Reasons for adding or updating:

• Correction of spelling/typing errors

Date of revision of text on the SPC: 18-May-2016

Legal Category:POM

Black Triangle (CHM): NO

Reasons for adding or updating:

• Change to section 4.4 - Special warnings and precautions for use
• Change to section 4.8 - Undesirable effects
• Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 18-May-2016

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 4.4 and 4.8 updated to include further information on ovarian cancer.

Reasons for adding or updating:

• Change to section 6.6 - Special precautions for disposal and other handling
• Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 12-Feb-2016

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

To change the wording of section 6.6 as follows

Special precautions for disposalInstructions for use and handling

 

Used transdermal patches should be folded in half with the adhesive side inwards, and discarded safely and out of the reach and sight of children. Any used or unused transdermal patches should be disposed of in accordance with local requirements or returned to the pharmacy, preferably in the original packaging.No special requirements.

 

Reasons for adding or updating:

• Change to section 4.8 - Undesirable effects
• Change to section 4.8 - Undesirable effects - how to report a side effect
• Change to section 10 - Date of revision of the text
• Change to section 4.4 - Special warnings and precautions for use
• Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Date of revision of text on the SPC: 27-Mar-2015

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 4.4

Add a paragraph on Severe anaphylactic/anaphylactoid reactions. Move the heading on Angioedema and add another sentence.

Section 4.5

Add the following sentence:

Estradiol is predominantly metabolized by CYP3A4, hence concomitant administration of inhibitors of CYP3A4 such as ketoconazole, erythromycin may result in increase in the exposure of estradiol.

Section 4.8

Add Anaphylactoid reaction. Angioedema, contact dermatitis, chloasma. Fibrocystic breast disease as Not known AE within the table.
Add '**' after Application site reactions and include this key at the end of the table.

Add the section on Reporting of suspected adverse reactions at the end of this section.

Reasons for adding or updating:

• Change to section 2 - Qualitative and quantitative composition
• Change to section 4.2 - Posology and method of administration
• Change to section 4.3 - Contraindications
• Change to section 4.4 - Special warnings and precautions for Use
• Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
• Change to section 4.6 - Pregnancy and Lactation
• Change to section 4.8 - Undesirable Effects
• Change to section 5.1 - Pharmacodynamic Properties
• Change to section 5.2 - Pharmacokinetic Properties
• Change to section 5.3 - Preclinical Safety Data
• Change to section 6.1 - List of Excipients
• Change to section 10 date of revision of the text

Date of revision of text on the SPC: 09-Mar-2012

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 2

For thea full list of excipients, see section 6.1.

Section 4.2

Change spelling of progestogen to progestagen.

Section 4.3

-   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),

-   Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency, see section   4.4),.

-   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 hHypersensitivity to the active substance or to any of the excipients listed in section 6.1.

-   Porphyria.

Section 4.4

First 2 paragraphs unchanged. Changes as follows:

Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women.

 

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 the contraindications sections 4.3 and warnings for use. 4.4.

 

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 appropriate imaging tools, e.g. 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:

 

 

bullet points have been replaced with dashes and first word for each point has been changed to lower case.

 

Reasons for immediate withdrawal of therapy:

 

Therapy should be discontinued in cases where a contraindication is discovered and in the following situations:

bullet points have been replaced with dashes and first word for each point has been changed to lower case.

   

 

 

 

Endometrial hyperplasia and carcinoma

 

In women with an intact uterus tThe risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods (see section 4.8).  The reported increase in endometrial cancer risk among oestrogen-only users varies from 2- to 12-fold greater compared with non-users, depending on the duration of treatment and oestrogen dose (see section 4.8). After stopping treatment risk may remain elevated for at least 10 years. The addition of a progestaogen cyclically for at least 12 days per month/28 day cycle or continuous combined oestrogen-progestagen therapy in non-hysterectomised women prevents the excess greatly reduces this risk associated with oestrogen-only HRT.

 

For Estradot 75 or 100 µg/day the endometrial safety of added progestaogens 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 progestaogens 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

 

The overall evidence suggests an increased risk of breast cancer in women taking combined oestrogen-progestagen and possibly also oestrogen-only HRT, that is dependent on the duration of taking HRT.

 

Combined oestrogen-progestagen therapy

The A randomised placebo-controlled trial, the Women’s Health Initiative study (WHI), and epidemiological studies are consistent in finding, including the Million Women Study (MWS), have reported an increased risk of breast cancer in women taking combined oestrogens, oestrogen-progestaogen combinations or tibolone for HRT that becomes apparent after about 3 for several years (see section 4.8).

 

Oestrogen-only therapy

The WHI trial found no increase in the risk of breast cancer in hysterectomised women using oestrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is substantially lower than that found in users of oestrogen-progestagen combinations (see section 4.8).

 

TFor all HRT, anhe 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, 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 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-progestaogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

 

Ovarian cancer

Ovarian cancer is much rarer than breast cancer. Long-term (at least 5-10 years) use of oestrogen-only HRT products has been associated with a slightly increased risk of ovarian cancer (see section 4.8).

 

Some studies including the WHI trial suggest that the long-term use of combined HRTs may confer a similar, or slightly smaller, risk (see section 4.8).

 

 

Venous thromboembolism

 

HRT is associated with a 1.3- to 3-fold 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 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 (see section 4.8). 

 

Generally recognised risk factors for VTE include use of oestrogens, older age, major surgery, prolonged immobilisation a personal history or family history, severe obesity (BMI > 30 kg/m²), pregnancy/postpartum period,and systemic lupus erythematosus (SLE) and cancer.

 

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. and HRT may add to this risk. HRT is therefore contraindicated in these patients (see section 4.3).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 wWomen already on chronic 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 need to be considered to prevent VTE following surgery. IfWhere 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 is recommended, if possible. Treatment should not be restarted until the woman is completely mobilised.

 

In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is ‘severe’ (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT is contraindicated.

 

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, dyspnoea). 

 

Coronary artery disease (CAD)

 

There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined oestrogen-progestagen or oestrogen-only HRTcardiovascular 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.

 

Combined oestrogen-progestagen therapy

The relative risk of CAD during use of combined oestrogen-progestagen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to oestrogen-progestagen use is very low in healthy women close to menopause, but will rise with more advanced age.

 

Oestrogen-only

Randomised controlled data found no increased risk of CAD in hysterectomised women using oestrogen-only therapy.

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.

Ischaemic Sstroke

Combined oestrogen-progestagen and oestrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see section 4.8).

 

Angioedema

Oestrogens may induce or exacerbate symptoms of angioedema, in particular in women with hereditary angioedema.

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.

 

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 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 and other complications, 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).

 

HRT use does not improve 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 or oestrogen-only HRT CEE and MPA after the age of 65.

 It is unknown whether the findings apply to younger postmenopausal women or other HRT products.

Last paragraph unchanged.

Section 4.5

Change spelling of progestogen to progestagen.

Paragraph changes as below:

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

 

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

 

Some laboratory tests may be influenced by oestrogen therapy, such as tests for glucose tolerance or thyroid function.

Section 4.6

Change Lactation ot Breast-feeding.

Section 4.8

First paragraph unchanged....then as below....

Adverse drug reactions (Table 1) are ranked under headings of frequency, the most frequent first, using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

 

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

 

The following adverse drug reactions have been reported from clinical trials and from post-marketing experience with either Estradot or oestrogen therapy in general:

 

 

Organ Class	Very Common (>1/10)	Common (> 1/100 to <1/10)	Uncommon (> 1/1,000 to <1/100)	Rare (>1/10,000 to <1/1,000)	Very Rare (< 1/10,000)
Immune system disorders	-	-	-	-	Urticaria, anaphylactic reaction
Metabolism and nutrient disorders	-	-	-	-	Decreased carbohydrate tolerance
Psychiatric disorders	-	Depression	-	-	-
Nervous system disorders	Headache	Nervousness, mood changes, insomnia	Migraine, Dizziness	Paraesthesia	Chorea
Vascular disorders	-	-	Increase in blood pressure	Venous thromboembolism	-
Eye disorders	-	-	-	-	Contact lens intolerance
Gastro-intestinal disorders	-	Nausea, dyspepsia, diarrhoea, abdominal pain, bloating	Vomiting	Gallstones	-
Skin and  subcutaneous tissue disorders	Application site reactions, erythema	Acne, rash, dry skin, pruritus	Skin discoloration	Alopecia	Skin necrosis, hirsutism
Musculo-skeletal disorders	-	-	-	Myasthenia	-
Reproductive system and breast disorders	Breast tension and pain, dysmenorrhoea, menstrual disorders	Breast enlargement, menorrhagia, leukorrhoea, irregular vaginal bleeding, uterine spasms, vaginitis, endometrial hyperplasia	-	Uterine leiomyomata, paratubular cysts, endocervical polyps	-
General disorders	-	Pain, back pain, asthenia, peripheral oedema, weight changes	-	Libido changes, allergic reaction	-
Laboratory abnormalities	-	-	Transaminases increase	-	-

Table 1

Neoplasms benign, malignant and unspecified (including cysts and polyps)
	Not known*:	Breast cancer.
Immune system disorders
	Rare:	Hypersensitivity.
	Very rare:	Urticaria, anaphylactic reaction.
Metabolism and nutrition disorders
	Very rare:	Decreased carbohydrate tolerance.
Psychiatric disorders
	Common:	Depression, nervousness, affect liability.
	Rare:	Libido disorder.
Nervous system disorders
	Very common:	Headache.
	Common:	Insomnia.
	Uncommon:	Migraine, dizziness.
	Rare:	Paraesthesia.
	Very rare:	Chorea.
Eye disorders
	Very rare:	Contact lens intolerance.
Vascular disorders
	Uncommon:	Hypertension.
	Rare:	Embolism venous.
	Not known*:	Embolism.
Gastrointestinal disorders
	Common:	Nausea, dyspepsia, diarrhoea, abdominal pain, abdominal distension.
	Uncommon:	Vomiting.
Hepatobiliary disorders
	Rare:	Cholelithiasis.
Skin and subcutaneous tissue disorders
	Very common:	Application site reactions, erythema.
	Common:	Acne, rash, dry skin, pruritus.
	Uncommon:	Skin discoloration.
	Rare:	Alopecia.
	Very rare:	Skin necrosis, hirsutism.
Musculoskeletal and connective tissue disorders
	Common:	Back pain.
	Rare:	Myasthenia.
	Not known*:	Pain in extremity.
Reproductive system and breast disorders
	Very common:	Breast tension and pain, dysmenorrhoea, menstrual disorder.
	Common:	Breast enlargement, menorrhagia, genital discharge, irregular vaginal bleeding, uterine spasms, vaginal infection, endometrial hyperplasia.
	Rare:	Uterine leiomyoma, fallopian tube cysts, cervical polyps.
General disorders and administration site conditions
	Common:	Pain, asthenia, oedema peripheral, weight fluctuation.
Investigations
	Uncommon:	Transaminases increased.
	Not known*:	Liver function test abnormal.

(*) Reported in post-marketing experience

 

Breast cancer risk

- An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestagen therapy for more than 5 years,

- Any increased risk in users of oestrogen-only therapy is substantially lower than that seen in users of oestrogen-progestagen combinations,

- The level of risk is dependent on the duration of use (see section 4.4),

- Results of the largest randomised placebo-controlled trial (WHI-study) and largest epidemiological study (MWS) are presented.

 

Million Women study– Estimated additional risk of breast cancer after 5 years’ use

Age range (years)	Additional cases per 1,000 never-users of HRT over a 5 year period*	Risk ratio#	Additional cases per 1,000 HRT users over 5 years (95%CI)
		Oestrogen only HRT
50 - 65	9 - 12	1.2	1-2 (0 - 3)
		Combined oestrogen-progestagen
50 - 65	9 - 12	1.7	6 (5 - 7)
#Overall risk ratio. The risk ratio is not constant but will increase with increasing duration on use Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately.

* Taken from baseline incidence rates in developed countries.

US WHI studies - additional risk of breast cancer after 5 years’ use

Age range (years)	Incidence per 1,000 women in placebo arm over 5 years	Risk ratio & 95%CI	Additional cases per 1000 HRT users over 5 years (95%CI)
		CEE oestrogen-only
50 - 79	21	0.8 (0.7 – 1.0)	-4 (-6 – 0)*
		CEE+MPA oestrogen & progestagen‡
50 - 79	17	1.2 (1.0 – 1.5)	+4 (0 – 9)

‡When the analysis was restricted to women who had not used HRT prior to the study there was no increased risk apparent during the first 5 years of treatment: after 5 years the risk was higher than in non-users.

* WHI study in women with no uterus, which did not show an increase in risk of breast cancer.

 

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 progestogen 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-progestogen 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-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:

· 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. 

·                        For users of oestrogen 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 oestrogen-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 oestrogen + 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 risk

 

Postmenopausal women with a uterus

The endometrial cancer risk is about 5 in every 1,000 women with a uterus not using HRT.

In women with a uterus, use of oestrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4).

 

Depending on the duration of oestrogen-only use and oestrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1,000 women between the ages of 50 and 65.

 

Adding a progestagen to oestrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study the use of five years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer (RR of 1.0 (0.8-1.2)).

 

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 1000 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 progestogen to oestrogen-only therapy greatly reduces this increased risk. 

 

 

Ovarian cancer

Long-term use of oestrogen-only and combined oestrogen-progestagen HRT has been associated with a slightly increased risk of ovarian cancer. In the Million Women Study 5 years of HRT resulted in 1 extra case per 2,500 users.

 

Risk of venous thromboembolism

HRT is associated with a 1.3- to 3-fold increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of using HRT (see section 4.4). Results of the WHI studies are presented:

 

WHI Studies - Additional risk of VTE over 5 years’ use

Age range (years)	Incidence per 1,000 women in placebo arm over 5 years	Risk ratio and 95%CI	Additional cases per 1,000 HRT users
Oral oestrogen-only*
50 - 59	7	1.2 (0.6 - 2.4)	1 (-3 – 10)
Oral combined oestrogen-progestagen
50 - 59	4	2.3 (1.2 – 4.3)	5 (1 - 13)

* Study in women with no uterus.

Risk of coronary artery disease

- The risk of coronary artery disease is slightly increased in users of combined estrogen-progestagen HRT over the age of 60 (see section 4.4).

 

Risk of ischaemic stroke

- The use of oestrogen-only and oestrogen-progestagen therapy is associated with an up to 1.5-fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT,

- This relative risk is not dependent on age or on duration of use, but as the baseline risk is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age, see section 4.4.

WHI studies combined - Additional risk of ischaemic stroke* over 5 years’ use

Age range (years)	Incidence per 1,000 women in placebo arm over 5 years	Risk ratio and 95%CI	Additional cases per 1,000 HRT users over 5 years
50 - 59	8	1.3 (1.1 - 1.6)	3 (1 - 5)

* No differentiation was made between ischaemic and haemorrhagic stroke.

 

Other adverse reactions have been reported in association with oestrogen/progestaogen 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.

Ggall  

bullet points changes to dashes and upper case changed to lower case...
after probably dementia, over the age of 65 as been added.

Section 5.1

Change spelling of progestogen to progestagen

Section 5.2

Absorption

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 25pg/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.

 

Distribution

Estradiol is more than 50% bound to plasma proteins such as sex hormone binding globulin and albumin. Only 2% is free and biologically active.

 

Metabolism

Transdermally applied estradiol is metabolised in the same way as the endogenous hormone. Estradiol is metabolised primarily in the liver to estrone, then later to estriol, epioestriol and catechol estrogens, which are then conjugated to sulphates and glucuronides. Cytochrome 450 isoforms CYP1A2 and CYP3A4 catalyze the hydroxylation of estradiol forming estriol. Estriol is glucuronidated by UGT1A1 and UGT2B7 in humans. Estradiol metabolites are subject to enterohepatic circulation.

 

Elimination

The sulphate and glucuronide esters along with a small proportion of estradiol and several other metabolites are excreted in the urine. Only a small amount is excreted in faeces. 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.

Section 5.3

The toxicity profile of estradiol has been well established. Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver as well as the frequency of lymphoid and pituitary tumours.

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.

Section 6.1

Change bullet points to dashes.

Reasons for adding or updating:

• Change to section 2 - Qualitative and quantitative composition
• Change to section 4.3 - Contraindications
• Change to section 4.4 - Special warnings and precautions for Use
• Change to section 4.8 - Undesirable Effects
• Change to section 6.1 - List of Excipients
• Change to section 9 - Date of first Authorisation/renewal of the Authorisation
• Change to section 10 date of revision of the text

Date of revision of text on the SPC: 10-Feb-2010

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Minor typographical changes to section 2, 4.3 and 4.8

In Section 4.4 under Medical examination/follow-up the words contraindications and special warnings and precautions for use have been deleted and the text now only refers to sections 4.3 and 4.4.

In Section 4.8 under Endometrial cancer and the second bullet point the words contraindications and special warnings and precautions for use have been deleted and the text now only refers to sections 4.3 and 4.4.

In Section 6.1, silicon dioxide/titanium dioxide has been added to the list of excipients.

In Section 9 the Renewal Date of 31st July 2006 has been added.

Reasons for adding or updating:

• Change to section 6. 5 - Nature and Contents of Container

Date of revision of text on the SPC: 11-Feb-2009

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Addition of a pack size of 26.

Reasons for adding or updating:

• Change to section 4.4 - Special Warnings and Precautions for Use
• Change to section 4.8 - Undesirable Effects

Date of revision of text on the SPC: 02-Jan-2006

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Reasons for adding or updating:

• New SPC for new product