1. Name Of The Medicinal Product
Elleste Solo MX 40 micrograms Transdermal Patch.
2. Qualitative And Quantitative Composition
Elleste Solo MX 40 contains 1.25 mg of estradiol (as hemihydrate) and each patch delivers approximately 40 micrograms of estradiol per 24 hours.
For excipients, see 6.1.
3. Pharmaceutical Form
Transdermal patch.
Elleste Solo MX 40 is a self-adhesive, flexible transdermal patch comprising a layer of clear adhesive sandwiched between a translucent patch and a metallised polyester backing. Elleste Solo MX 40 is a rectangular shape with rounded corners and has an active surface area of 14.25 cm².
4. Clinical Particulars
4.1 Therapeutic Indications
Hormone replacement therapy (HRT) for estrogen deficiency symptoms in peri-menopausal and post-menopausal women.
4.2 Posology And Method Of Administration
Elleste Solo MX 40 Transdermal Patch is an estrogen-only product for transdermal use.
Adults
Climacteric Symptoms:
For initiation and continuation of treatment of peri- and postmenopausal symptoms, the lowest effective dose for the shortest duration (see also Section 4.4) should be used. Therapy should be initiated with Elleste Solo MX 40 in women who have menopausal symptoms. The dosage may be increased if required by using Elleste Solo MX 80.
Dosage Schedule:
Therapy may start at any time in women with established amenorrhoea or who are experiencing long intervals between spontaneous menses. In women who are menstruating, it is advised that therapy starts within five days of the start of bleeding. Patients changing from a cyclical or continuous sequential preparation should complete the cycle, and after a withdrawal bleed, may then change to Elleste Solo MX 40. Patients changing from a continuous combined preparation may start therapy at any time if amenorrhoea is established, or otherwise start within five days of the start of bleeding.
One Elleste Solo MX 40 transdermal patch should be applied twice weekly on a continuous basis. Each patch should be removed after 3 to 4 days and replaced with a new patch applied to a slightly different site. Patches should be applied to clean, dry and intact areas of skin below the waist on the lower back or buttocks. Elleste Solo MX 40 should not be applied on or near the breasts.
Elleste Solo MX 40 should be given continuously and, in women with an intact uterus, a progestogen is recommended and should be added for at least 12-14 days each cycle. The benefits of the lower risk of endometrial hyperplasia and endometrial cancer, due to adding progestogen, should be weighed against the increased risk of Breast cancer, (See Sections 4.4 and 4.8). Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestogen in hysterectomised women.
If the patch is not replaced at the normal time, it should be changed as soon as practical.
There is an increased likelihood of break-through bleeding and spotting when a patch is not replaced at the normal time.
Children
Elleste Solo MX 40 is not indicated in children.
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 vein 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 substances or to any of the excipients;
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.
Assessment of each woman prior to taking hormone replacement therapy (and at regular intervals thereafter) should include a personal and family medical history. Physical examination should be guided by this and by the contraindications (see Section 4.3) and warnings (see Section 4.4) for this product. During assessment of each individual woman, clinical examination of the breasts and pelvic examination should be performed where clinically indicated rather than as a routine procedure. Women should be encouraged to participate in the national breast screening programme (mammography) and the national cervical screening programme (cervical cytology) as appropriate for their age. Breast awareness should also be encouraged and women advised to report any changes in their breasts to their doctor or nurse, (see “Breast Cancer” below).
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 Elleste Solo MX 40, in particular:
- Risk factors for estrogen dependent tumours, e.g. 1st degree heredity for breast cancer (see below);
- Diabetes mellitus with or without vascular involvement;
- Migraine or (severe) headache;
- Epilepsy;
- A history of, or risk of factors for, thromboembolic disorders (see below);
- Systemic lupus erythematosus, SLE;
- Liver disorders (e.g. liver adenoma);
- Leiomyoma (uterine fibroids) or endometriosis;
- Otosclerosis;
- Cholelithiasis;
- A history of endometrial hyperplasia (see below);
- Hypertension;
- Asthma.
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 progestogen for at least 12 days per cycle in non-hysterectomised women greatly reduces this risk (See Section 4.8).
The endometrial safety of added progestogen has not been studied for Elleste Solo MX 40.
The reduction in risk to the endometrium should be weighed against the increase in the risk of breast cancer of added progestogen (See 'Breast cancer' below, and in Section 4.8).
Breakthrough bleeding and spotting may occur during the first months of treatment. If breakthrough 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 transformation in the residual foci of endometriosis. Therefore, the addition of progestogens 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-progestogen 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 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 estrogens (CEE) or estradiol (E2) was greater when a progestogen was added, either 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 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-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
Venous Thromboembolism
HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. 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 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 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 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 doctor immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnea).
Coronary Artery Disease
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 medroxyprogesterone acetate. 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 medroxyprogesterone acetate 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.
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.
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 circulating active ingredients in Elleste Solo MX 40 is increased.
Women with pre-existing hypertriglyceridaemia 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 biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-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.
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 those contained in Elleste Solo MX 40. If severe upper abdominal complaints, enlarged liver or signs of intra-abdominal haemorrhage occur, a liver tumour should be considered in the differential diagnosis.
Women who may be at risk of pregnancy should be advised to adhere to non-hormonal contraceptive methods.
The requirement for oral anti-diabetics or insulin can change as a result of the effect on glucose tolerance.
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. phenobarbitol, phenytoin and carbamezapine) and anti-infectives, (e.g. rifampicin, rifabutin, nevirapine or efavirenz).
Ritonavir and nelfinavir, although known 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.
At transdermal administration, the first-pass effect in the liver is avoided and, thus, transdermally applied estrogens might be less affected than oral hormones by enzyme inducers.
Clinically, an increased metabolism of estrogens may lead to decreased effect and changes in the uterine bleeding profile.
Some laboratory tests can be influenced by estrogens such as tests for thyroid function or glucose tolerance, (see Section 4.4).
4.6 Pregnancy And Lactation
Pregnancy
Elleste Solo MX 40 is not indicated during pregnancy. If pregnancy occurs during medication with Elleste Solo MX 40, 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
Lactation
Elleste Solo MX 40 is not indicated during lactation.
4.7 Effects On Ability To Drive And Use Machines
None.
4.8 Undesirable Effects
Elleste Solo MX 40 is generally well tolerated. The most frequent side effects, (reported in 10 to 20 % of patients, on at least one occasion, in clinical trials with Elleste Solo MX 40) which do not normally prevent continued treatment include: breast tenderness, headaches and breakthrough bleeding. Some patients experience mild and transient local erythema at the site of application with or without itching; this usually disappears rapidly on removal of the patch. The overall incidence of general patch irritation in clinical studies is less than 5 %. In a clinical study 3 % of 102 patients showed well defined erythema (Draize scale) 30 minutes after patch removal. No instances of permanent skin damage have been reported. If unacceptable topical side effects do occur discontinuation of treatment should be considered.
The following adverse reactions have been reported with Elleste Solo MX 40 and/or estrogen therapy:
1. Genito-urinary tract: Endometrial neoplasia*, dysmenorrhoea, intermenstrual bleeding, increase in the size of uterine fibromyomata, endometrial proliferation or aggravation of endometriosis, vaginal haemorrhagic eruptions, changes in cervical eversion and excessive production of cervical mucus, cervical erosion, cystitis-like syndrome, candidal infections, thrush;
2. Breast: Tenderness, pain, enlargement or secretion, breast cancer*;
3. Gastro-intestinal tract: Nausea, vomiting, abdominal cramp, bloating;
4. Cardiovascular system: Hypertension, thrombosis, thrombophlebitis, venous thromboembolism*, myocardial infarction* and stroke*;
5. Liver/biliary system: In rare cases benign, and in even rarer cases malignant liver tumours, cholelithiasis, cholestatic jaundice, gall bladder disease;
6. Skin: Chloasma which may persist when the drug is discontinued, erythema multiforme, erythema nodosum, muscle cramps, vascular purpura, rash, loss of scalp hair, hirsutism;
7. Eyes: Steepening of corneal curvature, visual disturbances, intolerance to contact lenses;
8. CNS: Headache, migraine, dizziness, mood changes (elation or depression), chorea, probable dementia (see Section 4.4);
9. Miscellaneous: Sodium and water retention, reduced glucose tolerance, leg cramps, oedema, change in body weight, aggravation of porphyria, changes in libido.
* See sections 4.3, Contraindications and Section 4.4 Special Warnings and Special Precautions for Use.
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 progestogen 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-progestogen 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-progestogen 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:
•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.
• For 1000 current or recent users of HRT, the number of additional cases during the corresponding period will be
ο 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.
ο For users of estrogen plus progestogen 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-progestogen combined HRT (CEE + MPA) per 10,000 women years.
According to calculations from the trial data, it is estimated that:
• For 1000 women in the placebo group, about 16 cases of invasive breast cancer would be diagnosed in 5 years.
• For 1000 women who used estrogen + progestogen 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).
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 progestogen to estrogen-only therapy greatly reduces this increased risk.
4.9 Overdose
This is not likely due to the mode of administration. If it is necessary to stop delivery then the patch can be removed and plasma estradiol levels will fall rapidly.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group:
Natural and semisynthetic estrogens, plain.
ATC Code G03C A
The active ingredient, synthetic 17β-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.
5.2 Pharmacokinetic Properties
Estradiol is absorbed from the patch across the stratum corneum and is delivered systemically at a low but constant rate throughout the period of application (3 to 4 days). The estimated delivery of estradiol is approximately 40 μg/day for Elleste Solo MX 40.
Steady state plasma estradiol concentrations have been demonstrated in the range of 26 pg/ml to 34 pg/ml for the Elleste Solo MX 40 patch (including baseline levels) and these are maintained throughout the dose interval (for up to four days). Absorption rate may vary between individual patients. After removal of the last patch plasma estradiol and estrone concentrations return to baseline values in less than 24 hours.
Estradiol is mainly metabolized in the liver. Its main metabolites are estriol, estrone, and their conjugates. The plasma half life of estradiol is 1-2 hours. Metabolic plasma clearance varies between 450-625 ml/min/m2. The metabolites are mainly excreted via the kidneys as glucuronides and sulphates. Estrogens also undergo enterohepatic circulation.
5.3 Preclinical Safety Data
No additional information is available.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Diethyltoluamide
Acrylic adhesive (Dow Corning MG-0560)
Acrylic emulsion (Acrysol 33)
Backing: Polyester film (Scotchpak 9733)
Release liner: Siliconised aluminised polyester
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
3 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
Sachet made out of laminate comprising of paper (clay coated), bonding layer of LDPE, aluminium foil and heat seal layer of LDPE containing one transdermal patch . Each carton contains eight patches, sufficient for one 28 day cycle and a patient leaflet. An additional pack containing two patches may also be available.
6.6 Special Precautions For Disposal And Other Handling
Detailed instructions for use are provided in the patient leaflet.
7. Marketing Authorisation Holder
Meda Pharmaceuticals Ltd
249 West George Street
Glasgow
G2 4RB
Trading as:
Meda Pharmaceuticals Ltd
Skyway House
Parsonage Road
Takeley
Bishop's Stortford
CM22 6PU
8. Marketing Authorisation Number(S)
PL 15142/0060
9. Date Of First Authorisation/Renewal Of The Authorisation
26 February 2002
10. Date Of Revision Of The Text
1st August 2009
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