Oestrogens / progestogens.

Estradiol [oestradiol], norethisterone

EVOREL®CONTI 3.2 mg of estradiol hemihydrate 11.2 mg of norethisterone acetate

The EVOREL® CONTI Transdermal Delivery System (TDS), or transdermal patch, is a flat two-layer laminate which is 0.1 mm in thickness. The first layer is a flexible, translucent, and nearly colourless backing film. The second layer is a monolayer adhesive film (matrix) composed of acrylic adhesive and guar gum and contains the hormones. This system is protected by a polyester foil release liner, which is affixed to the adhesive matrix and is removed prior to application of the patch to the skin. The polyester foil used is coated with silicone on both sides. The release liner has a S-shaped opening to facilitate its removal prior to use. Each TDS is enclosed in a protective, hermetically-sealed sachet.

Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in peri- and post-menopausal women more than 6 months post-menopause (or 18 months since last period). 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. The experience treating women older than 65 years is limited.

Adults

Evorel Conti is a continuous combined HRT preparation. Patches are applied to the skin twice weekly.

One Evorel Conti patch should be worn at all times, without interruptions. For initiation and continuation of treatment of menopausal symptoms, the lowest effective dose for the shortest duration should be used.

Guidance on how to start therapy:

Post-menopausal women currently not on HRT may start Evorel Conti at any time.

Switching from other HRT

Women on a continuous combined regimen wishing to switch from another oestrogen to Evorel Conti may do so at any time.

Women on a cyclic or continuous sequential regimen wishing to switch from a sequential combined HRT preparation to Evorel Conti may do so at the end of a cycle of the current therapy or after a 7 day hormone free interval.

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

Method of Administration

The sachet containing one Evorel Conti patch should be opened and one part of the protective foil removed at the Sshaped incision. The patch should be applied to clean, dry, healthy, intact skin as soon as it is removed from the sachet.

The patient should avoid contact between fingers and the adhesive part of the patch during application. Each application should be made to a different area of the skin, on the trunk below the waist. The patch should not be applied on or near the breasts.

Evorel Conti patch should remain in place during bathing and showering.

Should a patch fall off, it should be replaced immediately with a new patch. However the usual day of changing Evorel Conti patches should be maintained.

Missed dose

If the patient forgets to change their patch, they should change it as soon as possible and apply the next one at the normal time. However, if it is almost time for the next patch, the patient should skip the missed one and go back to their regular schedule. Only one patch should be applied at a time.

Wearing a patch for more than 4 days by mistake or any period without a patch may increase the likelihood of breakthrough bleeding or spotting.

Children

Evorel Conti is not indicated in children.

Elderly

Data are insufficient in regard to the use of Evorel Conti in the elderly (>65 years old).

Route of administration

Transdermal use.

Not applicable.

Known, past or suspected breast cancer

Known or suspected estrogen-dependent malignant tumours (eg endometrial cancer)

Undiagnosed genital bleeding

Untreated endometrial hyperplasia

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

Active or recent arterial thrombo-embolic disease (eg 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 hypersensitivity to the active substances or to any of the excipients

Porphyria

For the treatment of menopausal 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 be continued as long as the benefit outweighs the risk

Medical examination/follow-up

Before initiating or re-instituting 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 contra-indications and warnings for use. 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 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 Evorel Conti, in particular:

Leiomyoma (uterine fibroids) or endometriosis

A history of, or risk factors for, thrombo-embolic disorders (see below)

Risk factors for oestrogen dependent tumours, eg 1^st degree heredity for breast cancer

Hypertension

Liver disorders (eg liver adenoma)

Diabetes mellitus with or without vascular involvement

Cholelithiasis

Migraine or (severe) headache

Systemic lupus erythematosus

A history of endometrial hyperplasia (see below)

Epilepsy

Asthma

Otosclerosis

Reasons for immediate withdrawal of therapy:

Therapy should be discontinued if a contra-indication 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. The addition of a progestogen for at least 12 days per cycle in non-hysterectomised women greatly reduces this risk.

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.

Breast cancer

A randomised placebo-controlled trial, the Women's Health Initiative (WHI) and epidemiological studies, including the Million Women Study (MWS) have reported an increased risk of breast cancer in women taking oestrogens or oestrogen-progestogen 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 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 estrogen 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-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Venous thrombo-embolism

HRT is associated with a higher 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.

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 thrombo-embolism 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 contra-indicated. The 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 thrombo-embolic symptom (eg, painful swelling of a leg, sudden pain in the chest, dyspnoea).

Coronary artery disease (CAD)

There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated estrogens and medroxyprogesterone acetate MPA. Two large clinical trials (WHI and HERS i.e. Heart and Oestrogen/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 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 HRT 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 ingredients in Evorel Conti 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 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-l-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.

Evorel Conti is not to be used for contraception. Women of child-bearing potential should be advised to use non-hormonal contraceptive methods to avoid pregnancy.

The metabolism of oestrogens and progestogens 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) and also bosentan.

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 raise the metabolism of oestrogens and progestogens.

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

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

In three clinical trials of one year's duration, the most commonly reported side effect was uterine bleeding occurring in 16% women (53 of 344). Overall 46% of the 344 women followed for up to one year reported at least one other adverse event possibly related to study therapy. Each of these adverse events are listed below.

Body System	Very common ADRs 1/10	Common ADRs 1/100 to <1/10	Uncommon ADRs 1/1,000 to <1/100	Rare ADRs 1/10,000 to <1/1,000<	Very Rare ADRs 1/10,000
		weight increase
Psychiatric disorders		decreased libido	depression, emotional lability, anti-social feelings, tenseness, irritability, insomnia
Nervous system disorders		migraine, paraesthesia		aggravation of epilepsy
Cardiac disorders		hypertension
Vascular disorders			varicose veins anaemia aggravated	thrombo-embolism (see below)
Respiratory, thoracic and mediastinal disorders			dyspnoea
Gastro-intestinal disorders		nausea	upper abdominal pain
Hepato-biliary disorders			Liver function tests elevated
Skin and subcutaneous tissue disorders		pruritus	rash, psoriasis aggravated, hirsutism		urticaria, angioedema
		generalised and local pain
Reproductive system and breast disorders<	uterine bleeding episodes	breast pain, dysmenorrhoea (including lower abdominal pain), leukorrhoea	premenstrual tension syndrome, uterine fluid retention uterine fibromyoma, endometrial polyps	galactorrhoea
General disorders and administration site conditions		application site erythema and irritation, oedema	allergic reaction

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

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:

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)

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 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.

Adverse events which have been reported in association with oestrogen/ progestogen treatment are:

Neoplasms benign and malignant; endometrial cancer

Venous thrombo-embolism, ie deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone HRT users than among non-users.

Myocardial infarction and stroke

Gall bladder disease

Skin and subcutaneous disorder: chloasma, erythema multiforme, erythema nodosum, vascular purpura.

Janssen-Cilag

(POM)