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: 25-Apr-2016

Legal Category:POM

Black Triangle (CHM): NO

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In section 4.4, wording has been updated in respect of the risk of ovarian cancer in women taking oestrogen-only or combined oestrogen-progestagen HRT.

In section 4.8, details have been added of an epidemiological study into the risk of ovarian cancer related to use of HRT.

Reasons for adding or updating:

• Change to section 7 - Marketing authorisation holder
• Change to section 8 - Marketing authorisation number(s)
• 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: 01-Apr-2016

Legal Category:POM

Black Triangle (CHM): NO

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The product licence has been transferred from Novartis Pharmaceuticals UK Ltd. to Merus Labs Luxco II S.a.R.L.

Reasons for adding or updating:

• Change to section 4.2 - Posology and method of administration
• 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: 12-Jan-2015

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 4.2

To add a paragraph on Special populations, Patients with renal and / or hepatic impairment.
Change Children to 'Estraderm MX is not indicated for use in children'.

Section 4.5

Oestradiol is predominantly metabolized by CYP3A4; concomitant administration of inhibitors of CYP3A4 such as ketoconazole, erythromycin or ritonavir may therefore result in an increase of approximately 50% in oestradiol exposure.

Caution should be used if the women is receiving protease inhibitors (e.g.rRitonavir and nelfinavir), which are although known as strong inhibitors, of cytochrome P450 enzymes, and by contrast exhibit inducing properties when used concomitantly with steroid hormones.

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: 16-Dec-2014

Legal Category:POM

Black Triangle (CHM): NO

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Sections 4.4 and 4.8 have been updated with information regarding anaphylactic/anaphylactoid reactions, dysmenorrhoea, fibrocystic breast disease, breast enlargement, breast disease in line with the Company Core Data Sheet.

Reasons for adding or updating:

• Change to section 4.1 - Therapeutic indications
• 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 - Fertility, pregnancy and lactation
• 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 6.6 - Special precautions for disposal and other handling
• Change to section 8 - Marketing authorisation number(s)
• Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 03-Jun-2014

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

To update SPC sections 4.3, 4.4 and 4.8 in line with the Core SPC for HRTs. To also make minor editorial chages to change estradiol/estrogen/progestogen to oestradiol/oestrogen/progestagen for SPC section 2, 4.1, 4.2, 4.5, 4.6, 4.9, 5.1, 5.2 5.3 and 6.6. The marketing authorisation number 8 is also being corrected to add the missing '0'.

Reasons for adding or updating:

• Change to section 4.4 - Special warnings and precautions for use
• 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: 19-Aug-2013

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 angioedema and anaphylactic reactions.

Section 4.4

The following paragraph added:

Severe anaphylactic/anaphylactoid reactions and Aangioedema

Cases of anaphylactic/anaphylactoid reactions, which developed anytime during the course of Estraderm treatment and required emergency medical management, have been reported in the post marketing setting. Involvement of skin (hives, pruritis, swollen lips-tongue-face) and either respiratory tract (respiratory compromise) or gastrointestinal tract (abdominal pain, vomiting) has been noted. Angioedema involving the eye/eyelid, face, larynx, pharynx, tongue and extremity (hands, legs, ankles and fingers) with or without urticaria requiring medical intervention has occurred in the post marketing experience of using Estraderm. If angioedema involves the tongue, glottis, or larynx, airway obstruction may occur. Patients who develop angioedema after treatment with Estraderm should not receive Estraderm again.

Section 4.8

The following added into the table.

Immune system disorders
	Very rare:	Anaphylactoid reaction.
	Not known*:	Hypersensitivity (incl. anaphylactic reaction and angioedema).

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: 19-Aug-2011

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 4.8

Organ system class (e.g. MedDRA SOC level)	Common ADRS ³ 1% to < 10%	Uncommon ADRs ³ 0.1% to < 1%	Rare ADRs ³0.01% to < 0.1%.
Central nervous system	Headache.		Dizziness
Cardiovascular Disorders			Thromboembolic disorders, exacerbation of varicose veins, hypertension
Gastrointestinal disorder	Nausea, abdominal cramps, bloating		Abnormal liver function tests, cholestatic jaundice.
Skin and subcutaneous tissue disorders	Transient erythema and irritation at the site of application with or without pruritis		Contact dermatitis, pigmentation disorders, generalised pruritis and exanthema.
Reproductive system and breast disorders	Breast discomfort, breakthrough bleeding	*breast cancer
General disorders			Oedema and/or weight changes, leg pain,  Anaphylactoid reactions

Adverse drug reactions from clinical trials (Table 1) and post-marketing experience are listed according to the system organ class in MedDRA. Within each system organ class, the adverse drug reactions are ranked by frequency, the most frequent first. Within each frequency grouping, adverse drug reactions are presented in the order of decreasing seriousness. In addition the corresponding frequency using the following convention (CIOMS III) is also provided for each adverse drug reaction: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000), and including not known (cannot be estimated from the available data).

Table 1

Neoplasms benign, malignant and unspecified (including cysts and polyps)
	Uncommon:	Breast cancer.
Immune system disorders
	Very rare:	Anaphylactoid reaction.
	Not known*:	Hypersensitivity.
Psychiatric disorders
	Not known*:	Depression, nervousness, affect lability, libido disorder.
Nervous system disorders
	Common:	Headache.
	Rare:	Dizziness.
	Not known*:	Migraine.
VascularCardiac disorders
	Very rare:	Embolism, hypertension, varicose veins (including exacerbation).
Gastrointestinal disorders
	Common:	Nausea, abdominal pain, abdominal distension.
	Very rare:	Liver function tests abnormal, jaundice cholestatic.
	Not known*:	Cholelithiasis, vVomiting, diarrhoea, gallbladder disorder.
Hepatobiliary disorders          Very rare:                  Liver function tests abnormal, jaundice cholestatic.          Not known*:                Cholelithiasis, gallbladder disorder. Skin and subcutaneous tissue disorders
	Very rare:	Contact dermatitis, pigmentation disorders, generalised pruritus, generalised exanthema.
	Not known*:	Alopecia, chloasma.
Musculoskeletal and connective tissue disorders
	Rare:	Pain in extremity (leg pain).
	Not known*:	Back pain.
Reproductive system and breast disorders
	Very common:	Breast discomfort, breakthrough bleeding.
	Not known*:	Endometrial hyperplasia, uterine leiomyoma, breast pain, breast tenderness.
General disorders and administration site conditions
	Very common:	Application site reactions.
	Rare:	Oedema, weight increased or decreased.

^(*)      Reported in post-marketing experience.

(1)   Sign of estrogen effect, sign of overdose.

(2)   Usually a sign of estrogen overdose.

(3)   If the estrogen is adequately combined with a progestogen, regular withdrawal bleeding occurs, as observed in the normal menstrual cycle. Like any estrogen therapy, transdermal estrogen treatment can induce endometrial hyperplasia unless estrogen intake is supplemented by adequate doses of a progestogen.

(4)   Not related to thromboembolic disease and usually transient, lasting 3-6 weeks. If symptoms persist, the estrogen dose should be reduced.

(5)   Some of the women had a previous history of allergy or allergic disorders.

 

 

*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 progestagen 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-progestagen 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-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:

 

Ø  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.

Ø  For 1000 current or recent users of HRT, the number of additional cases during the

      corresponding period will be:

Ø  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. 

Ø  For users of estrogen 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 estrogen-progestagen combined HRT (CEE + MPA) per 10,000 women years. 

 

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

 

Ø  For 1000 women in the placebo group,

·         about 16 cases of invasive breast cancer would be diagnosed in 5 years.

Ø  For 1000 women who used estrogen + 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 estrogens. 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 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 progestagen to estrogen-only therapy greatly reduces this increased risk.

 

Other adverse reactions have been reported in association with estrogen alone and estrogen-progestagen treatments:

 

·         Estrogen-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.  For further information, see section 4.3 Contraindications and 4.4 Special warnings and precautions for use

·         Myocardial infarction and stroke

·         Cerebrovascular accident

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

·         Gall bladder disease

·         Probable dementia (see section 4.4)

·         Dry eyes

·         Tear film composition changes

 

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: 19-May-2011

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 4.4

The following paragraph has been added under Ovarian Cancer:

Angioedema

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

Paragraph on thyroid function has been added as shown:

Although observations to date suggest that estrogens, including transdermal estradiol, do not impair carbohydrate metabolism, diabetic women should be monitored during initiation of therapy until further information is available.

 

Thyroid function should be monitored regularly in patients who require thyroid hormone replacement therapy and who are also taking estrogen in order to ensure that thyroid hormone levels remain within an acceptable range.

Reasons for adding or updating:

• New individual SPC (was previously included in combined SPC)

Legal Category:POM

Black Triangle (CHM): NO