Section:4.3

 

-        Untreated endometrial hyperplasia

-        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 listed in section 6.1

 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. (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 progestogen for at least 12 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 thromboembolism

HRT is associated with a 1.3-3 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 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 recognized risk factors for VTE include a personal history or family history, use of oestrogens, older age, major surgery, prolonged immobilisation,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. 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 thromboembolism 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 contraindicated.

Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

 

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-progestogen or oestrogen-only HRT.

Oestrogen-only: Randomised controlled data found no increased risk of CAD in hysterectomised women using oestrogen-only therapy. There is emerging evidence that initiation of oestrogen only therapy in early menopause may reduce CAD risk.

 

Ischaemic 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 medroxyprogesterone acetate  (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.

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 (see Section 4.8).

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 induce 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 4.6

 

Pregnancy

Evorel Conti is contraindicated during pregnancy. If pregnancy occurs during use of Evorel Conti, treatment should be withdrawn immediately.

Clinically, data on a limited number of exposed pregnancies indicate no adverse effects of norethisterone acetate on the foetus. At doses higher than normally used in oral contraceptives and HRT formulations, masculinisation of female foetuses was observed.

For Evorel Conti, no clinical data on exposed pregnancies are available.

 

 

 

Section 4.8

 

Second adverse event table added

 

Update /additon of warnings

 

Breast Cancer risk

Endometrial Cancer Risk

Ovarian cancer

Risk of venous thromboembolism

Risk of coronary artery disease

Risk of ischaemic stroke

 

Section 4.9 Overdose

Signs and symptoms

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

Treatment

These symptoms can be reversed by removing the Evorel Conti patch

Added to 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:

 

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

E-mail: medsafety@hpra.ie

 added: endometrial cancer, headache, epilepsy, dizziness, palipitations, vasodilatation, diarrhoea, flatulance, abdominal distension, cholelithiasis, rash eryhthrmatous, steven johnson syndrom, cervocakl polyps, endometrila hyperplasia breast enlargement.

deleted: Premenstrual syndrome, uterine fluid retention, postinflmmatory pigemntation, urticaria, angiodoema, liver function testa elevated, anti-socual feeling, irritability, anaemia aggravated, uterine fibromyoma, endometrial polyps

Section 3: administrative change

Section 4.2: minor amendment to the text

Section 4.3 Contraindications

Addition of:  pregnancy and lactation, or pre-malignant tumours (e.g. untreated atypical endometrial hyperplasia), cerebrovascular accident, known thrombophilic events.
Deletion of  Severe renal disease

 Section 4.4
Addition of Conditions that require monitoring  

Administrative update in line with Comapny core data sheet

Section 4.6  Fertility, pregnancy and lactation
, not indicated chnages to contraindicated

             



4.5	Interaction with other medicinal products and other forms of interaction		Addition of interaction with lamotrigine
10.		DATE OF REVISION OF THE TEXT	Changed to 30th April 2009

7.	MARKETING AUTHORISATION HOLDER		Changed to Janssen-Cilag Ltd 50 100 Holmers Farm Way High Wycombe Buckinghamshire HP12 4EG UK
10.		DATE OF REVISION OF THE TEXT	Changed from June 2008 to 17th October 2008

Change to section 4.8 – Undesirable effects	Addition of 2 adverse events
Change to section 10 – Date of revision of text	Change to June 2008

Change to section 1 – trade name NAME OF THE MEDICINAL PRODUCT	Updated to include pharmaceutical form and strength
Change to section 2 – quantitative and qualitative composition	Update to add ‘full list of excipients’
Change to section 4.4 – Special Warnings and Precautions for Use	Editorial changes and removal of paragraph relating to breast cancer and HRT use   Addition of warning relating to renal insufficiency
Change to section 6.1 – List of Excipients	Addition of tradenames to accompany generic names and in listed format
Change to section 6.3 – Shelf Life	Removed additional text and replaced with ‘2 years’
Change to section 6.4 – Special Precautions for Storage	Remove ‘Keep out of sight of children and other additional text.
Change to section 9 – Date of Renewal of Authorisation	Update Section to include the date of first authorisation and last renewal
Change to section 10 – Date of revision of text	Update revision date to ‘April 2008’

Change to section 4.5 –Interaction with other medicinal products and other forms of interaction	Add ‘bosentan’
Change to section 10 – Date of revision of text	Change to ‘March 2008’