Novartis Ireland Limited

Estradot 25 micrograms/24 hours, transdermal patch

Estradot 37.5 micrograms/24 hours, transdermal patch

Estradot 50 micrograms/24 hours, transdermal patch

Estradot 75 micrograms/24 hours, transdermal patch

Estradot 100 micrograms/24 hours, transdermal patch

2.5 cm² patch containing 0.39 mg estradiol (as hemihydrate) with a release rate of 25 micrograms estradiol per 24 hours.

3.75 cm² patch containing 0.585 mg estradiol (as hemihydrate) with a release rate of 37.5 micrograms estradiol per 24 hours.

5 cm² patch containing 0.78 mg estradiol (as hemihydrate) with a release rate of 50 micrograms estradiol per 24 hours.

7.5 cm² patch containing 1.17 mg estradiol (as hemihydrate) with a release rate of 75 micrograms estradiol per 24 hours.

10 cm² patch containing 1.56 mg estradiol (as hemihydrate) with a release rate 100 micrograms estradiol per 24 hours.

For a full list of excipients, see section 6.1.

Transdermal patch.

Rectangular patch with rounded corners, comprising a pressure-sensitive adhesive layer containing estradiol, with a translucent polymeric backing on one side and a protective liner on the other.

Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in postmenopausal women.

Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis (for Estradot 50, 75 and 100 only).

The experience treating women older than 65 years is limited.

Dosage

The transdermal patch is applied twice weekly, i.e. every three to four days.

Oestrogen deficiency symptoms:

Estradot is available in five strengths: 25, 37.5, 50, 75 and 100. For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see also section 4.4) should be used. Depending on the clinical response the dose can then be adjusted to the patient's individual needs. If, after three months, there is insufficient response in the form of alleviated symptoms, the dose can be increased. If symptoms of overdose arise (e.g. tender breasts) the dose must be decreased.

Prevention of postmenopausal osteoporosis:

Estradot is available in three strengths: 50, 75 and 100. Treatment must be initiated with an Estradot 50 microgram/24 hours patch. Adjustments can be made by using Estradot 50, 75 and 100 microgram patches.

General instructions

Estradot is administered as continuous therapy (uninterrupted application twice weekly).

In women with an intact uterus, Estradot should be combined with a progestagen approved for addition to oestrogen treatment in a continuous sequential dosing scheme: the oestrogen is dosed continuously. The progestagen is added for at least 12 to 14 days of every 28-day cycle, in a sequential manner.

Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestagen in hysterectomised women.

In women who are not taking HRT or women transferring from a continuous combined HRT product, treatment may be started on any convenient day. In women transferring from a sequential HRT regimen, treatment should begin the day following completion of the prior regimen.

Method of administration

The adhesive side of Estradot should be placed on a clean, dry area of the abdomen. Estradot should not be applied to the breasts.

Estradot should be replaced twice weekly. The site of application must be rotated, with an interval of at least 1 week allowed between applications to a particular site. The area selected should not be oily, damaged, or irritated. The waistline should be avoided, since tight clothing may dislodge the patch. The patch should be applied immediately after opening the sachet 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.

In the event that a patch should fall off, the same patch may be reapplied. If necessary, a new patch may be applied. In either case, the original treatment schedule should be continued. The patch may be worn during bathing.

If a woman has forgotten to apply a patch, she should apply a new patch as soon as possible. The subsequent patch should be applied according to the original treatment schedule. The interruption of treatment might increase the likelihood of irregular bleeding and spotting.

- Known, past or suspected breast cancer,

- Known or suspected oestrogen-dependent malignant tumours (e.g. endometrial cancer),

- Undiagnosed genital bleeding,

- Untreated endometrial hyperplasia,

- Previous idiopathic or current venous thromboembolism (deep venous thrombosis, pulmonary embolism),

- Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction),

- Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal,

- Hypersensitivity to the active substance or to any of the excipients,

- Porphyria.

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 continued as long as the benefit outweighs the risk.

Estradot 25 and Estradot 37.5 are not indicated for osteoporosis.

Medical examination/follow-up

Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by sections 4.3 and 4.4.

During treatment, periodic checkups 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 Estradot, in particular:

- leiomyoma (uterine fibroids) or endometriosis,

- a history of, or risk factors for, thromboembolic disorders (see below),

- risk factors for oestrogen-dependent tumours, e.g. 1^st-degree heredity for breast cancer,

- hypertension,

- liver disorders (e.g. liver adenoma),

- diabetes mellitus with or without vascular involvement,

- cholelithiasis,

- migraine or (severe) headache,

- systemic lupus erythematosus (SLE),

- a history of endometrial hyperplasia (see below),

- epilepsy,

- asthma,

- otosclerosis.

Reasons for immediate withdrawal of therapy:

Therapy should be discontinued in case a contraindication 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 progestagen for at least 12 days per cycle in non-hysterectomised women greatly reduces this risk.

For Estradot 75 or 100 µg/day the endometrial safety of added progestagens 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 progestagens 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-progestagen combinations or tibolone for HRT for several years (see section 4.8).

For all HRT, an excess risk becomes apparent within a few years of use and increases with duration of 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 progestagen was added, either sequentially or continuously, and regardless of type of progestagen. There was no evidence of a difference in risk between the different routes of administration.

In the WHI study, the continuous combined conjugated equine oestrogen and medroxy progesterone 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-progestagen 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 VTE cases that will occur over a 5-year period is about 3 per 1,000 women aged 50-59 years and 8 per 1,000 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 1,000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1,000 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 doctors 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 (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 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 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 1,000 women aged 50-59 years and 11 per 1,000 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 1,000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1,000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.

Ovarian cancer

Long-term (at least 5-10 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 HRTs confers to a different risk than oestrogen-only 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 substance in Estradot 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 unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).

There is no conclusive evidence for improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65. It is unknown whether the findings apply to younger post-menopausal women or other HRT products.

Contact sensitisation is known to occur with all topical applications. Although it is extremely rare, women 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.

The metabolism of oestrogens (and progestagens) may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine), and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones. Herbal preparations containing St. John's wort (Hypericum perforatum) may induce the metabolism of oestrogens (and progestagens).

At transdermal administration, the first-pass effect in the liver is avoided and, thus, transdermally applied oestrogens might be less affected than oral hormones by enzyme inducers.

Clinically, an increased metabolism of oestrogens and progestagens may lead to decreased effect and changes in the uterine bleeding profile.

Pregnancy

Estradot is not indicated during pregnancy. If pregnancy occurs during medication with Estradot, treatment should be withdrawn immediately.

The results of most epidemiological studies to date relevant to inadvertent foetal exposure to oestrogens indicate no teratogenic or foetotoxic effects.

Lactation

Estradot is not indicated during lactation.

Estradot has no or negligible influence on the ability to drive and use machines.

Mild erythema at the patch application site was the most reported undesirable effect (16.6%). The erythema was observed after removing the patch by peeling from the skin at the application site. Mild pruritus and rash were also reported around the application site.

The following adverse drug reactions have been reported with either Estradot or oestrogen therapy in general:

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 oestrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which>80% of HRT use was oestrogen-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 oestrogen plus progestagen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with oestrogens alone.

The MWS reported that, compared to never users, the use of various types of oestrogen-progestagen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of oestrogens 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 oestrogen-progestagen combined HRT (CEE + MPA) in all users compared with placebo.

The absolute risks calculated from the MWS and the WHI trial are presented below:

The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:

- For women not using HRT, about 32 in every 1,000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years.

- For 1,000 current or recent users of HRT, the number of additional cases during the corresponding period will be:

o For users of oestrogen-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.

o For users of oestrogen plus progestagen combined HRT

§ between 5 and 7 (best estimate = 6) for 5 years' use

§ between 18 and 20 (best estimate = 19) for 10 years' use.

The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to oestrogen-progestagen combined HRT (CEE + MPA) per 10,000 women years.

According to calculations from the trial data, it is estimated that:

- For 1,000 women in the placebo group, about 16 cases of invasive breast cancer would be diagnosed in 5 years.

- For 1,000 women who used oestrogen + progestagen combined HRT (CEE + MPA), the number of additional cases would be between 0 and 9 (best estimate = 4) for 5 years' use.

The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) (see section 4.4).

Endometrial cancer

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed oestrogens. According to data from epidemiological studies, the best estimate of the risk of endometrial cancer is that for women not using HRT, about 5 in every 1,000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. Depending on the duration of treatment and oestrogen dose, the reported increase in endometrial cancer risk among unopposed oestrogen users varies from 2- to 12-fold greater compared with non-users. Adding a progestagen to oestrogen-only therapy greatly reduces this increased risk.

Other adverse reactions have been reported in association with oestrogen/progestagen treatment:

- oestrogen-dependent neoplasms benign and malignant, e.g. endometrial cancer,

- venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism , is more frequent among hormone replacement therapy users than among non-users (see sections 4.3 and 4.4),

- myocardial infarction and stroke,

- gall bladder disease,

- skin and subcutaneous tissue disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura,

- probable dementia (see section 4.4).

Acute overdose is unlikely due to the method of administration. The most common symptoms of overdose in clinical use are breast tenderness and/or vaginal bleeding. If such symptoms occur, a reduction in dosage should be considered. The effects of overdose can be rapidly reversed by removal of the patch.

Pharmacotherapeutic group: Oestrogens, ATC code: G03C A 03

The active substance in Estradot, synthetic 17β-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of oestrogen production in menopausal women and alleviates menopausal symptoms.

•Relief of oestrogen-deficiency symptoms

- Relief of menopausal symptoms was achieved during the first few weeks of treatment.

-• Prevention of osteoporosis (for Estradot 50, 75 and 100 only)

- Oestrogens prevent bone loss following menopause or ovariectomy.

- Oestrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. The effect of oestrogens on the bone mineral density is dose-dependent. Protection appears to be effective for as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated women.

- Evidence from the WHI trial and meta-analysed trials show that current use of HRT, alone or in combination with a progestagen – given to predominantly healthy women – reduces the risk of hip, vertrebal, and other osteoporotic fractures. HRT may also prevent fractures in women with low bone density and/or established osteoporosis, but the evidence for that is limited.

Transdermal administration of estradiol achieves therapeutic plasma concentrations using a lower total dose of estradiol than required with oral administration, whereas plasma levels of estrone and estrone conjugates are lower with the transdermal route.

Estradiol is more than 50% bound to plasma proteins such as sex hormone binding globulin and albumin. It is excreted in the urine as sulphate and glucuronide esters along with a small proportion of estradiol and several other metabolites. Only a small amount is excreted in faeces.

In studies in postmenopausal women with application of Estradot 25, 37.5, 50, and 100 µg/24 hours patches, average peak estradiol serum levels (C_max) were approximately 25 pg/ml, 35 pg/ml, 50-55 pg/ml and 95-105 pg/ml, respectively. Linear pharmacokinetics have been demonstrated for estradiol following transdermal administration.

Since estradiol has a short half-life (approximately one hour), serum concentrations of estradiol and estrone returned to baseline values within 24 hours following removal of the patch.

At steady state, after repeated applications of Estradot 50 µg/24 hours patches, C_max and C _min values were 57 and 28 pg/ml for estradiol and 42 and 31 pg/ml for estrone, respectively.

The toxicity profile of estradiol is well known. There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Adhesive matrix:

- acrylic adhesive,

- silicone adhesive,

- oleyl alcohol,

- dipropylene glycol,

- povidone (E1201).

Backing layer:

- ethylene/vinyl acetate copolymer,

- polyethylene,

- vinylidene/vinyl chloride copolymer,

- polyethylene,

- ethylene/vinyl acetate copolymer co-extruded film

- silicon dioxide/titanium dioxide.

Release liner:

- fluoropolymer-coated polyester film.

Not applicable.

2 years

Do not refrigerate or freeze.

Store in the original pouch and carton.

Each Estradot patch is individually sealed in an aluminium laminate sachet.

Sachets may be provided in cartons of 2, 8 and 24.

Not all pack sizes may be marketed.

No special requirements

Novartis Pharmaceuticals UK Ltd.,

Frimley Business Park,

Frimley,

Surrey GU16 7SR,

England

PA 13/110/1-5

13/110/1-4: 08/02/02

13/110/5: 21/5/04

September 2006