EVOREL 50 PATCH
one Evorel 50 patch (delivering 50 micrograms of estradiol/24 hours)
EVOREL 50 PATCH
Hormone Replacement Therapy (HRT) for oestrogen deficiency symptoms in peri- and post-menopausal women
Therapeutic indications
Hormone Replacement Therapy (HRT) for oestrogen deficiency symptoms in peri- and post-menopausal women.
Evorel 50, 75 and 100 only:
Prevention of osteoporosis in post-menopausal women at high risk of future fractures who are intolerant of, or contra-indicated for, other medicinal products approved for the prevention of osteoporosis. (See Section 4.4)
The experience of treating women older than 65 years is limited.
Posology and method of administration
Adults
Evorel is an oestrogen-only HRT patch applied to the skin twice weekly.
For initiation and continuation of treatment of menopausal symptoms, the lowest effective dose for the shortest duration (see also Section 4.4) should be used.
Treatment of oestrogen deficiency symptoms
Therapy should be started with one Evorel 50 patch (delivering 50 micrograms of estradiol/24 hours) and the dose adjusted after the first month if necessary depending on efficacy and signs of over-oestrogenisation (eg breast tenderness). For maintenance therapy the lowest effective dose should be used; a maximum dose of 100 micrograms of estradiol/24 hours should not be exceeded.
Evorel 50, 75, 100
Prevention of post-menopausal osteoporosis
Therapy should be started with Evorel 50. The dose may be adjusted depending on efficacy and signs of over-oestrogenisation (eg breast tenderness). Note, however, that the efficacy of Evorel 25 for the prevention of post-menopausal osteoporosis has not been demonstrated. For maintenance therapy, the lowest effective dose should be used. A dose of 100micrograms of estradiol/24 hours should not be exceeded.
Progestogen use
For women with an intact uterus progestogen should normally be added to Evorel for the prevention of adverse endometrial effects, eg hyperplasia and cancer. The regimen may be either cyclic or continuous sequential.
Only progestogens approved for addition to oestrogen treatment may be prescribed (eg oral norethisterone, 1mg/day or medroxyprogesterone acetate, 2.5mg/day) and should be added for at least 12-14 days every month/28 day cycle.
Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestogen in hysterectomised women.
Guidance on how to start therapy:
Post-menopausal women currently not on HRT may start Evorel at any time.
Peri-menopausal women who are still having regular menstrual cycles and are not currently on HRT should start Evorel within 5 days of the start of bleeding. Peri-menopausal women with irregular menstrual cycles, for whom pregnancy has been excluded, can start Evorel at any time.
Switching from other HRT
The switch from another oestrogen-only therapy in post-menopausal women to Evorel may occur at any time.
Women on a continuous combined regimen wishing to switch from another oestrogen to Evorel may do so at any time.
Women on a cyclic or continuous sequential regimen wishing to switch from a sequential combined HRT preparation to Evorel may do so at the end of a cycle of the current therapy or after a 7 day hormone free interval.
Method of Administration
Evorel should be applied to the skin as soon as it is removed from the wrapper. Recommended application sites are on clean, dry, healthy, intact skin and each application should be made to a slightly different area of skin on the trunk below waistline. Evorel should not be applied on or near the breasts.
Evorel should remain in place during bathing and showering. Should it fall off during bathing or showering the patient should wait until cutaneous vasodilation ceases before applying a replacement patch to avoid potential excessive absorption. Should a patch fall off at other times it should be replaced immediately.
Patients can be advised to use baby oil to help remove any gum/glue which may remain on their skin after patch removal.
Missed dose
If the patient forgets to change their patch, they should change it as soon as possible and apply the next one at the normal time. However, if it is almost time for the next patch, the patient should skip the missed one and go back to their regular schedule. Only one patch should be applied at a time.
There is an increased likelihood of break-through bleeding and spotting when a patch is not replaced at the normal time.
Children
Evorel is not indicated in children.
Elderly
Data are insufficient in regard to the use of Evorel in the elderly (>65 years old).
Route of administration
Transdermal use.
Contraindications
Known, past or suspected breast cancer
Known or suspected oestrogen-dependent malignant tumours (eg endometrial cancer)
Undiagnosed genital bleeding
Untreated endometrial hyperplasia
Previous idiopathic or current venous thrombo-embolism (deep venous thrombosis, pulmonary embolism),
Active or recent arterial thrombo-embolic disease (eg 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 substances or to any of the excipients
Porphyria
Special warnings and precautions for use
For the treatment of menopausal 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 re-instituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see 'Breast cancer' below). Investigations, including mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.
Conditions which 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 Evorel, in particular:
Leiomyoma (uterine fibroids) or endometriosis
A history of, or risk factors for, thrombo-embolic disorders (see below)
Risk factors for oestrogen dependent tumours, eg 1st degree heredity for breast cancer
Hypertension
Liver disorders (eg 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 oestrogens are administered alone for prolonged periods (see Section 4.8). The addition of a progestogen for at least 12 days per cycle in non-hysterectomised women greatly reduces this risk.
For Evorel 75 and 100 the endometrial safety of added progestogens has not been studied.
Break-through bleeding and spotting may occur during the first months of treatment. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.
Unopposed oestrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of a progestogen to oestrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis if they are known to have residual endometriosis.
Breast cancer
A randomised placebo- controlled trial, the Women's Health Initiative study (WHI), and epidemiological studies, including the Million Women Study (MWS) have reported an increased risk of breast cancer in women taking oestrogens, oestrogen-progestogen combinations or tibolone for HRT for several years (see Section 4.8, Undesirable Effects). For all HRT, an excess risk becomes apparent within a few years of use and increases with duration of intake but returns to baseline within a few (at most five) years after stopping treatment.
In the MWS, the relative risk of breast cancer with conjugated equine oestrogens (CEE) or estradiol (E2) was greater when a progestogen was added, whether sequentially or continuously, and regardless of type of progestogen. There was no evidence of a difference in risk between the different routes of administration.
In the WHI study, the continuous combined conjugated equine oestrogen and medroxyprogesterone acetate (CEE +MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.
HRT, especially oestrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
Ovarian cancer
Long-term (at least 5-10 years) use of oestrogen-only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRT confers a different risk than oestrogen-only products.
Venous thrombo-embolism
HRT is associated with a higher relative risk of developing venous thrombo-embolism (VTE), ie deep vein thrombosis or pulmonary embolism. One randomised controlled trial and epidemiological studies found a two- to threefold higher risk for users compared with non-users. For non-users, it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate = 4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later.
Generally recognised risk factors for VTE include a personal history or family history, severe obesity (BMI > 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 thrombo-embolism 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. 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 thrombo-embolic symptom (eg, painful swelling of a leg, sudden pain in the chest, dyspnoea).
Coronary artery disease (CAD)
There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated oestrogens and medroxyprogesterone acetate (MPA). Two large clinical trials (WHI and HERS i.e. Heart and Oestrogen/progestin Replacement Study) showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products there are only limited data from randomised controlled trials examining effects in cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.
Stroke
One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated oestrogens and MPA. For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 11 per 1000 women aged 60-69 years. It is estimated that for women who use conjugated oestrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate = 1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.
Other conditions
Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients in Evorel is increased.
Women with pre-existing hypertriglyceridaemia should be followed closely during oestrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.
Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unchanged. 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.
Evorel is not to be used for contraception. Women of child-bearing potential should be advised to use non-hormonal contraceptive methods to avoid pregnancy.
Interaction with other medicinal products and other forms of interaction
The metabolism of oestrogens (and progestogens) may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (eg, phenobarbital, phenytoin, carbamazepine) and anti-infectives (eg, rifampicin, rifabutin, nevirapine, efavirenz) and also bosentan.
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 raise the metabolism of oestrogens (and progestogens).
With transdermal administration, the first-pass effect in the liver is avoided and thus, transdermal oestrogens (and progestogens) might be less affected by enzyme inducers than oral hormones.
Clinically, an increased metabolism of oestrogens (and progestogens) may lead to decreased effect and changes in the uterine bleeding profile.
Estrogen-containing oral contraceptives have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered due to induction of lamotrigine glucuronidation. This may reduce seizure control. Although the potential interaction between estrogen-containing hormone replacement therapy and lamotrigine has not been studied, it is expected that a similar interaction exists, which may lead to a reduction in seizure control among women taking both drugs together. Therefore, dose adjustment of lamotrigine may be necessary.
Pregnancy and lactation
Pregnancy
Evorel is not indicated during pregnancy. If pregnancy occurs during use of Evorel, treatment should be withdrawn immediately.
There are no clinical data on exposed pregnancies.
Studies in animals have not shown reproductive toxicity.
The results of most epidemiological studies to date relevant to inadvertent fetal exposure to combinations of oestrogens (and progestogens) indicate no teratogenic or foetotoxic effect.
Lactation
Evorel is not indicated during lactation.
Effects on ability to drive and use machines
In normal use, Evorel would not be expected to have any effect on the ability to drive or use machinery
Undesirable effects
Information on undesirable effects was obtained in two clinical trials comparing Evorel 100 and Evorel 50 to placebo. Of the just over 100 women in each group, one half (with an intact uterus) were followed for up to three years, the other half (hysterectomised) for up to 24 months. 21 % of women on Evorel 100 followed for up to three months reported at least one drug related adverse event. During follow-up for up to 25 months, the proportion was 26%. Of women on Evorel 50, 18% of those followed for up to three months and 27% of those followed for up to 24 months reported at least one drug related adverse event. Breast pain, reported by 17% of women on Evorel 100 was the most frequent adverse event. In two clinical trials with Evorel Sequi (which contains Evorel 50 patches), the most frequent adverse event was irritation at the application site reported in ~13% of subjects
