Janssen-Cilag Ltd

Evorel^® Conti 50/170 micrograms per 24 hours Transdermal patch

Each transdermal patch contains:

3.2 mg of estradiol hemihydrate equivalent to 3.1 mg estradiol

11.2 mg of norethisterone acetate equivalent to 9.82 mg norethisterone

Each patch releases a nominal 50 μg estradiol and 170 µg norethisterone acetate over 24 hours.

For a full list of excipients, see Section 6.1.

Transdermal patch.

Description of the product

Each patch has an area of 16 cm². Patches are square with rounded corners and are 0.1mm thick. A patch is made of a flat, two-layer laminate. The outer layer is a flexible, translucent and nearly colourless backing film. It is marked on the outer side with "CEN1" in the centre of the lower edge. The inner layer is an adhesive film (matrix) composed of acrylic adhesive and guar gum, which contains the active ingredients. This adhesive layer is protected by a polyester foil release liner, which is removed prior to application of the patch to the skin. The polyester foil used is coated with silicone on both sides. It has an S-shaped incision to facilitate its removal prior to use. Each patch is individually enclosed in a protective, hermetically sealed, labelled sachet.

Hormone replacement therapy (HRT) for the relief of menopausal symptoms in post-menopausal women more than 6 months post-menopause.

For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see also Section 4.4) should be used.

Adults

Guidance on how to start therapy:

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

Women on continuous sequential HRT wishing to switch to Evorel Conti may start Evorel Conti immediately after a cycle of the sequential HRT or after a hormone free period of two weeks. Starting Evorel Conti after a hormone free period may reduce the likelihood of uterine bleeding during the initial period of use of Evorel Conti.

Evorel Conti patches should be worn continuously, without interruption. Patches should be applied to the trunk, below the waist. The patch should be changed twice a week, i.e. every three to four days. Application of a new patch should be to a site different from the previous application site.

If a patch detaches partially or completely prior to a scheduled change, it should be replaced immediately. However, the day of changing patches should be maintained. Wearing a patch by mistake for more than 4 days or any period without a patch may increase the likelihood of break-through bleeding or spotting.

It is not necessary to remove the patch during bathing or showering.

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).

Method of Administration

Transdermal use.

− 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 thromboembolism (deep venous thrombosis, pulmonary embolism)

− Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction), thrombophlebitis

− Acute liver disease or a history of liver disease as long as liver function tests have failed to return to normal

− Severe renal disease

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

− Porphyria.

For the treatment of postmenopausal 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, thromboembolic disorders (see below)

− Risk factors for estrogen dependent tumours, e.g. 1^st degree heredity for breast cancer

− Hypertension

− Liver disorders (e.g. liver adenoma)

− Kidney disorders

− Diabetes mellitus with or without vascular involvement

− Cholelithiasis

− Migraine or (severe) headache

− Systemic lupus erythematosus.

− A history of endometrial hyperplasia (see below)

− Epilepsy

− Asthma

− Hereditary or idiopathic angioedema

− Otosclerosis

− Mastopathy.

Reasons for immediate withdrawal of therapy:

Therapy should be discontinued in case a contraindication 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 estrogens are administered alone for prolonged periods (see section 4.8). The addition of a progestagen 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 study (WHI), and epidemiological studies, including the Million Women Study (MWS) have reported an increased risk of breast cancer in women taking oestrogens, oestrogen-progestagen combinations or tibolone for HRT for several years (see Section 4.8, Undesirable Effects). 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 progestagen was added, whether sequentially or continuously, and regardless of type of progestagen. 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-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Venous thromboembolism

HRT is associated with a 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.

Generally recognized 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 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 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 thromboembolic 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 Estrogen/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 without evidence of ischaemic heart disease. Nevertheless a trend towards an increased cardiac event risk has been observed in postmenopausal women with angiographically proven ischaemic heart disease treated with transdermal estrogens.

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 estrogens 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 estrogens 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 estrogen-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 estrogen-only products.

Other conditions

Estrogens 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 hypertriglyceridemia should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition.

Oral estrogens 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-1-antitrypsin, ceruloplasmin). With transdermal administration, stimulation of the liver by the first-pass effect is avoided and thus, transdermally applied estrogens and progestagens might affect hormone binding proteins and other liver products less than oral hormones.

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 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 as contraception.

The Evorel Conti patches should be kept away from children and pets.

The metabolism of estrogens and progestagens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as barbiturates, phenylbutazone, meprobamate, 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 induce the metabolism of estrogens and progestagens.

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

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

Estrogen-containing oral contraceptives have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered due to induction of lamotrigine glucuronidation. This may reduce seizure control. Although the potential interaction between estrogen-containing hormone replacement therapy and lamotrigine has not been studied, it is expected that a similar interaction exists, which may lead to a reduction in seizure control among women taking both drugs together. Therefore, dose adjustment of lamotrigine may be necessary.

Pregnancy

Evorel Conti is not indicated during pregnancy. If pregnancy occurs during use of Evorel Conti, treatment should be withdrawn immediately.

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

Studies in animals have not shown reproductive toxicity.

The results of most epidemiological studies to date relevant to inadvertent fetal exposure to combinations of estrogens and progestagens indicate no teratogenic or foetotoxic effect.

Lactation

Evorel Conti is not indicated during lactation.

There are no known data on the effects of Evorel Conti on the ability to drive or use machinery.

In three clinical trials of one year's duration, uterine bleeding episodes were reported as an adverse event by 53 of 344 (16%) women - the most frequently reported undesirable effect. 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 other adverse events, mostly mild and transient, were reported by <10% of women. They are listed below.

*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 progestagen 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-progestagen 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-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:

The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 70 years, an additional 8 cases of invasive breast cancer would be due to oestrogen-progestagen 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) (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 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 progestagen to oestrogen-only therapy greatly reduces this increased risk.

Adverse events have been reported in association with estrogen/progestagen treatment:

− Estrogen-dependent neoplasms benign and malignant, e.g. endometrial cancer

− **Venous thrombo-embolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among HRT users than among non-users. For further information see section 4.3 Contraindications and 4.4 Special Warnings and Special Precautions for Use.

− Myocardial infarction and stroke

− Galactorrhea

− Aggravation of epilepsy

− Gall bladder disease, liver adenoma

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

− Probable dementia (see Section 4.4)

Symptoms of overdose of oestrogen and progestagen therapy may include nausea, break-through bleeding, breast tenderness, abdominal cramps and/or bloating. These symptoms can be reversed by removing the patch.

ATC code: G03F A01

Estradiol hemihydrate:

The active ingredient, estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of estrogen production in menopausal women, and alleviates menopausal symptoms. Estrogens prevent bone loss following menopause or ovariectomy.

Norethisterone:

As estrogens promote the growth of the endometrium, unopposed estrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestagen reduces but does not eliminate the estrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

Clinical trial information:

Relief of estrogen-deficiency symptoms and bleeding patterns:

− Relief of menopausal symptoms was achieved during the first few weeks of treatment.

− When starting Evorel Conti, bleeding episodes occur mostly during the first month of treatment, with a quick improvement of the bleeding profile. In first time users of HRT, or after a hormone free period of at least 2 weeks, absence of bleeding was seen in 33% of women during the first three months of treatment and 54% were bleed-free during months 2 and 3. When Evorel Conti was started directly after a cycle of sequential HRT, only 7.5% of the women were bleed-free during the first three months, 47% reported no bleeding for months 2 and 3. Over time, bleeding stops in the majority of women so that 63% of women from either group were bleed-free during the last 3 months of 12 months therapy with Evorel Conti. In women with well established menopause (mean 7 years since the last natural menstrual period), 56% were bleed-free during the first three months of treatment and 92% were bleed-free during months 10-12.

− Bleeding lasted five or less days in not more than 2 episodes per quarter year in>95% of subjects.

The estradiol hemihydrate of the patch is taken up through the skin as estradiol. Estradiol is metabolised primarily in the liver to oestrone with weak estrogenic activity. Oestrone is either conjugated with glucuronic or sulphuric acid or reconverted to estradiol. Conjugates are excreted mainly through the kidneys. The estradiol / oestrone ratio on use of Evorel Conti is close to one, similar to pre-menopausal women. Estradiol circulates in the blood bound to sex hormone binding globulin (35-45%) and albumin (60-65%).

Norethisterone acetate is cleaved immediately on resorption to yield norethisterone. Norethisterone distributes widely in the body and circulates bound to sex hormone binding globulin (about 36%) and albumin (about 61%). It is metabolised mainly in the liver. Metabolites are conjugated with glucuronic or sulphuric acid. Conjugates are excreted in faeces and urine.

The hepatic metabolism of both estradiol and norethisterone is mediated primarily by the P450 enzyme system. While neither the amounts of circulating estradiol / oestrone nor of norethisterone after use of Evorel Conti are considered clinically relevant modifiers of the activity of the P450 enzyme system, other drugs metabolised through the same pathway might inhibit or increase the metabolism of the hormones (see Section 4.5, Interactions with other medicinal products and other forms of interaction).

Due to the transdermal administration, there is no first-pass effect.

Estradiol pharmacokinetics

Following first use of an Evorel Conti patch by post-menopausal women, serum estradiol levels rise within 23 hours (T_max, single application) from, on average, ~ 18 pmol/L (~5 pg/ml) by an average of 150 pmol/L (41 pg/mL) (C_max, single application). Levels decrease over 3.5 days to an average of 66 pmol/L (18 pg/mL). During continued use of Evorel Conti, estradiol levels rise over 21 hours from patch change (T_max, multiple application) by an average of 121 pmol/L (33 pg/mL) (C_max, multiple applications). The 95% confidence interval for C_max ranges from 77 to 165 pmol/L (21 to 45 pg/mL). When patch use is discontinued, serum estradiol levels decrease with a half-life of 6.6 hours. After 24 hours, baseline levels are again observed.

Norethisterone pharmacokinetics

Following first use of Evorel Conti by post-menopausal women, serum norethisterone levels rise over 37 hours (T_max, single application) to 706 pmol/L (240 pg/mL)(C_max, single application) and then decrease to 420 pmol/L (143 pg/mL) at day 3.5. On patch change, levels rise again over 22 hours (T_max, multiple applications) to 756 pmol/L (257 pg/mL)(C_max, multiple applications). When patch use is discontinued, norethisterone levels decrease with a half-life of ~15 hours.

Estradiol and norethisterone acetate, which have been used in clinical practice worldwide for many years, are the subject of monographs in a number of major pharmacopoeias and have recognised efficacy and an acceptable level of safety. Estradiol is the natural estrogen in humans and animals.

Preclinical effects were observed at exposures considered sufficiently in excess of the maximum human exposure, or were related to an exaggerated pharmacological effect, or were related to differences between species regarding hormonal regulation/metabolism and indicate little relevance to clinical use.

Local tolerance studies with Evorel Conti were conducted in rabbits. In this model, Evorel Conti showed a mild irritation potential. It is recognised that the rabbit model is over-predictive of irritation of human skin.

Sensitisation studies with Evorel Conti in guinea pigs showed a weak sensitisation potential. Clinical trial experience with Evorel Conti use for up to two years gave no evidence of a clinically relevant sensitisation potential in humans.

Adhesive:

acrylate-vinyl acetate copolymer (Duro-Tak 387-2287)

Guar gum

Backing film:

polyethylene terephthalate foil (Hostaphan MN19)

Release liner:

siliconised polyethylene terephthalate foil (removed before application)

No creams, lotions, or powders should be applied to the skin area where the patch is to be applied to prevent interference with the adhesive properties of the patch.

2 years

Do not store above 25ºC. Store in the original sachet and box.

Each carton box has 8 patches in individual foil-lined sachets. The sachet comprises a 4 layer laminate including an aluminium humidity barrier and paper exterior surface.

Patches should be placed on a clean, dry area of skin on the trunk of the body below the waist. Creams, lotions, shower soaps, oils, liniments or powders may interfere with the adhesive properties of the patch. The patch should not be applied on or near to the breasts. The area of application should be changed, with an interval of at least one week allowed between applications to a particular site. The skin area selected should not be damaged or irritated. The waistline should not be used because excessive rubbing of the patch may occur.

Patches should be used immediately after opening the sachet. Remove one part of the protecting foil. Apply the exposed part of adhesive to the application site from the edge to the middle; avoid wrinkling of the patch. The second part of the protective foil should now be removed and the freshly exposed adhesive applied. Wrinkling should again be avoided. The palm of the hand should be used to press the patch onto the skin for approximately 30 seconds to bring the patch to skin temperature, at which the adhesive effect is optimised. . Do not touch the adhesive part of the patch.

To remove the patch, peel away an edge of the patch and pull smoothly from the skin.

Any gum that remains on the skin after removal of the patch may be removed by rubbing it off with the fingers or washing with soap and water or by using baby oil.

Patches should be folded in half and disposed of in household waste (do not flush down the toilet).

Janssen-Cilag Ltd

50 – 100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

PA 748/8/1

Date of first Authorisation: 3rd April 1998

Date of last Renewal: 3rd April 2008

30th April 2009