and the primary adverse outcome of invasive breast cancer, and the following secondary outcomes: stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes. The women enrolled in the study had a mean age at entry of 63.3 years. On average they were overweight (mean body mass index [BMI] = 28.5) and one-third were obese (BMI=> 30), 50% were previous or current smokers, one-third had received treatment for high blood pressure and over 10% had raised cholesterol levels requiring medication.
After a mean of 5.2 years of follow-up, the study was stopped prematurely because the preset criterion for invasive breast cancer was fulfilled and the global index supported risks exceeding benefits. Estimated hazard ratios (HRs)(nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63); breast cancer, 1.26 (1.00-1.59); stroke, 1.41 (1.07-1.85); PE, 2.13 (1.39-3.25); colorectal cancer, 0.63 (0.43-0.92); endometrial cancer, 0.83 (0.47-1.47); hip fracture, 0.66 (0.45-0.98), and death due to other causes, 0.92 (0.74-1.14). Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer and 1.15 (1.03-1.28) for the global index. The HR for total fractures was 0.76 (0.69-0.85) while total mortality was unchanged [0.98 (0.82-1.18)].
In this study, the absolute excess risks per 10,000 person-years attributable to oestrogen plus progestin were small, i.e. 7 more cases of CHD (37 vs 30), 8 more strokes (29 vs 21), 8 more pulmonary emboli (15 vs 7) and 8 more invasive breast cancers (38 vs 30), while the absolute risk reductions per 10,000 person-years were 6 fewer colorectal cancers (10 vs 16), 1 less endometrial cancer (5 vs 6), 5 fewer hip fractures (10 vs 15), 44 fewer total fractures (147 vs 191) and one less death (52 vs 53) than in women not using that form of HRT.
In the Million Women Study 1,084,110 women were followed up for cancer incidence and death. The average age of the women at recruitment was 55.9 years, and the average period of follow-up was 2.6 years for the analyses of cancer incidence and 4.1 years for the analyses of mortality. Overall 50% of the study population had used HRT at some point. There were 9,364 newly diagnosed cases of invasive breast cancer and 637 breast cancer deaths. Current users of HRT at recruitment were more likely to develop breast cancer and die from it than patients who had never used HRT. Patients who had used HRT previously but were no longer using it were however not at an increased risk of newly diagnosed or fatal disease. The incidence was significantly increased for current users of preparations containing oestrogen only, oestrogen/progestogen and tibolone, but the magnitude of the associated risk was greater for the combined treatment than for other types of HRT.
| HRT use at baseline | Cases/population | Relative risk (95% FCI)* |
|---|---|---|
| All never users | 2894/392,757 | 1.00 (0.96-1.04) |
| All past users | 1044/150,170 | 1.01 (0.95-1.08) |
| Current users of: | ||
| Oestrogen only | 991/115,383 | 1.30 (1.22-1.38) |
| Oestrogen- | 1934/142,870 | 2.00 (1.91-2.09) |
| progestogen | 184/18,186 | 1.45 (1.25-1.67) |
| Tibolone | 93/9548 | 1.44 (1.17-1.76) |
| Other/unknown types | ||
| Relative risk of newly diagnosed invasive breast cancer in relation to recency and type of HRT used. FCI=floated CI. *Relative to never users, stratified by age, time since menopause, parity and age at first birth, family history of breast cancer, body-mass index, region and deprivation index. | ||
Results varied little between specific oestrogens and progestogens or their doses, or between continuous of sequential
regimens. The relative risks were significantly increased separately for oral, transdermal and implanted oestrogen-only
formulations. In terms of absolute risk, after ten years of HRT use it is estimated that there would be 5 (95%CI 3-7)
additional cases of breast cancer per 1000 users of oestrogen-only preparations, and 19 (95% CI 15-23) additional cases
of breast cancer per 1000 users of oestrogen-progestogen combinations. The elevated risk reduces after discontinuation
of HRT and is effectively lost after five years.
In the HRT subset of WHI a 26% increase in invasive breast cancer (38 vs 30 per person-years) after an average of 5.2 years of treatment was observed in women receiving the oestrogen/progestogen combination compared to women receiving placebo. The increased risk of breast cancer became apparent after four years on study medication. Women reporting prior postmenopausal hormone use had a higher relative risk for breast cancer associated with HRT than those who had never used postmenopausal hormones.
The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, reported a two-fold increase in the risk of developing probable dementia in postmenopausal women 65 years of age or older (n=4,532, 54% older than 70) during four years of treatment with oral conjugated oestrogens plus medroxyprogesterone acetate relative to placebo. After an average follow-up of four years the absolute risk of probable dementia was 45 per 10,0000 person-years in the oestrogen plus progestogen group and 22 per 10,000 person-years in the placebo group. It is not known whether these findings apply to younger postmenopausal women.
The risks and benefits in women receiving treatment for the short-term management of menopausal symptoms of oestrogen deficiency or for the management of premature menopause were not examined in the WHI and WHIMS studies. As well, the studies did not include other formulations, dosage regimens or routes of administration of HRT; such as transdermal patches containing estradiol. However, in the absence of comparable data, these risks should be assumed to be similar. If prescribing any form of hormone replacement therapy, the potential for increased cardiovascular, thrombotic and neoplastic adverse events must be considered.
Since prolonged use of oestrogens influences the metabolism of calcium and phosphorous FEMTRAN should be used with caution in women with metabolic bone diseases associated with hypercalcaemia.
Patients with uterine leiomyomas, which may become enlarged during oestrogen therapy, should be carefully monitored.
It is recommended that diabetic patients requiring combined treatment be kept under special surveillance.
There have been occasional reports of elevated blood pressure with the use of transdermal estradiol patches in the menopause; therefore blood pressure should be monitored.
Caution is advised in patients with a long history of oestrogen related jaundice. If cholestatic jaundice develops in a patient receiving oestrogen, treatment should be discontinued while the cause is investigated.
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 while on HRT.
In primary dermal irritation studies in rabbits, application of FEMTRAN resulted in mild irritation related to mechanical trauma at removal. In sensitisation studies in guinea pigs, FEMTRAN had no dermal sensitising potential.
The components of the adhesive matrix of FEMTRAN (monomer and polymer) have been studied extensively and, at many multiples of the projected human exposure, present a low risk. Additional excipients used in the adhesive matrix are either generally regarded as safe for use in food components or considered acceptable as an inactive ingredient for prescription and topical transdermal products.
The adhesive backing and release liner of FEMTRAN were tested in biological test methods and were considered to be compatible with biologic systems.
Pregnancy category B1. Oestrogens must not be used during pregnancy (see Contraindications).
Oestrogens must not be used during lactation (see Contraindications).
Of the total number of subjects in the conjugated equine oestrogens in combination with medroxyprogesterone acetate sub-study of the WHI study, 44% (7320) were 65 years and over, while 6.6% (1095) were 75 years and over. No significant differences in safety were observed between subjects 65 years and over compared to younger subjects. There was a higher incidence of stroke and invasive breast cancer in women 75 years and over compared to younger subjects.
In the Women's Health Initiative Memory Study, including 4532 women 65 years of age and older followed up for an average of four years, 71% (3762) were 65-74 while 18% (806) were 75 and over. Most women (80%) had no prior HRT use. Women treated with 0.625mg conjugated oestrogens plus 2.5mg medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing probable dementia. Ninety percent of cases of probable dementia occurred in the 54% of women that were older than 70.
FEMTRAN is unlikely to produce an effect on the ability to drive or use machinery.
See also Contraindications and Warnings and Precautions sections.
In clinical trials adverse reactions were reported at the frequencies reported below.
very common > or = 1/10
common > or = 1/100 and < 1/10
uncommon > or = 1/1000 and < 1/100
very common: application site reaction, tape site reaction.
Application site reactions were the most commonly reported adverse experiences in all trials. Symptoms are generally
mild and include erythema, itching, stinging, and vesicle formation.
common: increased sweating.
very common: headache, oedema
common: back pain, fatigue, pain
uncommon: tachycardia.
common: dizziness, cramp legs.
common: abdominal pain, flatulence, nausea.
common: alteration in body weight.
common: depressive moods, nervousness.
very common: breast pain, menstrual disorders
common: breast engorgement, endometrial hyperplasia, leucorrhoea, pelvic pain, uterine disorder, uterine spasm, vaginal
disorder, vaginal moniliasis.
common: acne, pruritus, rash.
In addition to the above adverse reactions, the following adverse reactions are also known to be oestrogen related and therefore may be associated with FEMTRAN therapy:
migraine.
vomiting, cholestatic jaundice, increased incidence of gall bladder disease, abdominal cramps, bloating.
rise in blood pressure in susceptible individuals.
thromboembolism and thrombotic disorders (see Warnings and Precautions).
increase in size of uterine leiomyomata, alterations in the amount of cervical secretion, change in cervical erosion, reactivation of endometriosis, cystitis-like syndrome.
chloasma or melasma, allergic contact dermatitis, haemorrhagic eruptions, erythema nodosum, erythema multiforme, rash.
worsening of porphyria, changes in libido, premenstrual-like syndrome.
steepening of corneal curvature, intolerance of contact lenses.
Interaction studies have not been performed with FEMTRAN patches or with other estradiol transdermal systems. As for other steroid hormones it may be anticipated that medicines which induce microsomal liver enzymes, such as antiepileptics, antibiotics or products containing St John's wort (Hypericum perforatum) could reduce the systemic bioavailability of transdermal estradiol. However, it is probable that the systemic bioavailability of transdermally applied estradiol is less affected by such an interaction than that of oestrogens taken orally. The requirement for oral antidiabetics or insulin can change.
Oestrogen overdose is unlikely with this type of application. Overdosage may cause nausea and vomiting and withdrawal bleeding may occur in some women. There is no specific antidote. Signs of overdosage may be one or more of the following: breast discomfort, breakthrough bleeding, fluid retention and bloating (see Dosage and Administration). Toxicity is unlikely following acute single exposure; ingestion may cause nausea and vomiting. Treatment should be symptomatic and the patch(es) should be removed.
Shelf life is 36 months from the date of manufacture, when stored below 30°C. Do not store unpouched. Apply immediately upon removal from the protective pouch. Keep out of reach of children.
Prescription Medicine.
Packs containing 4 patches individually wrapped in a protective pouch. The pouch contains a desiccant.
Nil.
3M Pharmaceuticals
a division of 3M New Zealand Limited
PO Box 33246
Takapuna 1332
AUCKLAND
Telephone (09) 444 5289
Facsimile: (09) 444 5770
8 July 2005
FEMTRAN and 3M are registered trademarks
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