Reasons for adding or updating:

• 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 4.8 - Undesirable effects
• Change to section 4.9 - Overdose
• Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 16-Jun-2016

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Section 4.3

 

 

-          Known, current or past or suspected breast cancer

-          Untreated endometrial hyperplasia

-          Known hypersensitivity to the active substances or to any of the excipients (listed in section 6.1)

-          Porphyria

 

Section 4.4

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. 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, the risk may remain elevated for at least 10 years.   The addition of a progestogen for 12-14 days per cycle or continuous combined oestrogen/progestogen therapy in non-hysterectomised women prevents the excess risk associated with oestrogen-only HRT.greatly reduces this risk.

 

Ovarian cancer

Ovarian cancer is much rarer than breast cancer.  Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking oestrogen-only or combined oestrogen-progestogen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping. Some other studies, including the WHI trial, suggest that the use of combined HRTs may be associated with a similar or slightly smaller risk (see Section 4.8).

Venous  thrombo-embolism

HRT is associated with a 1.3-3 foldhigher relative risk of developing venous thrombo-embolism (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 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 a personal history or family history, major surgery, prolonged immobilisation, severe obesity (BMI > 30 kg/m²), use of oestrogens, older age, 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. HRT may add to this risk, HRT is therefore contraindicated in these patients (see section 4.3).

In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age Personal or strong family history of thrombo-embolism or recurrent spontaneous abortion, 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.

 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 contra-indicated.

Hypothyroidism

 

Patients who require thyroid hormone replacement therapy should have their thyroid function monitored regularly while on HRT to ensure that thyroid hormone levels remain in an acceptable range.

 

Angioedema

 

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

 

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.

 

Section 4.5

Ritonavir, telaprevir 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.

 

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

  Section 4,8

 

Additional Adverse event table

 

 

Breast Cancer Risk

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.An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestogen 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-progestogen 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.

 

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 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 year’s use
	between 3 and 7 (best estimate  = 5) for 10 year’s use.
For users of oestrogen plus progestogen combined HRT,
		between 5 and 7 (best estimate = 6) for 5 year’s 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 year’s use.

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

Age range (years)	Additional cases per 1000 never-users of HRT over a 5 year period*	Risk ratio #	Additional cases per 1000 HRT users over 5 years (95% CI)
		Oestrogen only HRT
50-65	9-12	1.2	1-2 (0 - 3)
		Combined oestrogen-progestogen
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 year’s use

Age range (years)	Incidence per 1000 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 & progestogens ‡
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.

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 1000 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 1000 women between the ages of 50 and 65.

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 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 for at least 12 days per cycle can prevent   greatly reduces 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)).

Ovarian cancer

Use of oestrogen-only or combined oestrogen-progestogen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed (see Section 4.4).

A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.31-1.56). For women aged 50 to 54 years taking 5 years of HRT, this results in about 1 extra case per 2000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5-year period.

Risk of venous thromboembolism

HRT is associated with a 1.3-3-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 HT (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 1000 women in placebo arm over 5 years	Risk ratio & 95%CI	Additional cases per 1000 HRT users
Oral, oestrogen-only*
50-59	7	1.2 (0.6 - 2.4)	1 (-3 - 10)
Oral combined, oestrogen -progesterone
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 oestrogen-progestogen HRT over the age of 60 (see section 4.4).

 

Risk of ischaemic stroke

·         The use of oestrogen-only and oestrogen + progestogen 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 1000 women in placebo arm over 5 years	Risk ratio & 95%CI	Additional cases per 1000 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/progestogen treatment:

·         Gall bladder disease

·         Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, ,vascular purpura

·         Probable dementia over the age of 65 (see section 4.4)

·         Dry eyes

·         Tear film composition changes

4.9    Overdose

Signs and symptoms

Due to the mode of administration,Symptoms of overdose of oestradiologen andor norethisterone progestogen is unlikely to occur.  Symptoms of overdose with oral oestrogens are therapy may include nausea, break-through bleeding, breast tenderness, nausea, vomiting and/or metrorrhagia abdominal cramps and/or bloating.  Over dosage of progestogens may lead to a depressive mood, fatigue, acne and hirsutism.

Reasons for adding or updating:

• Change to section 4.8 - Undesirable effects - how to report a side effect
• Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 07-Apr-2015

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Section 4.8

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

 

Reasons for adding or updating:

• Change to section 4.4 - Special warnings and precautions for Use
• Change to section 10 date of revision of the text

Date of revision of text on the SPC: 27-Mar-2012

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Section 4.4

Addition of:   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

Conditions which need supervision:   Mastopathy added

Conditions which require monitoring while on oestrogen therapy:

·         Oestrogens may cause fluid retention. Cardiac or renal dysfunction should be carefully observed

·         Disturbances or mild impairment of liver function

·         History of cholestatic jaundice

·         Pre-existing hypertriglyceridaemia.  Rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition

Endometrial hyperplasia

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)

All text under the heading ‘Breast cancer’ has been replaced

Venous thrombo-embolism:  Recognised risk factors oestrogens, older age, pregnancy/ postpartum period added

Coronary artery disease (CAD); All text replaced

Stroke,  Addition of:

Combined oestrogen-progestogen 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.

Ovarian cancer

Ovarian cancer is much rarer than breast 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.  Some studies including the WHI trial suggest that the long-term use of combined HRTs may confer a similar, or slightly smaller, risk. It is uncertain whether long-term use of combined HRT confers a different risk than oestrogen-only products

 Dementia  statement updated

Reasons for adding or updating:

• Change to section 4.3 - Contraindications
• Change to section 10 date of revision of the text

Date of revision of text on the SPC: 05-Mar-2012

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Section 4.3 Contraindications

 Additions in Bold and underlined.   Deletions scored out

Known, current or past, or suspected breast cancer

Known or suspected oestrogen-dependent malignant tumours (eg endometrial cancer) or pre-malignant tumours (e.g. untreated atypical endometrial hyperplasia)

Undiagnosed genital bleeding

Untreated endometrial hyperplasia

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

Active or recent past arterial thrombo-embolic disease (eg cerebrovascular accident, 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 thrombophilic conditions (e.g. protein C, protein S or antithrombin deficiency, see section 4.4)

Known hypersensitivity to the active substances or to any of the excipients

Porphyria

Reasons for adding or updating:

• 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: 03-Jan-2012

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section 4.8

frequency estimate of ADRs updated.

Addition of : fatigue, oedema, breast enlargement cervical polyps, endometrial hyperplasia, Stevens- johnson-syndrome, rash erythematous, cholethiasis, abdominal distention, Flatulance, diarrhoea, candidiasis, breast cancer, endometrial cancer dizziness, palpitations, vasodilatation

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• Change to section 4.1 - Therapeutic indications

Date of revision of text on the SPC: 16-May-2011

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Section 4.1 removal of peri-menopausal as a indication as thei was an error

Reasons for adding or updating:

• Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
• Change to section 10 date of revision of the text

Date of revision of text on the SPC: 02-Jun-2009

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Change to section 4.5 - Addition of lamotrigine wording.
Change to section 10 - Changed to 2 June 2009.

Reasons for adding or updating:

• Change to section 7 - Marketing Authorisation Holder
• Change to section 10 date of revision of the text

Date of revision of text on the SPC: 12-Jan-2009

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Change to section 10 – Date of revision of the text	Changed to 2 December 2008
Change to section 7 – Marketing Authorisation Holder	Change to Janssen-Cilag Ltd 50 -100 Holmers Farm Way High Wycombe Buckinghamshire HP12 4EG UK

Reasons for adding or updating:

• 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: 02-Dec-2008

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Change to section 4.8 - Addition of 'urticaria' wording.
Change to section 10 - Changed to 2 December 2008.

Reasons for adding or updating:

• Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Date of revision of text on the SPC: 01-May-2008

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	Change	eMC - Summary of Change Details Per Section
	Change to section 4.5 –Interaction with other medicinal products and other forms of interaction	Addition of Bosentan interaction

 

Reasons for adding or updating:

• Change to section 1 - trade name
• Change to section 2 - qualitative and quantitative composition
• Change to section 3 - pharmaceutical form
• Change to section 4.1 - Therapeutic Indications
• Change to section 4.2 - Posology and Method of Administration
• Change to section 4.3 - Contra-indications
• Change to section 4.4 - Special Warnings and Precautions for Use
• Change to section 4.5 - Interactions with other Medicaments and other forms of Interaction
• Change to section 4.6 - Pregnancy and Lactation
• Change to section 4.7 - Effects on Ability to Drive and Use Machines
• Change to section 4.8 - Undesirable Effects
• Change to section 4.9 - Overdose
• 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. 4 - Special Precautions for Storage
• Change to section 6. 5 - Nature and Contents of Container
• Change to section 6. 6 - Instruction for Use/Handling
• Change to section 10 (date of (partial) revision of the text

Reasons for adding or updating:

• Change to section 10 (date of (partial) revision of the text
• Change from the BAN of the active substance to the rINN

Reasons for adding or updating:

• Change to separate SPCs covering individual presentations

Reasons for adding or updating:

• Addition of separate SPCs covering individual presentations